Heather Wakelee

All Publications

• Circulating Tumor DNA Changes During Chemoradiation for Lung Cancer Predict Patient Outcomes Moding, E. J., Nabet, B. Y., Liu, Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Binkley, M. S., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S., Neal, W., Wakelee, H. A., Gensheimer, M. F., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2019: S113

  View details for DOI 10.1016/j.ijrobp.2019.06.610

  View details for Web of Science ID 000485671502643

• Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research Jeong, Y., Hellyer, J. A., Stehr, H., Hoang, N. T., Niu, X., Das, M., Padda, S. K., Ramchandran, K., Neal, J. W., Wakelee, H. A., Diehn, M. 2019

  Abstract

  Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.

  View details for DOI 10.1158/1078-0432.CCR-19-1237

  View details for PubMedID 31548347

• Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. Lung cancer (Amsterdam, Netherlands) Hellyer, J. A., Gubens, M. A., Cunanan, K. M., Padda, S. K., Burns, M., Spittler, A. J., Riess, J. W., San Pedro-Salcedo, M., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loehrer, P. J. 2019; 137: 71?75

  Abstract

  There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor.This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40?mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35?mg/m2 for the final 15 patients.A total of 33 patients (14?T/19?TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; T?=?4/14 (29%), TC?=?2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient.Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.

  View details for DOI 10.1016/j.lungcan.2019.09.015

  View details for PubMedID 31557562

• Keynote Address: When Breath Becomes Air-As Physician Becomes Patient JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Kalanithi, L., Wakelee, H., Carlson, R. W. 2017; 15 (5.5): 696?98

  Abstract

  As part of the NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, Lucy Kalanithi, MD, wife of now-deceased best-selling author Paul Kalanithi (When Breath Becomes Air), and Heather Wakelee, MD, Paul's oncologist, discussed-for the first time together in a public forum-Paul's experience of going from a neurosurgery resident to a patient with cancer with a terminal diagnosis. Robert Carlson, MD, moderated the discussion.

  View details for DOI 10.6004/jnccn.2017.0076

  View details for Web of Science ID 000402785200010

  View details for PubMedID 28515247

• Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial LANCET ONCOLOGY Neal, J. W., Dahlberg, S. E., Wakelee, H. A., Aisner, S. C., Bowden, M., Huang, Y., Carbone, D. P., Gerstner, G. J., Lerner, R. E., Rubin, J. L., Owonikoko, T. K., Stella, P. J., Steen, P. D., Khalid, A. A., Ramalingam, S. S. 2016; 17 (12): 1661-1671

  Abstract

  Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC.This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954.Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination.Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population.ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.

  View details for DOI 10.1016/S1470-2045(16)30561-7

  View details for Web of Science ID 000389537700035

  View details for PubMedID 27825638

  View details for PubMedCentralID PMC5154681

• Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 2016; 34 (5): 547-555

  Abstract

  High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ?15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.

  View details for DOI 10.1038/nbt.3520

  View details for PubMedID 27018799

• Racial and Ethnic Variations in Lung Cancer Incidence and Mortality: Results From the Women's Health Initiative. Journal of clinical oncology Patel, M. I., Wang, A., Kapphahn, K., Desai, M., Chlebowski, R. T., Simon, M. S., Bird, C. E., Corbie-Smith, G., Gomez, S. L., Adams-Campbell, L. L., Cote, M. L., Stefanick, M. L., Wakelee, H. A. 2016; 34 (4): 360-368

  Abstract

  This study aimed to evaluate racial/ethnic differences in lung cancer incidence and mortality in the Women's Health Initiative Study, a longitudinal prospective cohort evaluation of postmenopausal women recruited from 40 clinical centers.Lung cancer diagnoses were centrally adjudicated by pathology review. Baseline survey questionnaires collected sociodemographic and health information. Logistic regression models estimated incidence and mortality odds by race/ethnicity adjusted for age, education, calcium/vitamin D, body mass index, smoking (status, age at start, duration, and pack-years), alcohol, family history, oral contraceptive, hormones, physical activity, and diet.The cohort included 129,951 women--108,487 (83%) non-Hispanic white (NHW); 10,892 (8%) non-Hispanic black (NHB); 4,882 (4%) Hispanic; 3,696 (3%) Asian/Pacific Islander (API); 534 (< 1%) American Indian/Alaskan Native; and 1,994 (1%) other. In unadjusted models, Hispanics had 66% lower odds of lung cancer compared with NHW (odds ratio [OR], 0.34; 95% CI, 0.2 to 0.5), followed by API (OR, 0.45; 95% CI, 0.27 to 0.75) and NHB (OR, 0.75; 95% CI, 0.59 to 0.95). In fully adjusted multivariable models, the decreased lung cancer risk for Hispanic compared with NHW women attenuated to the null (OR, 0.59; 95% CI, 0.35 to 0.99). In unadjusted models Hispanic and API women had decreased risk of death compared with NHW women (OR, 0.30 [95% CI, 0.15 to 0.62] and 0.34 [95% CI, 0.16 to 0.75, respectively); however, no racial/ethnic differences were found in risk of lung cancer death in fully adjusted models.Differences in lung cancer incidence and mortality are associated with sociodemographic, clinical, and behavioral factors. These findings suggest modifiable exposures and behaviors may contribute to differences in incidence of and mortality by race/ethnicity for postmenopausal women. Interventions focused on these factors may reduce racial/ethnic differences in lung cancer incidence and mortality.

  View details for DOI 10.1200/JCO.2015.63.5789

  View details for PubMedID 26700122

• Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors. Journal of thoracic oncology Padda, S. K., Riess, J. W., Schwartz, E. J., Tian, L., Kohrt, H. E., Neal, J. W., West, R. B., Wakelee, H. A. 2015; 10 (3): 500-508

  Abstract

  Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 and the remaining as PD-L1.PD-L1 scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

  View details for DOI 10.1097/JTO.0000000000000429

  View details for PubMedID 25402569

• Lung cancer incidence in never smokers JOURNAL OF CLINICAL ONCOLOGY Wakelee, H. A., Chang, E. T., Gomez, S. L., Keegan, T. H., Feskanich, D., Clarke, C. A., Holmberg, L., Yong, L. C., Kolonel, L. N., Gould, M. K., West, D. W. 2007; 25 (5): 472?78

  View details for DOI 10.1200/JCO.2006.07.2983

  View details for Web of Science ID 000244176000003

• Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Horn, L., Whisenant, J. G., Wakelee, H., Reckamp, K. L., Qiao, H., Leal, T. A., Du, L., Hernandez, J., Huang, V., Blumenschein, G. R., Waqar, S. N., Patel, S. P., Nieva, J., Oxnard, G. R., Sanborn, R. E., Shaffer, T., Garg, K., Holzhausen, A., Harrow, K., Liang, C., Lim, L. P., Li, M., Lovly, C. M. 2019

  Abstract

  INTRODUCTION: Despite initial effectiveness of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK+ non-small cell lung cancer (NSCLC), therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.METHODS: Pre-treatment plasma was collected from 76 patients with ALK+ NSCLC who were ALK TKI naive or had received prior ALK TKI, and analyzed for specific genetic alterations. Longitudinal plasma samples were analyzed from a subset (N=11) of patients. Analysis of pre-treatment tumor biopsies from 22 patients was compared with plasma.RESULTS: Disease-associated genetic alterations were detected in 74% (56/76) of patients, the most common being EML4-ALK. Concordance of ALK fusion between plasma and tissue was 91% (20/22). Twenty-four ALK kinase domain mutations were detected in 15 patients, all had previously received an ALK TKI; G1269A was the most prevalent (4/24). Patients with a detectable EML4-ALK variant 1 (V1) fusion had improved response (9/17, 53%) to ensartinib compared to patients with EML4-ALK V3 fusion (1/7, 14%). Serial changes in ALK alterations were observed during therapy.CONCLUSIONS: Clinical utility of ctDNA was demonstrated, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients that may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs.

  View details for DOI 10.1016/j.jtho.2019.08.003

  View details for PubMedID 31446141

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study ONCOLOGIST Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2019; 24 (6): 836?43

  View details for DOI 10.1634/theoncologist.2018-0264

  View details for Web of Science ID 000471906300044

• Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib ANTI-CANCER DRUGS Wang, S. Y., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019; 30 (5): 537?41

  View details for DOI 10.1097/CAD.0000000000000765

  View details for Web of Science ID 000466009600014

• Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Annals of oncology : official journal of the European Society for Medical Oncology Mazieres, J., Drilon, A., Lusque, A., Mhanna, L., Cortot, A. B., Mezquita, L., Thai, A. A., Mascaux, C., Couraud, S., Veillon, R., Van Den Heuvel, M., Neal, J., Peled, N., Fruh, M., Ng, T. L., Gounant, V., Popat, S., Diebold, J., Sabari, J., Zhu, V. W., Rothschild, S. I., Bironzo, P., Martinez, A., Curioni-Fontecedro, A., Rosell, R., Lattuca-Truc, M., Wiesweg, M., Besse, B., Solomon, B., Barlesi, F., Schouten, R. D., Wakelee, H., Camidge, D. R., Zalcman, G., Novello, S., Ou, S. I., Milia, J., Gautschi, O. 2019

  Abstract

  BACKGROUND: Anti-PD1/PD-L1 directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS) and overall survival (OS) from ICI initiation. The primary endpoint was PFS under ICI. Secondary endpoints were best response (RECIST 1.1) and overall survival (OS) from ICI initiation.RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60 years, gender-ratio was 1:1, never/former/current smokers were 28/51/21% respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).CONCLUSIONS: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared to the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy.

  View details for DOI 10.1093/annonc/mdz167

  View details for PubMedID 31125062

• ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer. Moding, E. J., Liu, Y., Nabet, B., Chabon, J. J., Chaudhuri, A., Hui, A. B., He, J., Qiao, Y., Heymach, J., Tsao, A. S., Liao, Z. X., Gomez, D., Ramchandran, K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2547

  View details for Web of Science ID 000487345804497

• Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC:An ETCTN California cancer consortium phase I study. Riess, J. W., Groshen, S. G., Reckamp, K. L., Wakelee, H. A., Oxnard, G. R., Padda, S., Koczywas, M., Piotrowska, Z., Sholl, L. M., Paweletz, C. P., Lau, C. J., Kolesar, J., Mack, P. C., Moscow, J., Janne, P. A., Lara, P., Newman, E. M., Gandara, D. R. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806498

• Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis. Neal, J. W., Hausrath, D., Wakelee, H. A., Cunanan, K., Liu, S. V., Banwait, M., Sequist, L. V., Stirling, K., Piotrowska, Z. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806523

• Role of mTOR Inhibitor Everolimus in the Treatment of Metastatic Thymic Epithelial Tumors Hellyer, J., Padda, S., Wakelee, H. A. ELSEVIER SCIENCE INC. 2019: 239

  View details for Web of Science ID 000463830100062

• Increased Galectin-1 Expression in Thymic Epithelial Tumors CLINICAL LUNG CANCER Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2019; 20 (3): E356?E361

  View details for DOI 10.1016/j.cllc.2018.12.005

  View details for Web of Science ID 000467981200020

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers JOURNAL OF CLINICAL ONCOLOGY Sikic, B., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019; 37 (12): 946-+

  View details for DOI 10.1200/JCO.18.02018

  View details for Web of Science ID 000466717700002

• Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK plus non-small cell lung cancer (NSCLC) Horn, L., Whisenant, J. G., Wakelee, H., Reckamp, K. L., Qiao, H., Du, L., Hernandez, J., Huang, V., Waqar, S. N., Patel, S., Sanborn, R. E., Shaffer, T., Garg, K., Holzhausen, A., Harrow, K., Liang, C., Lim, L. P., Li, M., Lovly, C. M. OXFORD UNIV PRESS. 2019: 44

  View details for Web of Science ID 000478089000111

• Tumor heterogeneity and testing discrepancy confound ROS1 detection in NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Sun, T. Y., Stehr, H., Suarez, C. J., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.jtho.2019.03.011

  View details for PubMedID 30914313

• Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer CLINICAL LUNG CANCER Myall, N. J., Henry, S., Wood, D., Neal, J. W., Han, S. S., Padda, S. K., Wakelee, H. A. 2019; 20 (2): E208?E217

  View details for DOI 10.1016/j.cllc.2018.10.003

  View details for Web of Science ID 000459793100012

• First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A. D., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. 2019: JCO1802018

  Abstract

  PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

  View details for PubMedID 30811285

• Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib. Anti-cancer drugs Wang, S. X., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019

  Abstract

  The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

  View details for PubMedID 30762593

• Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Horn, L., Bauml, J., Forde, P. M., Davis, K. L., Myall, N. J., Sasane, M., Dalal, A., Culver, K., Wozniak, A. J., Baik, C. S., Mutebi, A., Zhang, P., Wakelee, H. A., Johnson, B. E. 2019; 128: 74?90

  Abstract

  INTRODUCTION: Clinical outcomes data on BRAF-mutated non-small cell lung cancer (NSCLC) patients treated in routine practice is limited. To address this gap, we described treatment patterns and survival in a cohort of these patients evaluated/treated at 7 US academic cancer centers during 2009-2016.METHODS: This was a retrospective chart review. Patients with BRAF V600-mutated metastatic NSCLC were selected. Current/previous participants in BRAF-related trials were excluded. Onset of metastatic NSCLC defined a patient's index date, which had to occur ?6 months before the chart review date. Analyses were descriptive, including Kaplan-Meier analyses for overall survival (OS).RESULTS: The study included 72 patients. At index, median age (range) was 65 (44-90) years; 61.1% were female. Fifty-two patients received ?1 line of systemic therapy for metastatic disease. Platinum-based doublet chemotherapy was the most common first-line (1L) regimen (76.9% of 1l recipients); no patient received 1l targeted therapy (TT) with a BRAF/MEK inhibitor. In total, 20 patients received TT in any treatment line (2l or later). At time of review, 38 patients were deceased. Median (95%CI) OS from index for all patients was 31.0 (14.5, 63.8) months. Median (95%CI) OS was 56.5 (13.4, 89.1) months from index for TT recipients and 27.2 (10.6, 64.6) months in patients not treated with TT.CONCLUSION: Survival time in BRAF V600-mutated metastatic NSCLC patients studied here was higher than expected based on indirect comparisons with historical NSCLC cohorts for whom no oncogenic driver (BRAF or otherwise) was present. TT recipients had a numerically longer OS from metastatic onset than patients receiving usual care, further highlighting the importance of TT in BRAF V600-mutant NSCLC.

  View details for PubMedID 30642457

• Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive Non-Small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Sun, T., Niu, X., Chakraborty, A., Neal, J. W., Wakelee, H. A. 2019; 14 (2): E21?E24

  View details for DOI 10.1016/j.jtho.2018.08.2030

  View details for Web of Science ID 000456410800001

• Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer LUNG CANCER Horn, L., Bauml, J., Forde, P. M., Davis, K. L., Myall, N. J., Sasane, M., Dalal, A., Culver, K., Wozniak, A. J., Baik, C. S., Mutebi, A., Zhang, P., Wakelee, H. A., Johnson, B. E. 2019; 128: 74?90

  View details for DOI 10.1016/j.lungcan.2018.12.003

  View details for Web of Science ID 000457504800012

• Response to comment on "Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes". Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.lungcan.2019.08.020

  View details for PubMedID 31492438

• A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors. Oncology Hong, D., Rasco, D., Veeder, M., Luke, J. J., Chandler, J., Balmanoukian, A., George, T. J., Munster, P., Berlin, J. D., Gutierrez, M., Mita, A., Wakelee, H., Samakoglu, S., Guan, S., Dimery, I., Graef, T., Borazanci, E. 2019: 1?10

  Abstract

  Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors.This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab.The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ?3 adverse events in ?5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%).The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

  View details for DOI 10.1159/000500571

  View details for PubMedID 31230047

• Role of Immunotherapy in Small Cell Lung Cancer, Thymic Epithelial Tumors, and Mesothelioma. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Hann, C. L., Scherpereel, A., Hellyer, J. A., Wakelee, H. A. 2019: 543?52

  Abstract

  The introduction of programmed death receptor ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) inhibitors into the field of non-small cell lung cancer (NSCLC) was practice changing. The pivotal trials consistently showed a clinically meaningful improvement in overall survival (OS) for patients with driver mutation-negative NSCLC, a field in which outcomes had been stagnant for decades. The success of immune checkpoint inhibitor (ICI) therapy in NSCLC has led to enthusiasm to expand the reach of these drugs into other thoracic malignancies such as thymic epithelial tumors (TETs), mesothelioma, and small cell lung cancer (SCLC). Unfortunately, the improvement in outcomes with ICI therapy in these rarer thoracic tumors has been somewhat modest, and in the case of thymoma, rates of adverse events are too high to routinely justify their use. Although the response rates seen in ICI therapy in these tumor types are similar to those seen with other available single-agent therapies for advanced disease, ICIs do present another option for clinicians treating patients with mesothelioma, small cell carcinoma, and thymic carcinoma (TC), diseases in which approved treatment options are limited. Here we review the latest trials of ICI therapy in mesothelioma, SCLC, and TETs.

  View details for DOI 10.1200/EDBK_237847

  View details for PubMedID 31099677

• Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019; 133: 144?50

  Abstract

  Concurrent genetic mutations are prevalent in KRAS-mutant non-small cell lung cancer (NSCLC) and may differentially influence patient outcomes. We sought to characterize the effects of KRAS mutation subtypes and concurrent pathogenic mutations on overall survival (OS) and PD-L1 expression, a predictive biomarker for anti-PD-1/PD-L1 immunotherapy.We retrospectively identified patients with KRAS-mutant NSCLC at a single institution and abstracted clinical, molecular, and pathologic data from electronic health records. Cox regression and multinomial logistic regression were used to determine how KRAS mutation subtypes and concurrent pathogenic mutations are associated with OS and tumor PD-L1 expression, respectively.A total 186 patients were included. Common KRAS mutation subtypes included G12C (35%) and G12D (17%). Concurrent pathogenic mutations were identified in TP53 (39%), STK11 (12%), KEAP1 (8%), and PIK3CA (4%). On multivariable analysis, KRAS G12D mutations were significantly associated with poor OS (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.15-5.16; P?=?0.021), as were STK11 co-mutations (HR 2.95, 95% CI 1.27-6.88; P?=?0.012). Compared to no (<1%) PD-L1 expression, KRAS G12C mutations were significantly associated with positive yet low (1-49%) PD-L1 expression (odds ratio [OR] 4.94, 95% CI 1.07-22.85; P?=?0.041), and TP53 co-mutations with high (?50%) PD-L1 expression (OR 6.36, 95% CI 1.84-22.02; P?=?0.004).KRAS G12D and STK11 mutations confer poor prognoses for patients with KRAS-mutant NSCLC. KRAS G12C and TP53 mutations correlate with a biomarker that predicts benefit from immunotherapy. Concurrent mutations may represent distinct subsets of KRAS-mutant NSCLC; further investigation is warranted to elucidate their role in guiding treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.015

  View details for PubMedID 31200821

• Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Hellyer, J. A., Stehr, H., Das, M., Padda, S. K., Ramchandran, K., Neal, J. W., Diehn, M., Wakelee, H. A. 2019; 134: 42?45

  Abstract

  For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance.We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined.Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival.For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.002

  View details for PubMedID 31319993

• Increased Galectin-1 Expression in Thymic Epithelial Tumors. Clinical lung cancer Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2018

  Abstract

  INTRODUCTION: Thymic epithelial tumors (TET) are rare malignancies with a paucity of data on biology and therapeutics. Galectin-1 is a member of the beta-galactoside binding protein family and has been shown to mediate tumor growth via modulation of immune cell function. This study examined galectin-1 expression in TET.PATIENTS AND METHODS: A tissue microarray of 68 patients with TET and 8 benign thymus controls were stained for galectin-1 expression and scored by a pathologist blinded to patient clinical and pathologic data. Galectin-1 expression+1 or greater staining intensity was considered positive. Clinical and pathologic data were abstracted from institutional databases. Expression of galectin-1 in thymic tumor was compared to benign thymus controls and correlated with pertinent clinical and pathologic data.RESULTS: Galectin-1 expression was higher in TET compared to benign thymus controls (65% vs. 0%). No significant association between galectin-1 expression and the development of recurrent disease, paraneoplastic syndromes, or overall survival was noted.CONCLUSION: Galectin-1 is overexpressed in the majority of TET. Detection of galectin-1 may differentiate benign from neoplastic thymic processes. Additional studies are needed to assess the role of galectin-1 in the development of TET.

  View details for PubMedID 30773448

• EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Marcoux, N., Gettinger, S. N., O'Kane, G., Arbour, K. C., Neal, J. W., Husain, H., Evans, T. L., Brahmer, J. R., Muzikansky, A., Bonomi, P. D., Del Prete, S., Wurtz, A., Farago, A. F., Dias-Santagata, D., Mino-Kenudson, M., Reckamp, K. L., Yu, H. A., Wakelee, H. A., Shepherd, F. A., Piotrowska, Z., Sequist, L. V. 2018: JCO1801585

  Abstract

  PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.

  View details for DOI 10.1200/JCO.18.01585

  View details for PubMedID 30550363

• Case closed: another prophylactic cranial irradiation trial for stage 3 non-small cell lung cancer fails to improve overall survival ANNALS OF TRANSLATIONAL MEDICINE Moghavem, N., Wakelee, H. A., Nagpal, S. 2018; 6

  View details for DOI 10.21037/atm.2018.12.24

  View details for Web of Science ID 000454556000033

• SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pennell, N. A., Neal, J. W., Chaft, J. E., Azzoli, C. G., Janne, P. A., Govindan, R., Evans, T. L., Costa, D. B., Wakelee, H. A., Heist, R. S., Shapiro, M. A., Muzikansky, A., Murthy, S., Lanuti, M., Rusch, V. W., Kris, M. G., Sequist, L. V. 2018: JCO1800131

  Abstract

  PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC.MATERIALS AND METHODS: In this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%.RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.

  View details for DOI 10.1200/JCO.18.00131

  View details for PubMedID 30444685

• Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam JOURNAL OF GLOBAL ONCOLOGY Nguyen, K. H., Stehr, H., Zhou, L., Anh-Hoa Nguyen, Pham Nhu Hiep, Nguyen Van Cau, Phan Canh Duy, Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018; 4

  View details for DOI 10.1200/JGO.18.00086

  View details for Web of Science ID 000462471900001

• Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam. Journal of global oncology Nguyen, K. H., Stehr, H., Zhou, L., Nguyen, A., Hiep, P. N., Van Cau, N., Duy, P. C., Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018: 1?9

  Abstract

  PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States.METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared.RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET.CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.

  View details for PubMedID 30422746

• Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer. Clinical lung cancer Myall, N. J., Henry, S., Wood, D., Neal, J. W., Han, S. S., Padda, S. K., Wakelee, H. A. 2018

  Abstract

  BACKGROUND: BRAF mutations occur in 1% to 4% of non-small-cell lung cancer (NSCLC) cases. Previous retrospective studies have reported similar outcomes for BRAF-mutated NSCLC as compared with wild-type tumors without a known driver mutation or tumors harboring other mutations. However, select cases of prolonged survival have also been described, and thus, the natural history of BRAF-mutated NSCLC remains an area of ongoing study. The aim of this series was to describe the natural history, clinical outcomes, and occurrence of co-mutations in patients with BRAF-mutated NSCLC.PATIENTS AND METHODS: Patients with BRAF-mutated NSCLC seen at Stanford University Medical Center from January 1, 2006 through July 31, 2015 were reviewed. The Kaplan-Meier method was used to calculate median overall survival, and the generalized Wilcoxon test was used to compare median survivals across subgroups of patients.RESULTS: Within a cohort of 18 patients with BRAF-mutated NSCLC, V600E mutations were most common (72%; 13/18). Clinicopathologic features were similar between patients with V600E versus non-V600E mutations, although there was a trend toward more patients with non-V600E mutations being heavy smokers (80% vs. 31%; P= .12). Co-occurring mutations in TP53 were identified most commonly (28%; 5/18). The median overall survival for the entire cohort was 40.1 months, and the median survival from the onset of metastases (n= 16) was 28.1 months. Survival rates at 2 and 5 years from the onset of metastases were 56% and 13%, respectively.CONCLUSION: The clinical behavior of BRAF-mutated NSCLC is variable, but favorable outcomes can be seen in a subset of patients.

  View details for PubMedID 30442523

• How I Treat Advanced Stage Thymic Malignancy Patients Wakelee, H. ELSEVIER SCIENCE INC. 2018: S222?S223

  View details for DOI 10.1016/j.jtho.2018.08.074

  View details for Web of Science ID 000454014500064

• Intracranial activity of ensartinib in patients with anaplastic lymphoma kinase positive (ALK plus ) non-small cell lung cancer (NSCLC) Wakelee, H., Reckamp, K. L., Leal, T. A., Patel, S. P., Blumenschein, G., Shum, E., Nieva, J., Oxnard, G., Sanborn, R. E., Waqar, S., Zeman, K., Dukart, G., Harrow, K., Liang, C., Holzhausen, A., Horn, L. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277303266

• eXalt3: Phase III randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase positive non-small cell lung cancer patients Horn, L., Wu, Y., Reck, M., Wakelee, H., Liang, C., Harrow, K., Oertel, V., Mok, T. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277303270

• Prediction of PD-1 immunotherapy (IO) response for KRAS mutated non-small cell lung cancer (NSCLC) based on co-mutations using a computational biological model Wakelee, H., Aredo, J., Vali, S., Singh, N. K., Vasista, S. V., Mitra, U., Abbasi, T., Padda, S. K. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277303184

• Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma ANNALS OF ONCOLOGY Krug, A. K., Enderle, D., Karlovich, C., Priewasser, T., Bentink, S., Spiel, A., Brinkmann, K., Emenegger, J., Grimm, D. G., Castellanos-Rizaldos, E., Goldman, J. W., Sequist, L. V., Soria, J., Camidge, D. R., Gadgeel, S. M., Wakelee, H. A., Raponi, M., Noerholm, M., Skog, J. 2018; 29 (10): 2143

  View details for PubMedID 30060089

• Identification of Molecular Subtypes of Thymic Epithelial Tumors and Novel Treatments Using a Computational Biological Model Padda, S., Gokmen-Polar, Y., Badve, S., Vasista, S., Basu, K., Kumar, A., Vali, S., Abbasi, T., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S606

  View details for DOI 10.1016/j.jtho.2018.08.919

  View details for Web of Science ID 000454014502074

• Computational Biological Model Prediction of PD-L1 Expression and Immunotherapy Response for KRAS Mutated Lung Cancer Based on Co-Mutations Padda, S., Aredo, J., Vali, S., Singh, N., Vasista, S., Mitra, U., Abbasi, T., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S533

  View details for DOI 10.1016/j.jtho.2018.08.735

  View details for Web of Science ID 000454014501368

• Co-Mutations, Natural History, and Outcomes of BRAF-Mutated Non-Small Cell Lung Cancer at a Single Academic Cancer Center Myall, N., Henry, S., Wood, D., Neal, J., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S489?S490

  View details for DOI 10.1016/j.jtho.2018.08.627

  View details for Web of Science ID 000454014501261

• Evolving Immunotherapy Practice Patterns in Advanced NSCLC: Analysis of an Online Treatment Decision Tool Gandara, D., Quill, T., Edelman, M., Ramalingam, S., Wakelee, H., Fea, H., Obholz, K. ELSEVIER SCIENCE INC. 2018: S421

  View details for DOI 10.1016/j.jtho.2018.08.472

  View details for Web of Science ID 000454014501109

• Ensartinib Treatment Beyond Disease Progression in Stage IV ALK plus Non-Small Cell Lung Cancer Horn, L., Pate, S., Waqar, S., Blumenschein, G., Harrow, K., Holzhausen, A., Liang, C., Dukart, G., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S583

  View details for DOI 10.1016/j.jtho.2018.08.860

  View details for Web of Science ID 000454014502015

• Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry Gautschi, O., Drilon, A., Milia, J., Lusque, A., Mhanna, L., Li, B., Sabari, J., Cortot, A., Besse, B., Mezquita, L., Solomon, B., Thai, A., Couraud, S., Veilion, R., Mascaux, C., Barlesi, F., Van den Heuvel, M., Schouten, R., Wakelee, H., Mah, A., Camidge, D. R., Ng, T., Peled, N., Lilach, Y., Popat, S., Ou, S., Zhu, V., Velcheti, V., Fontecedro, A., Akhoundova, D., Fruh, M., Zalcman, G., Gounant, V., Novello, S., Bironzo, P., Felip, E., Martinez-Marti, A., Moro-Sibilot, D., Rosell, R., Karachaliou, N., Schuler, M., Wiesweg, M., Diebold, J., Mazieres, J. ELSEVIER SCIENCE INC. 2018: S367

  View details for DOI 10.1016/j.jtho.2018.08.342

  View details for Web of Science ID 000454014500323

• Effect of Induction Chemotherapy in the PACIFIC Study Spigel, D., Vansteenkiste, J., Reck, M., Wakelee, H., Ozguroglu, M., Daniel, D., Villegas, A., Vicente, D., Hui, R., Murakami, S., Paz-Ares, L., Poole, L., Wadsworth, C., Dennis, P., Antonia, S. ELSEVIER SCIENCE INC. 2018: S629

  View details for DOI 10.1016/j.jtho.2018.08.974

  View details for Web of Science ID 000454014502127

• Metabolomic Profiling for Second Primary Lung Cancer Among Lung Cancer Survivors Han, S., Su, L., Diao, N., Christiani, D., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S567

  View details for DOI 10.1016/j.jtho.2018.08.821

  View details for Web of Science ID 000454014501453

• eXalt3: Phase 3 Randomized Study Comparing Ensartinib to Crizotinib in Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer Patients Horn, L., Wu, Y., Reck, M., Wakelee, H., Liang, C., Harrow, K., Oertel, V., Mok, T. ELSEVIER SCIENCE INC. 2018: S582

  View details for DOI 10.1016/j.jtho.2018.08.858

  View details for Web of Science ID 000454014502014

• Lengthy progression-free survival and intracranial activity of cabozantinib in patients with crizotinib and ceritinib-resistant ROS1-positive non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Sun, T. Y., Niu, X., Chakraborty, A., Neal, J. W., Wakelee, H. A. 2018

  View details for PubMedID 30217491

• Caution Needed for Analyzing the Risks of Second Cancers JOURNAL OF THORACIC ONCOLOGY Han, S. S., Plevritis, S. K., Wakelee, H. A. 2018; 13 (9): E172?E173

  View details for DOI 10.1016/j.jtho.2018.04.018

  View details for Web of Science ID 000444520200004

• Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy CLINICAL LUNG CANCER Shukla, N. D., Salahudeen, A. A., Taylor, G. A., Ramalingam, S. S., Vokes, E. E., Goss, G. D., Decker, R. H., Kelly, K., Scagliotti, G. V., Mok, T. S., Wakelee, H. A. 2018; 19 (5): 377?86

  View details for DOI 10.1016/j.cllc.2018.03.004

  View details for Web of Science ID 000442538700036

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer CLINICAL LUNG CANCER Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H., Neal, J. W., Diehn, M., Loo, B. W., Gensheimer, M. F. 2018; 19 (5): E581?E588

  View details for DOI 10.1016/j.cllc.2018.04.003

  View details for Web of Science ID 000442538700007

• A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies CANCER CHEMOTHERAPY AND PHARMACOLOGY Das, M., Padda, S. K., Frymoyer, A., Molina, J., Adjei, A., Lensing, J. L., Miles, D., Sikic, B. I., Wakelee, H. A. 2018; 82 (3): 541?50

  View details for DOI 10.1007/s00280-018-3646-0

  View details for Web of Science ID 000442431600017

• Caution Needed for Analyzing the Risks of Second Cancers. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Han, S. S., Plevritis, S. K., Wakelee, H. A. 2018; 13 (9): e172?e173

  View details for PubMedID 30166015

• Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC JOURNAL OF THORACIC ONCOLOGY Rolfo, C., Mack, P. C., Scagliotti, G. V., Baas, P., Barlesi, F., Bivona, T. G., Herbst, R. S., Mok, T. S., Peled, N., Pirker, R., Raez, L. E., Reck, M., Riess, J. W., Sequist, L. V., Shepherd, F. A., Sholl, L. M., Tan, D. W., Wakelee, H. A., Wistuba, I. I., Wynes, M. W., Carbone, D. P., Hirsch, F. R., Gandara, D. R. 2018; 13 (9): 1248?68

  Abstract

  The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests - such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.

  View details for PubMedID 29885479

• Ensartinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients: Updated Data Leal, T., Wakelee, H., Reckamp, K., Waqar, S., Patel, S., Blumenschein, G., Neal, J., Harrow, K., Holzhausen, A., Liang, C., Dukart, G., Horn, L. ELSEVIER SCIENCE INC. 2018: S156

  View details for Web of Science ID 000444519200009

• Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer ANNALS OF ONCOLOGY Bonomi, P. D., Gandara, D., Hirsch, F. R., Kerr, K. M., Obasaju, C., Paz-Ares, L., Bellomo, C., Bradley, J. D., Bunn, P. A., Culligan, M., Jett, J. R., Kim, E. S., Langer, C. J., Natale, R. B., Novello, S., Perol, M., Ramalingam, S. S., Reck, M., Reynolds, C. H., Smit, E. F., Socinski, M. A., Spigel, D. R., Vansteenkiste, J. F., Wakelee, H., Thatcher, N. 2018; 29 (8): 1701?9

  Abstract

  Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs.Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized.Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ?200) and/or gene copy numbers of EGFR (e.g. ?40% cells with ?4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ?10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents.Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

  View details for PubMedID 29905778

• A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies. Cancer chemotherapy and pharmacology Das, M., Padda, S. K., Frymoyer, A., Molina, J., Adjei, A., Lensing, J. L., Miles, D., Sikic, B. I., Wakelee, H. A. 2018

  Abstract

  PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.METHODS: Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs.RESULTS: In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.CONCLUSIONS: For oral XL647, the MTD was 4.68mg/kg or 350mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.

  View details for PubMedID 30030583

• Development of a multilevel integrated dataset to study lung cancer incidence and risk factors in never-smoking Asian American, Native Hawaiian, and Pacific Islander females. DeRouen, M. C., Shariff-Marco, S., Lichtensztajn, D., Jin, A., Daide, Y., Canchola, A. J., Li, Y., Jain, J., Hertz, A., Allen, L., Nie, S., Wong, C. P., Haile, R., Patel, M. I., Nelson, D., Reynolds, P., Wakelee, H. A., Luft, H., Thompson, C., Waitzfelder, B. E., Cheng, I., Gomez, S. L. AMER ASSOC CANCER RESEARCH. 2018: 81?82

  View details for Web of Science ID 000437526000094

• Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies CLINICAL LUNG CANCER Hirsch, F. R., Kerr, K. M., Bunn, P. A., Kim, E. S., Obasaju, C., Perol, M., Bonomi, P., Bradley, J. D., Gandara, D., Jett, J. R., Langer, C. J., Natale, R. B., Novello, S., Paz-Ares, L., Ramalingam, S. S., Reck, M., Reynolds, C. H., Smit, E. F., Socinski, M. A., Spigel, D. R., Stinchcombe, T. E., Vansteenkiste, J. F., Wakelee, H., Thatcher, N. 2018; 19 (4): 331?39

  Abstract

  Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.

  View details for PubMedID 29773328

• Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study CLINICAL CANCER RESEARCH Horn, L., Infante, J. R., Reckamp, K. L., Blumenschein, G. R., Leal, T. A., Waqar, S. N., Gitlitz, B. J., Sanborn, R. E., Whisenant, J. G., Du, L., Neal, J. W., Gockerman, J. P., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Holzhausen, A., Lovly, C. M., Wakelee, H. A. 2018; 24 (12): 2771?79

  Abstract

  Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ?200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.

  View details for PubMedID 29563138

  View details for PubMedCentralID PMC6004248

• Oral bisphosphonate use and lung cancer incidence among postmenopausal women ANNALS OF ONCOLOGY Tao, M. H., Chen, S., Freudenheim, J. L., Cauley, J. A., Johnson, K. C., Mai, X., Sarto, G. E., Wakelee, H., Boffetta, P., Wactawski-Wende, J. 2018; 29 (6): 1476?85

  Abstract

  Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.The association between oral bisphosphonate use and lung cancer risk was examined in 151?432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.After a mean follow-up of 13.3?years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio?=?0.91; 95% confidence intervals, 0.80-1.04; P?=?0.16). However, an inverse association was observed among those who were never smokers (hazard ratio?=?0.57, 95% confidence interval, 0.39-0.84; P?

  View details for PubMedID 29617712

  View details for PubMedCentralID PMC6005043

• Perspectives on Acquired Resistance to PD-1 Axis Inhibitors in Patients with Non-Small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Tseng, D., Padda, S. K., Wakelee, H. A. 2018; 13 (6): 741?44

  View details for DOI 10.1016/j.jtho.2018.04.008

  View details for Web of Science ID 000436559300009

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer Chaudhuri, A. A., Nabet, B. Y., Merriott, D. J., Jin, M., Chen, E. L., Chabon, J. J., Newman, A. M., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H., Das, M., Padda, S. K., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E1?E2

  View details for Web of Science ID 000432447200003

• Perspectives on Acquired Resistance to PD-1 AxisInhibitors in Patients with Non-Small Cell LungCancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Tseng, D., Padda, S. K., Wakelee, H. A. 2018; 13 (6): 741?44

  View details for PubMedID 29793645

• Incidence of lung cancer histologic cell-types according to neighborhood factors: A population based study in California PLOS ONE DeRouen, M. C., Hu, L., McKinley, M., Gali, K., Patel, M., Clarke, C., Wakelee, H., Haile, R., Gomez, S., Cheng, I. 2018; 13 (5): e0197146

  Abstract

  The relationships between neighborhood factors (i.e., neighborhood socioeconomic status (nSES) and ethnic enclave) and histologic subtypes of lung cancer for racial/ethnic groups, particularly Hispanics and Asian American/Pacific Islanders (AAPIs), are poorly understood.We conducted a population-based study of 75,631 Californians diagnosed with lung cancer from 2008 through2012. We report incidence rate ratios (IRRs) for lung cancer histologic cell-types by nSES among racial/ethnic groups (non-Hispanic (NH) Whites, NH Blacks, Hispanics and AAPIs) and according to Hispanic or Asian neighborhood ethnic enclave status among Hispanics and AAPIs, respectively. In addition, we examined incidence jointly by nSES and ethnic enclave.Patterns of lung cancer incidence by nSES and ethnic enclave differed across race/ethnicity, sex, and histologic cell-type. For adenocarcinoma, Hispanic males and females, residing in both low nSES and high nSES neighborhoods that were low enclave, had higher incidence rates compared to those residing in low nSES, high enclave neighborhoods; males (IRR, 1.17 [95% CI, 1.04-1.32] and IRR, 1.15 [95% CI, 1.02-1.29], respectively) and females (IRR, 1.29 [95% CI, 1.15-1.44] and IRR, 1.51 [95% CI, 1.36-1.67], respectively). However, AAPI males residing in both low and high SES neighborhoods that were also low enclave had lower adenocarcinoma incidence.Neighborhood factors differentially influence the incidence of lung cancer histologic cell-types with heterogeneity in these associations by race/ethnicity and sex. For Hispanic males and females and AAPI males, neighborhood ethnic enclave status is strongly associated with lung adenocarcinoma incidence.

  View details for PubMedID 29791458

• Computed Tomography Features associated With the Eighth Edition TNM Stage Classification for Thymic Epithelial Tumors JOURNAL OF THORACIC IMAGING Padda, S. K., Terrone, D., Tian, L., Khuong, A., Neal, J. W., Riess, J. W., Berry, M. F., Hoang, C. D., Burt, B. M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. 2018; 33 (3): 176?83

  Abstract

  The eighth edition of the TNM classification of malignant tumors for the first time includes an official staging system for thymic epithelial tumors (TETs) recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Staging is critical for the management of TETs, and determining stage accurately from imaging has the potential to improve clinical outcomes. We examine preoperative computed tomography (CT) characteristics of TETs associated with AJCC/UICC pathologic TNM stage.In this retrospective study, patients were included if they met all the following criteria: (1) diagnosis of TET, (2) had primary curative intent surgery performed at Stanford University, and (3) had available preoperative CT imaging for review. Tumor pathology was staged according to the eighth edition TNM classification. Fifteen CT scan features were examined from each patient case according to the International Thymic Malignancy Interest Group standard report terms in a blinded manner. A Lasso-regularized multivariate model was used to produce a weighted scoring system predictive of pathologic TNM stage.Examining the 54 patients included, the following CT characteristics were associated with higher pathologic TNM stage when using the following scoring system: elevated hemidiaphragm (score of 6), vascular endoluminal invasion (score of 6), pleural nodule (score of 2), lobulated contour (score of 2), and heterogeneous internal density (score of 1). Area under the receiver operating characteristic curve was 0.76.TETs with clearly invasive or metastatic features seen on CT are associated with having higher AJCC/UICC pathologic TNM stage, as expected. However, features of lobulated contour and heterogeneous internal density are also associated with higher stage disease. These findings need to be validated in an independent cohort.

  View details for PubMedID 29219888

• Circulating tumor DNA testing in advanced non-small cell lung cancer LUNG CANCER Moding, E. J., Diehn, M., Wakelee, H. A. 2018; 119: 42?47

  View details for DOI 10.1016/j.lungcan.2018.02.019

  View details for Web of Science ID 000431157800007

• Circulating tumor DNA testing in advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Moding, E. J., Diehn, M., Wakelee, H. A. 2018; 119: 42?47

  Abstract

  Circulating tumor DNA (ctDNA) shed from cancer cells into the peripheral blood can be non-invasively collected and tested for the presence of tumor-specific mutations. Mutations identified in ctDNA can predict responses to targeted therapies and emerging evidence suggests that changes in ctDNA levels over time can be used to monitor response to therapy and detect disease recurrence. Given the emergence of targeted therapies in advanced non-small cell lung cancer (NSCLC), liquid biopsies utilizing ctDNA testing represent a powerful approach to genotype tumors and monitor for the development of resistance. Here, we review current and potential future clinical applications of ctDNA testing for patients with advanced NSCLC.

  View details for PubMedID 29656751

• A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors CLINICAL CANCER RESEARCH Miller, J. S., Morishima, C., McNeel, D. G., Patel, M. R., Kohrt, H. K., Thompson, J. A., Sondel, P. M., Wakelee, H. A., Disis, M. L., Kaiser, J. C., Cheever, M. A., Streicher, H., Creekmore, S. P., Waldmann, T. A., Conlon, K. C. 2018; 24 (7): 1525?35

  Abstract

  Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing.Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated.Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ? 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525-35. ©2017 AACR.

  View details for PubMedID 29203590

• Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease CANCER MEDICINE Varlotto, J., Voland, R., McKie, K., Flickinger, J. C., DeCamp, M. M., Maddox, D., Rava, P., Fitzgerald, T. J., Graeber, G., Rassaei, N., Oliveira, P., Ali, S., Belani, C., Glanzman, J., Wakelee, H. A., Patel, M., Baima, J., Zhang, J., Walsh, W. 2018; 7 (4): 1211?20

  Abstract

  To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.

  View details for PubMedID 29533006

• Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy. Clinical lung cancer Shukla, N. D., Salahudeen, A. A., Taylor, G. A., Ramalingam, S. S., Vokes, E. E., Goss, G. D., Decker, R. H., Kelly, K., Scagliotti, G. V., Mok, T. S., Wakelee, H. A. 2018

  Abstract

  Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.

  View details for PubMedID 29653819

• EGFR Genotyping of Matched Urine, Plasma , and Tumor Tissue in Patients With Non-Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor JCO PRECISION ONCOLOGY Goldman, J. W., Karlovich, C., Sequist, L., Melnikova, V., Franovic, A., Gadgeel, S. M., Reckamp, K. L., Camidge, D., Perol, M., Ou, S., Liu, S., Yu, H. A., Soria, J., Socinski, M. A., Mekhail, T. M., Solomon, B. J., Natale, R. B., Otterson, G. A., Papadimitrakopoulou, V., Langer, C. J., Neal, J. W., Despain, D., Yurasov, S., Litten, J. B., Erlander, M., Raponi, M., Wakelee, H. A. 2018; 2: 1?13

  Abstract

  OBJECTIVECerebral cavernous malformations (CCMs) are frequently diagnosed vascular malformations of the brain. Although most CCMs are asymptomatic, some can be responsible for intracerebral hemorrhage or seizures. In selected cases, microsurgical resection is the preferred treatment option. Treatment with the unselective ?-blocker propranolol has been presumed to stabilize and eventually lead to CCM size regression in a limited number of published case series; however, the underlying mechanism and evidence for this effect remain unclear. The aim of this study was to investigate the risk for CCM-related hemorrhage in patients on long-term ?-blocker medication.METHODSA single-center database containing data on patients harboring CCMs was retrospectively interrogated for a time period of 35 years. The database included information about hemorrhage and antihypertensive medication. Descriptive and survival analyses were performed, focusing on the risk of hemorrhage at presentation and during follow-up (first or subsequent hemorrhage) in patients on long-term ?-blocker medication versus those who were not. Follow-up was censored at the first occurrence of new hemorrhage, surgery, or the last clinical review. For purposes of this analysis, the ?-blocker group was divided into the following main subgroups: any ?-blocker, ?1-selective ?-blocker, and any unselective ?-blocker.RESULTSOf 542 CCMs among 408 patients, 81 (14.9%) were under treatment with any ?-blocker; 65 (12%) received ?1-selective ?-blocker, and 16 (3%) received any unselective ?-blocker. One hundred thirty-six (25.1%) CCMs presented with hemorrhage at diagnosis. None of the ?-blocker groups was associated with a lower risk of hemorrhage at the time of diagnosis in a univariate descriptive analysis (any ?-blocker: p = 0.64, ?1-selective: p = 0.93, any unselective ?-blocker: p = 0.25). Four hundred ninety-six CCMs were followed up after diagnosis and included in the survival analysis, for a total of 1800 lesion-years. Follow-up hemorrhage occurred in 36 (7.3%) CCMs. Neither univariate descriptive nor univariate Cox proportional-hazards regression analysis showed a decreased risk for follow-up hemorrhage under treatment with ?-blocker medication (any ?-blocker: p = 0.70, HR 1.19, 95% CI 0.49-2.90; ?1-selective: p = 0.78, HR 1.15, 95% CI 0.44-3.00; any unselective ?-blocker: p = 0.76, HR 1.37, 95% CI 0.19-10.08). Multivariate Cox proportional-hazards regression analysis including brainstem location, hemorrhage at diagnosis, age, and any ?-blocker treatment showed no reduced risk for follow-up hemorrhage under any ?-blocker treatment (p = 0.53, HR 1.36, 95% CI 0.52-3.56).CONCLUSIONSIn this retrospective cohort study, ?-blocker medication does not seem to be associated with a decreased risk of CCM-related hemorrhage at presentation or during follow-up.

  View details for DOI 10.1200/PO.17.00116

  View details for Web of Science ID 000462068300001

  View details for PubMedID 29905510

• Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer LUNG CANCER Gerber, D. E., Socinski, M. A., Neal, J. W., Wakelee, H. A., Shirai, K., Sequist, L. V., Rosovsky, R. P., Lilenbaum, R. C., Bastos, B. R., Huang, C., Johnson, M. L., Hesketh, P. J., Subramaniam, D. S., Dietrich, M. F., Chai, F., Wang, Y., Kazakin, J., Schwartz, B., Schiller, J. H., Brahmer, J. R., Kelly, R. J. 2018; 117: 44?49

  Abstract

  KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P?

  View details for PubMedID 29496255

• Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Yao, X., Antonicelli, A., Riess, J. W., Shang, Y., Shrager, J. B., Korst, R., Detterbeck, F., Huang, J., Burt, B. M., Wakelee, H. A., Badve, S. S. 2018; 13 (3): 436?46

  Abstract

  Thymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.The International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.A total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.Previously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.

  View details for PubMedID 29191778

• Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma ANNALS OF ONCOLOGY Krug, A. K., Enderle, D., Karlovich, C., Priewasser, T., Bentink, S., Spiel, A., Brinkmann, K., Emenegger, J., Grimm, D. G., Castellanos-Rizaldos, E., Goldman, J. W., Sequist, L. V., Soria, J., Camidge, D. R., Gadgeel, S. M., Wakelee, H. A., Raponi, M., Noerholm, M., Skog, J. 2018; 29 (3): 700?706

  Abstract

  A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients.Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing.For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n?=?21), the sensitivity increased from 26% to 74% for activating mutations (P?=?0.003) and from 19% to 31% for T790M (P?=?0.5) when using exoNA for detection.Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone.NCT01526928.

  View details for PubMedID 29216356

  View details for PubMedCentralID PMC5889041

• Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Socinski, M. A., Obasaju, C., Gandara, D., Hirsch, F. R., Bonomi, P., Bunn, P. A., Kim, E. S., Langer, C. J., Natale, R. B., Novello, S., Paz-Ares, L., Perol, M., Reck, M., Ramalingam, S. S., Reynolds, C. H., Spigel, D. R., Wakelee, H., Thatcher, N. 2018; 13 (2): 165?83

  Abstract

  Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.

  View details for PubMedID 29175116

• Progress in the Management of Early-Stage Non-Small Cell Lung Cancer in 2017. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Donington, J. S., Kim, Y. T., Tong, B., Moreira, A. L., Bessich, J., Weiss, K. D., Colson, Y. L., Wigle, D., Osarogiagbon, R. U., Zweig, J., Wakelee, H., Blasberg, J., Daly, M., Backhus, L., Van Schil, P. 2018; 13 (6): 767?78

  Abstract

  The landscape of care for early-stage non-small cell lung cancer continues to evolve. While some of the developments do not seem as dramatic as what has occurred in advanced disease in recent years, there is a continuous improvement in our ability to diagnose disease earlier and more accurately. We have an increased understanding of the diversity of early-stage disease and how to better tailor treatments to make them more tolerable without impacting efficacy. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in the care of early-stage lung cancer patients have provided focused updates across multiple areas including screening, pathology, staging, surgical techniques and novel technologies, adjuvant therapy, radiotherapy, surveillance, disparities, and quality of life. The source for information includes large academic meetings, the published literature, or novel unpublished data from other international oncology assemblies.

  View details for PubMedID 29654928

• Case closed: another prophylactic cranial irradiation trial for stage 3 non-small cell lung cancer fails to improve overall survival. Annals of translational medicine Moghavem, N., Wakelee, H. A., Nagpal, S. 2018; 6 (Suppl 2): S118

  View details for PubMedID 30740439

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study. The oncologist Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2018

  Abstract

  Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting.Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

  View details for PubMedID 30126856

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer. Clinical lung cancer Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H., Neal, J. W., Diehn, M., Loo, B. W., Gensheimer, M. F. 2018

  Abstract

  Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

  View details for PubMedID 29759331

• A pooled analysis of advanced nonsquamous non-small cell lung cancer patients with stable treated brain metastases in two phase II trials receiving bevacizumab and pemetrexed as second-line therapy JOURNAL OF THORACIC DISEASE Gubens, M. A., Chuang, J. C., Akerley, W., Langer, C. J., Clement-Duchene, C., San Pedro-Salcedo, M., Colevas, A., Dragnev, K., Socinski, M. A., Wakelee, H. A. 2018; 10 (1): 219?27

  Abstract

  Brain metastases are a common complication of advanced non-small cell lung cancer (NSCLC). Patients with brain metastases were excluded from the registration trials of bevacizumab that showed a survival benefit with the use of angiogenesis inhibition.In this study, we pooled data from two separate trials designed to evaluate the risk of central nervous system (CNS) hemorrhage in patients with stable treated brain metastases to look specifically at both the safety and efficacy of bevacizumab and pemetrexed when used as second-line treatment in NSCLC patients with stable treated brain metastases.We report acceptable safety and promising efficacy from our analysis.Our study adds further evidence of safety of administering pemetrexed and bevacizumab to patients with stable brain metastases. There is increasing roles for systemic therapies to treat stable brain metastases for patients with advanced NSCLC.

  View details for PubMedID 29600052

  View details for PubMedCentralID PMC5863135

• Anaplastic Lymphoma Kinase Testing: IHC vs. FISH vs. NGS CURRENT TREATMENT OPTIONS IN ONCOLOGY Niu, X., Chuang, J. C., Berry, G. J., Wakelee, H. A. 2017; 18 (12): 71

  Abstract

  Personalized targeted therapy has emerged as a promising strategy in lung cancer treatment, with current attention focused on elucidation and detection of oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, several oncogenic drivers have been reported, triggering the application of tyrosine kinase inhibitors (TKIs) to target these dysfunctional genes. The anaplastic lymphoma kinase (ALK) rearrangement is responsible for about 4-7% of all non-small cell lung cancers (NSCLCs) and perhaps as high as a third in specific patient populations such as younger, male, non-smokers with advanced stage, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) wild type, and signet ring cell adenocarcinoma with abundant intracytoplasmic mucin. The selection of patients based on their ALK status is vital on account of the high response rates with the ALK-targeted agents in this subset of patients. Standardization and validation of ALK rearrangement detection methods is essential for accurate and reproducible results. There are currently three detection methods widely available in clinical practice, including fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and polymerase chain reaction (PCR)-based next generation sequencing (NGS) technology. However, the choice of diagnostic methodology for ALK rearrangement detection in clinical practice remains a matter of debate. With accumulating data enumerating the advantages and disadvantages of each of the three methods, combining more than one testing method for ALK fusion detection may be beneficial for patients. In this review, we will discuss the current methods used in ALK rearrangement detection with emphasis on their key advantages and disadvantages.

  View details for PubMedID 29143897

• Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial LANCET ONCOLOGY Wakelee, H. A., Dahlberg, S. E., Keller, S. M., Tester, W. J., Gandara, D. R., Graziano, S. L., Adjei, A. A., Leighl, N. B., Aisner, S. C., Rothman, J. M., Patel, J. D., Sborov, M. D., McDermott, S. R., Perez-Soler, R., Traynor, A. M., Butts, C., Evans, T., Shafqat, A., Chapman, A. E., Kasbari, S. S., Horn, L., Ramalingam, S. S., Schiller, J. H., ECOG-ACRIN 2017; 18 (12): 1610?23

  Abstract

  Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.We did an open-label, randomised, phase 3 trial of adult patients (aged ?18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (?4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.National Cancer Institute of the National Institutes of Health.

  View details for PubMedID 29129443

• Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma Gao, R. W., Berry, M. F., Kunder, C. A., Khuong, A. A., Wakelee, H., Neal, J. W., Backhus, L. M., Shrager, J. B. MOSBY-ELSEVIER. 2017: 2092-+

  Abstract

  It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs.Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan-Meier method.Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 ± 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 ± 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4).At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT.

  View details for PubMedID 28863952

• Liquid Biopsy Wakelee, H. ELSEVIER SCIENCE INC. 2017: S1666?S1667

  View details for DOI 10.1016/j.jtho.2017.09.197

  View details for Web of Science ID 000463860800102

• Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer RADIOTHERAPY AND ONCOLOGY Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C., Zhu, H., Eclov, N. W., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q., Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. 2017; 125 (2): 338?43

  Abstract

  Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

  View details for PubMedID 28830717

• Response to Ensartinib in TKI Naive ALK plus NSCLC Patients Wakelee, H., Sanborn, R., Nieva, J., Waqar, S., Brzezniak, C., Bauman, J., Neal, J., Dukart, G., Tan, F., Harrow, K., Liang, C., Horn, L. ELSEVIER SCIENCE INC. 2017: S1826

  View details for DOI 10.1016/j.jtho.2017.09.504

  View details for Web of Science ID 000463860800400

• Activity of Ensartinib after Second Generation Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKI) Horn, L., Leal, T. A., Oxnard, G., Wakelee, H., Blumenschein, G. R., Waqar, S., Gandhi, L., Chiappori, A. A., Dukart, G., Harrow, K., Liang, C., Tan, F., Gockerman, J. P., Reckamp, K. ELSEVIER SCIENCE INC. 2017: S1556

  View details for DOI 10.1016/j.jtho.2017.09.020

  View details for Web of Science ID 000461257300019

• Oral Bisphosphonate Use and Lung Cancer Incidence among Postmenopausal Women Tao, M., Chen, S., Freudenheim, J. L., Cauley, J. A., Johnson, K. C., Ma, X., Sarto, G. E., Wakelee, H., Boffetta, P., Wactawski-Wende, J. ELSEVIER SCIENCE INC. 2017: S1564?S1565

  View details for DOI 10.1016/j.jtho.2017.09.040

  View details for Web of Science ID 000461257300038

• A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naive EGFR-Mutated Metastatic Non-Small Cell Lung Padda, S., Reckamp, K., Koczywas, M., Neal, J., Kawashima, J., Kong, S., Xin, Y., Huang, D., Wakelee, H. ELSEVIER SCIENCE INC. 2017: S2142?S2143

  View details for Web of Science ID 000463860801716

• IMpower010: A Phase III Study of Atezolizumab vs Best Supportive Care Following Adjuvant Chemotherapy in Completely Resected NSCLC Felip, E., Wakelee, H., Vallieres, E., Zhou, C., Zuo, Y., Xia, F., Sandler, A., Altorki, N. ELSEVIER SCIENCE INC. 2017: S2398?S2399

  View details for DOI 10.1016/j.jtho.2017.11.017

  View details for Web of Science ID 000463860802553

• Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC) Yang, J. C., Reckamp, K., Kim, Y., Novello, S., Smit, E., Lee, J., Su, W., Akerley, W., Blakely, C., Bazhenova, L., Chiari, R., Hsia, T., Golsorkhi, T., Despain, D., Shih, D., Rolfe, L., Popat, S., Wakelee, H. ELSEVIER SCIENCE INC. 2017: S2397

  View details for DOI 10.1016/j.jtho.2017.11.013

  View details for Web of Science ID 000463860802549

• Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA Chabon, J., Chaudhuri, A., Azad, T., Kurtz, D., Stehr, H., Liu, C. L., Martin, J., Merriott, D., Carter, J., Ayers, K., Mansfield, A., Jen, J., Ren, H., West, R., Nair, V., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1851

  View details for DOI 10.1016/j.jtho.2017.09.560

  View details for Web of Science ID 000463860800456

• Characterization of Autoantibody Responses in Thymoma with Myasthenia Gravis by Single-Cell Sequencing of B-cells Gomez, A., Adamska, J., Padda, S., Preiss, J., Lingampalli, N., Wakelee, H., Robinson, W. ELSEVIER SCIENCE INC. 2017: S1866?S1867

  View details for DOI 10.1016/j.jtho.2017.09.596

  View details for Web of Science ID 000463860801028

• First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study Wu, Y., Mok, T., Reck, M., Wakelee, H., Liang, C., Tan, F., Harrow, K., Oertel, V., Dukart, G., Ding, L., Horn, L. ELSEVIER SCIENCE INC. 2017: S2402

  View details for DOI 10.1016/j.jtho.2017.11.025

  View details for Web of Science ID 000463860802561

• Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A., Stehr, H., Azad, T. D., Carter, J. N., Merriott, D. J., Liu, C. L., Kurtz, D. M., Gensheimer, M. F., Shrager, J. B., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S114

  View details for DOI 10.1016/j.ijrobp.2017.06.269

  View details for Web of Science ID 000411559107060

• Outcomes of Moderately Hypofractionated Intensity-Modulated Thoracic Radiotherapy with Concurrent Chemotherapy for Treatment of Non-Small Cell Lung Cancer Xiang, M., Gensheimer, M. F., Maxim, P. G., Wakelee, H. A., Neal, J. W., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E504

  View details for DOI 10.1016/j.ijrobp.2017.06.1806

  View details for Web of Science ID 000411559104073

• Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Non-small Cell Lung Cancer Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C. N., Eclov, N., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q. T., Hara, W., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E456

  View details for DOI 10.1016/j.ijrobp.2017.06.1695

  View details for Web of Science ID 000411559103253

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer Merriott, D. J., Chaudhuri, A. A., Jin, M., Chabon, J. J., Newman, A., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H. R., Das, M., Padda, S., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S20?S21

  View details for DOI 10.1016/j.ijrobp.2017.06.061

  View details for Web of Science ID 000411559106127

• Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Merriott, D. J., Carter, J. N., Azad, T. D., Padda, S., Gensheimer, M. F., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1?S2

  View details for DOI 10.1016/j.ijrobp.2017.06.021

  View details for Web of Science ID 000411559106087

• The Evolution of Frontline Therapy in ALK-Positive Advanced NSCLC: Which ALK TKI to Use Upfront? AMERICAN JOURNAL OF HEMATOLOGY-ONCOLOGY Zweig, J., Wakelee, H. 2017; 13 (9): 32?36

  View details for Web of Science ID 000419469500007

• Risk Stratification for Second Primary Lung Cancer JOURNAL OF CLINICAL ONCOLOGY Han, S. S., Rivera, G. A., Tammemagi, M. C., Plevritis, S. K., Gomez, S. L., Cheng, I., Wakelee, H. A. 2017; 35 (25): 2893-+

  Abstract

  Purpose This study estimated the 10-year risk of developing second primary lung cancer (SPLC) among survivors of initial primary lung cancer (IPLC) and evaluated the clinical utility of the risk prediction model for selecting eligibility criteria for screening. Methods SEER data were used to identify a population-based cohort of 20,032 participants diagnosed with IPLC between 1988 and 2003 and who survived ? 5 years after the initial diagnosis. We used a proportional subdistribution hazards model to estimate the 10-year risk of developing SPLC among survivors of lung cancer LC in the presence of competing risks. Considered predictors included age, sex, race, treatment, histology, stage, and extent of disease. We examined the risk-stratification ability of the prediction model and performed decision curve analysis to evaluate the clinical utility of the model by calculating its net benefit in varied risk thresholds for screening. Results Although the median 10-year risk of SPLC among survivors of LC was 8.36%, the estimated risk varied substantially (range, 0.56% to 14.3%) when stratified by age, histology, and extent of IPLC in the final prediction model. The stratification by deciles of estimated risk showed that the observed incidence of SPLC was significantly higher in the tenth-decile group (12.5%) versus the first-decile group (2.9%; P < 10-10). The decision curve analysis yielded a range of risk thresholds (1% to 11.5%) at which the clinical net benefit of the risk model was larger than those in hypothetical all-screening or no-screening scenarios. Conclusion The risk stratification approach in SPLC can be potentially useful for identifying survivors of LC to be screened by computed tomography. More comprehensive environmental and genetic data may help enhance the predictability and stratification ability of the risk model for SPLC.

  View details for PubMedID 28644772

• The J-ALEX trial-is frontline alectinib a new standard of care? JOURNAL OF THORACIC DISEASE Zweig, J., Wakelee, H. A. 2017; 9 (8): 2242?45

  View details for PubMedID 28932515

  View details for PubMedCentralID PMC5594119

• Does Plasma-Based Molecular Testing Have a Role in the Routine Care of Lung Cancer? CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Wakelee, H. 2017; 15 (8): 599?601

  View details for PubMedID 28949946

• Calcium plus vitamin D supplementation and lung cancer incidence among postmenopausal women in the Women's Health Initiative LUNG CANCER Tao, M., Dai, Q., Chen, S., Freudenheim, J. L., Rohan, T., Wakelee, H., Datta, M., Wactawski-Wende, J. 2017; 110: 42?47

  Abstract

  Magnesium and calcium are antagonistic in many physiologic processes. However, few studies have investigated the associations of supplemental calcium with lung cancer risk taking this antagonism into account. We evaluated the effect of calcium and vitamin D supplementation on lung cancer incidence and explored whether the ratio of baseline calcium to magnesium (Ca:Mg) intake modifies the association in the Women's Health Initiative (WHI) calcium plus vitamin D supplementation (CaD) trial.The intervention phase of the WHI CaD was a double-blinded, randomized, placebo-controlled trial in 36,382 postmenopausal women aged 50-79 years, recruited at 40U.S. centers. Post-intervention follow-up continued among 29,862 (86%) of the surviving participants. Risk of lung cancer in association with CaD supplementation was evaluated using proportional hazard regression models.After 11 years' cumulative follow-up, there were 207 lung cancers (incidence 0.11% per year) in the supplement arm and 241 (0.12%) in the placebo arm (hazard ratio (HR) for the intervention, 0.91; 95% confidence interval (CI), 0.71-1.17). Subgroup analyses suggested that the HR for lung cancer varied by baseline Ca:Mg intake ratio among women who were current smokers at enrollment (p=0.04 for interaction).Over the entire follow-up period, calcium and vitamin D supplementation did not reduce lung cancer incidence among postmenopausal women. In exploratory analyses, an interaction was found for the baseline Ca:Mg intake ratio on lung cancer among current smokers at the trial entry. This findings need to be further studied for the role of calcium with magnesium in lung carcinogenesis in current smokers.

  View details for PubMedID 28676217

• Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4

  View details for DOI 10.1016/j.ijrobp.2017.02.048

  View details for Web of Science ID 000403079100013

• Heather Wakelee on the role of checkpoint inhibitors in advanced lung cancer ONCOLOGY-NEW YORK Wakelee, H. 2017; 31 (6): 440-+

  View details for Web of Science ID 000403633000001

  View details for PubMedID 28620899

• A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer LUNG CANCER Harris, J. P., Patel, M. I., Loo, B. W., Wakelee, H. A., Diehn, M. 2017; 108: 173?82

  Abstract

  In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach.Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ?65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach.1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide.Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.

  View details for PubMedID 28625632

• Lung cancer incidence trends in California by race/ethnicity, histology, sex, and neighborhood socioeconomic status: An analysis spanning 28 years LUNG CANCER Patel, M. I., McKinley, M., Cheng, I., Haile, R., Wakelee, H., Gomez, S. 2017; 108: 140?49

  Abstract

  Lung cancer incidence trends by histology, sex, race/ethnicity, and neighborhood socioeconomic status (nSES) have not been previously reported. We conducted a population-based study of lung cancer incidence over three peri-censal periods: 1988-1992, 1998-2002, and 2008-2012.We abstracted lung cancer cases from the California Cancer Registry and used US Census and American Community Survey data to develop multidimensional nSES indices for each census period. We calculated nSES tertile-specific incidence rates and rate ratios for each peri-censal period and used incidence rate ratios (IRR) to assess changes in rates from 1988 to 1992 to 1998-2002 and 2008-2012.There were a total of 231,205 lung cancer cases. Males: Among males, incidence rates of lung cancer decreased over time, all race/ethnicities, and all nSES tertiles, with larger declines among males in higher nSES areas. Rates either declined or were stable for adenocarcinoma, with larger declines for other histologic subtypes. Females: Among females, declines in incidence rates of lung cancer were more pronounced for females in higher nSES areas, but diverged more so than for males, with variations by histology and race/ethnicity. Incidence rates of adenocarcinoma increased over time among all females, with greater increase among females in low nSES areas.Our findings demonstrate differences in incidence trends over three decades by histology, gender, race/ethnicity, and nSES. While incidence rates consistently declined over time for males, there were greater declines in incidence for high nSES populations. In contrast, among females, there was evidence of increases in lung cancer incidence among low SES API females, and for adenocarcinoma.

  View details for PubMedID 28625626

• Scientific Advances in Thoracic Oncology 2016. Journal of thoracic oncology Soo, R. A., Stone, E. C., Cummings, K. M., Jett, J. R., Field, J. K., Groen, H. J., Mulshine, J. L., Yatabe, Y., Bubendorf, L., Dacic, S., Rami-Porta, R., Detterbeck, F. C., Lim, E., Asamura, H., Donington, J., Wakelee, H. A., Wu, Y. L., Higgins, K., Senan, S., Solomon, B., Kim, D., Johnson, M., Yang, J. C., Sequist, L. V., Shaw, A. T., Ahn, M., Costa, D. B., Patel, J. D., Horn, L., Gettinger, S., Peters, S., Wynes, M. W., Faivre-Finn, C., Rudin, C. M., Tsao, A., Baas, P., Kelly, R. J., Leighl, N. B., Scagliotti, G. V., Gandara, D. R., Hirsch, F. R., Spigel, D. R. 2017

  Abstract

  Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The IASLC and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for non-small cell lung cancer, small cell lung cancer, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.

  View details for DOI 10.1016/j.jtho.2017.05.019

  View details for PubMedID 28579481

• The morbidity and mortality conference (MMC) concept applied to contemporary oncology practice: Retrospective findings on management of 233 patients (pts) who died of ovarian cancer (OC), colorectal cancer (CRC) and wild-type (no identified targetable mutation) nonsquamous non-small cell lung cancer (WTLC) Ziel, K., Birrer, M. J., Hecht, J., Wakelee, H. A., Chen, G., Deutsch, M., Picton, M., Rodriguez, E., Willmott, L., Kelly, G., Miller, K., Moss, J., Paley, D., Love, N. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.e18195

  View details for Web of Science ID 000411931707084

• Risk factors associated with brain metastases in ECOG-ACRIN E1505, a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely resected stage IB (>/=4 cm) - IIIA non-small cell lung cancer (NSCLC). Varlotto, J. M., Dahlberg, S., Wakelee, H. A., Ramalingam, S. S., Schiller, J. H. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.8539

  View details for Web of Science ID 000411932201117

• A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010. Wakelee, H. A., Altorki, N. K., Vallieres, E., Zhou, C., Zuo, Y., Howland, M., Xia, F., Sandler, A., Felip, E. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS8576

  View details for Web of Science ID 000411932201153

• -Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy. oncologist Baik, C. S., Myall, N. J., Wakelee, H. A. 2017

  Abstract

  Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.

  View details for DOI 10.1634/theoncologist.2016-0458

  View details for PubMedID 28487464

• -Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy. oncologist Baik, C. S., Myall, N. J., Wakelee, H. A. 2017

  Abstract

  Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.

  View details for DOI 10.1634/theoncologist.2016-0458

  View details for PubMedID 28487464

• Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry JOURNAL OF CLINICAL ONCOLOGY Gautschi, O., Milia, J., Filleron, T., Wolf, J., Carbone, D. P., Owen, D., Camidge, R., Narayanan, V., Doebele, R. C., Besse, B., Remon-Masip, J., Janne, P. A., Awad, M. M., Peled, N., Byoung, C., Karp, D. D., van den Heuvel, M., Wakelee, H. A., Neal, J. W., Mok, T. S., Yang, J. C., Ou, S. I., Pall, G., Froesch, P., Zalcman, G., Gandara, D. R., Riess, J., Velcheti, V., Zeidler, K., Diebold, J., Frueh, M., Michels, S., Monnet, I., Popat, S., Rosell, R., Karachaliou, N., Rothschild, S. I., Shih, J., Warth, A., Muley, T., Cabillic, F., Mazieres, J., Drilon, A. 2017; 35 (13): 1403-?

  Abstract

  Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

  View details for DOI 10.1200/JCO.2016.70.9352

  View details for PubMedID 28447912

• METLung: a disappointing result in a challenging patient population TRANSLATIONAL CANCER RESEARCH Zweig, J., Wakelee, H. 2017; 6: S489?S493

  View details for DOI 10.21037/tcr.2017.04.02

  View details for Web of Science ID 000404110200011

• A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Gettinger, S., Engelman, J., Janne, P. A., West, H., Subramaniam, D. S., Leach, J., Wax, M., Yaron, Y., Miles, D. R., Lara, P. N. 2017; 79 (5): 923-932

  Abstract

  Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N?=?15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N?=?13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.

  View details for DOI 10.1007/s00280-017-3283-z

  View details for Web of Science ID 000400070400009

  View details for PubMedID 28352985

• Case Series of MET Exon 14 Skipping Mutation-positive Non-Small Cell Lung Cancers and Response to Crizotinib. International journal of radiation oncology, biology, physics Wang, S. X., Zhang, B., Wakelee, H. A., Diehn, M., Kunder, C., Neal, J. W. 2017; 98 (1): 239-?

  View details for DOI 10.1016/j.ijrobp.2017.01.170

  View details for PubMedID 28587017

• CNS activity of ensartinib in ALK1 non-small cell lung cancer (NSCLC) patients (pts) Reckamp, K. L., Wakelee, H. A., Patel, S., Blumenschein, G., Neal, J. W., Gitlitz, B., Waqar, S. N., Tan, F., Harrow, K., Horn, L. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000405512800076

• The morbidity and mortality conference (MMC) concept applied to contemporary oncology practice: Retrospective findings on management of 233 patients (pts) who died of ovarian cancer (OC), colorectal cancer (CRC), and wild-type (no identified targetable mutation) nonsquamous non-small cell lung cancer (WTLC) Love, N., Birrer, M. J., Hecht, J., Wakelee, H. A., Chen, G., Deutsch, M., Picton, M., Rodriguez, E., Willmott, L., Kelly, G., Miller, K., Moss, J., Paley, D., Ziel, K. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for Web of Science ID 000443301600240

• Elusive Target of Angiogenesis in Small-Cell Lung Cancer. Journal of clinical oncology Neal, J. W., Wakelee, H. A. 2017: JCO2016716084-?

  View details for DOI 10.1200/JCO.2016.71.6084

  View details for PubMedID 28165898

• ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies. Journal of thoracic oncology Chuang, J. C., Stehr, H., Liang, Y., Das, M., Huang, J., Diehn, M., Wakelee, H. A., Neal, J. W. 2017

  Abstract

  Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

  View details for DOI 10.1016/j.jtho.2017.01.023

  View details for PubMedID 28167203

• Neoadjuvant and Adjuvant Therapy for Non-Small Cell Lung Cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Chuang, J. C., Liang, Y., Wakelee, H. A. 2017; 31 (1): 31-?

  Abstract

  The use of 4 cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA non-small cell lung cancer. Neoadjuvant chemotherapy lacks the same level of data as adjuvant treatment, but meta-analyses of this approach support its use. Selection of patients who are most likely to benefit from chemotherapy remain elusive. Ongoing adjuvant trials are exploring biomarkers, molecularly targeted agents, postoperative radiation therapy, and immunotherapy.

  View details for DOI 10.1016/j.hoc.2016.08.011

  View details for PubMedID 27912832

• Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry JOURNAL OF THORACIC ONCOLOGY Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2017; 12 (1): 129-136

  Abstract

  Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

  View details for DOI 10.1016/j.jtho.2016.08.131

  View details for Web of Science ID 000391518500015

• Monitoring Neutropenia for Cancer Patients at the Point of Care. Small methods Inan, H., Kingsley, J. L., Ozen, M. O., Tekin, H. C., Hoerner, C. R., Imae, Y., Metzner, T. J., Preiss, J. S., Durmus, N. G., Ozsoz, M., Wakelee, H., Fan, A. C., Tüzel, E., Demirci, U. 2017; 1 (9)

  Abstract

  Neutrophils have a critical role in regulating the immune system. The immune system is compromised during chemotherapy, increasing infection risks and imposing a need for regular monitoring of neutrophil counts. Although commercial hematology analyzers are currently used in clinical practice for neutrophil counts, they are only available in clinics and hospitals, use large blood volumes, and are not available at the point of care (POC). Additionally, phlebotomy and blood processing require trained personnel, where patients are often admitted to hospitals when the infections are at late stage due to lack of frequent monitoring. Here, a reliable method is presented that selectively captures and quantifies white blood cells (WBCs) and neutrophils from a finger prick volume of whole blood by integrating microfluidics with high-resolution imaging algorithms. The platform is compact, portable, and easy to use. It captures and quantifies WBCs and neutrophils with high efficiency (>95%) and specificity (>95%) with an overall 4.2% bias compared to standard testing. The results from a small cohort of patients (N = 11 healthy, N = 5 lung and kidney cancer) present a unique disposable cell counter, demonstrating the ability of this tool to monitor neutrophil and WBC counts within clinical or in resource-constrained environments.

  View details for PubMedID 30740513

• Chart Review Versus an Automated Bioinformatic Approach to Assess Real-World Crizotinib Effectiveness in Anaplastic Lymphoma Kinase?Positive Non?Small-Cell Lung Cancer JCO: Clinical Cancer Informatics Bui, N., Henry, S., Wood, D., Wakelee, H. A., Neal, J. W. 2017

  View details for DOI 10.1200/CCI.16.00055

• The CD47 Macrophage Checkpoint as a New Immunotherapy Target Sikic, B. I., Padda, S. K., Shah, S. A., Colevas, D., Narayanan, S., Fisher, G. A., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Villalobos, V. M., Liu, J., Takimoto, C., Chao, M. P., Volkmer, J. P., Majeti, R., Weissman, I. L. ELSEVIER SCIENCE INC. 2017: S108?S109

  View details for Web of Science ID 000413055800089

• IMpower010: Phase III Study of Atezolizumab vs BSC after Adjuvant Chemotherapy in Patients with Completely Resected NSCLC Wakelee, H., Altorki, N., Vallieres, E., Zhou, C., Zuo, Y., Howland, M., Xia, F., Hoang, T., Sandler, A., Felip, E. ELSEVIER SCIENCE INC. 2017: S1305

  View details for Web of Science ID 000413055803094

• Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers Gautschi, O., Milia-Baron, J., Filleron, T., Wolf, J., Carbone, D., Owen, D., Camidge, D., Narayanan, V., Doebele, R., Besse, B., Remon, J., Janne, P., Awad, M., Peled, N., Byoung, C., Karp, D., Van den Heuve, M., Wakelee, H., Nea, J., Mok, T., Yang, J., Ou, S., Pa, G., Froesch, P., Zalcman, G., Gandara, D. R., Riess, J., Velcheti, V., Zeidler, K., Diebold, J., Fruh, M., Michels, S., Monnet, I., Popat, S., Rosell, R., Karachaliou, N., Rothschild, S., Shih, J., Warth, A., Muley, T., Cabillic, F., Mazieres, J., Drilon, A. ELSEVIER SCIENCE INC. 2017: S435?S436

  View details for Web of Science ID 000413055801012

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L., Scherer, F., Kurtz, D. M., Say, C., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• Monitoring Neutropenia for Cancer Patients at the Point of Care Small Methods Inan, H., et al 2017

  View details for DOI 10.1002/smtd.201700193

• Clinical Activity of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib Gadgeel, S., Chen, W., Piotrowska, Z., Goldman, J. W., Wakelee, H., Camidge, D., Varga, A., Yu, H., Papadimitrakopoulou, V., Nea, J., Soria, J., Wozniak, A., Riely, G., Narayanan, V., Mendenhal, M., Sequist, L. ELSEVIER SCIENCE INC. 2017: S1263

  View details for Web of Science ID 000413055803032

• Smoking Behavior in Patients with Early Stage Non-Small Cell Lung Cancer: A Report from ECOG-ACRIN 1505 Trial Ramalingam, S., Dahlberg, S., Wakelee, H., Keller, S., Tester, W., Gandara, D. R., Graziano, S., Adjei, A., Butts, C., Schiller, J. ELSEVIER SCIENCE INC. 2017: S256

  View details for Web of Science ID 000413055800233

• Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC Wakelee, H. ELSEVIER SCIENCE INC. 2017: S45?S46

  View details for Web of Science ID 000413055800037

• Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer Chaudhuri, A., Lovejoy, A., Chabon, J., Newman, A., Stehr, H., Say, C., Carter, J., Zhou, L., West, R., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S445

  View details for Web of Science ID 000413055801024

• A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma Wakelee, H., Melnikova, V., Karlovich, C., Gadgeel, S., Reckamp, K., Goldman, J. W., Camidge, D., Perol, M., Ou, S., Liu, S., Yu, H., Socinski, M., Mekhai, T., Solomon, B., Natale, R., Otterson, G., Papadimitrakopoulou, V., Soria, J., Langer, C., Neal, J., Despain, D., Yurasov, S., Litten, J., Raponi, M., Erlander, M., Sequist, L. ELSEVIER SCIENCE INC. 2017: S384?S385

  View details for Web of Science ID 000413055800415

• A Phase lb Study of Erlotinib and Momelotinib for EGFR TKI Naive EGFR Mutated Metastatic Non-Small Cell Lung Cancer Padda, S., Reckamp, K., Koczywas, M., Neal, J., Brachmann, C., Kawashima, J., Kong, S., Xin, Y., Huang, D., Wakelee, H. ELSEVIER SCIENCE INC. 2017: S1070?S1071

  View details for Web of Science ID 000413055802312

• A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer Nagpal, S., Wakelee, H., Padda, S., Bertrand, S., Acevedo, B., Tisch, A., Pagtama, J., Soltys, S., Neal, J. ELSEVIER SCIENCE INC. 2017: S940

  View details for Web of Science ID 000413055802110

• Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (Pts) with ALK plus NSCLC Horn, L., Wakelee, H., Reckamp, K., Blumenschein, G., Infante, J., Carter, C., Waqar, S., Neal, J., Gockerman, J., Harrow, K., Dukart, G., Liang, C., Gibbons, J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. ELSEVIER SCIENCE INC. 2017: S1159

  View details for Web of Science ID 000413055802442

• Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial. International journal of radiation oncology, biology, physics Choi, C. Y., Wakelee, H. A., Neal, J. W., Pinder-Schenck, M. C., Yu, H. M., Chang, S. D., Adler, J. R., Modlin, L. A., Harsh, G. R., Soltys, S. G. 2017; 99 (1): 16?21

  Abstract

  To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ?2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

  View details for PubMedID 28816142

• Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non Small-Cell Lung Cancer CLINICAL LUNG CANCER Wakelee, H., Zvirbule, Z., de Braud, F., Kingsley, C. D., Mekhail, T., Lowe, T., Schuette, W., Lena, H., Lawler, W., Braiteh, F., Cosgriff, T., Kaen, D., Boyer, M., Hsu, J., Phan, S., Novello, S. 2017; 18 (1): 50-59

  Abstract

  Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics.Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%).Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

  View details for DOI 10.1016/j.cllc.2016.09.013

  View details for PubMedID 27856142

• Reply to Comment on 'Statin use and all-cancer survival: prospective results from the Women's Health Initiative'. British journal of cancer Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. 2017; 116 (3)

  View details for DOI 10.1038/bjc.2016.396

  View details for PubMedID 27923034

• Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe. Clinical lung cancer Salahudeen, A. A., Patel, M. I., Baas, P., Curran, W. J., Bradley, J. D., Gandara, D. R., Goss, G. D., Mok, T. S., Ramalingam, S. S., Vokes, E. E., Malik, S. M., Wakelee, H. A. 2017; 18 (1): 5-12

  Abstract

  Survival rates of patients with either early and advanced stage non-small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.

  View details for DOI 10.1016/j.cllc.2016.06.007

  View details for PubMedID 27473736

• Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 2016; 113 (52): E8379-E8386

  Abstract

  Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.

  View details for DOI 10.1073/pnas.1608461113

  View details for PubMedID 27956614

• Protective Effects of Statins in Cancer: Should They Be Prescribed for High-Risk Patients? Current atherosclerosis reports Wang, A., Wakelee, H. A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Stefanick, M. L. 2016; 18 (12): 72-?

  Abstract

  Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer.A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.

  View details for PubMedID 27796821

• IMpower010: A Phase III trial investigating atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy (chemo) in patients (pts) with completely resected NSCLC Zhou, C., Altorki, N., Vallieres, E., Felip, E., Zuo, Y., Howland, M., Xia, F., Hoang, T., Sandler, A., Wakelee, H. OXFORD UNIV PRESS. 2016

  View details for Web of Science ID 000393980600427

• Physical activity and sedentary behavior in relation to lung cancer incidence and mortality in older women: The Women's Health Initiative. International journal of cancer Wang, A., Qin, F., Hedlin, H., Desai, M., Chlebowski, R., Gomez, S., Eaton, C. B., Johnson, K. C., Qi, L., Wactawski-Wende, J., Womack, C., Wakelee, H. A., Stefanick, M. L. 2016; 139 (10): 2178-2192

  Abstract

  Physical activity has been associated with lower lung cancer incidence and mortality in several populations. We investigated these relationships in the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT) prospective cohort of postmenopausal women. The WHI study enrolled 161,808 women aged 50-79 years between 1993-1998 at 40 U.S. clinical centers; 129,401 were eligible for these analyses. Cox proportional hazards models were used to assess the association of baseline physical activity levels [metabolic equivalent (MET)-minutes/week: none <100 (reference), low 100-<500, medium 500-<1200, high 1200+] and sedentary behavior with total lung cancer incidence and mortality. Over 11.8 mean follow-up years, 2,148 incident lung cancer cases and 1,365 lung cancer deaths were identified. Compared to no activity, higher physical activity levels at study entry were associated with lower lung cancer incidence [p=0.009; hazard ratios (95% confidence intervals) for each physical activity category: low, HR: 0.86 (0.76-0.96); medium, HR: 0.82 (0.73-0.93); and high, HR: 0.90 (0.79-1.03)], and mortality [p<0.0001; low, HR: 0.80 (0.69-0.92); medium, HR: 0.68 (0.59-0.80); and high, HR: 0.78 (0.66-0.93)]. Body mass index (BMI) modified the association with lung cancer incidence (p=0.01), with a stronger association in women with BMI<30 kg/m(2) . Significant associations with sedentary behavior were not observed. In analyses by lung cancer subtype, higher total physical activity levels were associated with lower lung cancer mortality for both overall NSCLC and adenocarcinoma. In conclusion, physical activity may be protective for lung cancer incidence and mortality in postmenopausal women, particularly in non-obese women. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ijc.30281

  View details for PubMedID 27439221

• Corrigendum: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nature communications Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Thomas Purcell, W., Ross Camidge, D., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7: 13513-?

  View details for DOI 10.1038/ncomms13513

  View details for PubMedID 27841271

  View details for PubMedCentralID PMC5114547

• Adding to the targeted therapy toolbox: BRAF and MEK inhibition in the treatment of BRAF V600E metastatic non-small cell lung cancer TRANSLATIONAL CANCER RESEARCH Myall, N. J., Wakelee, H. A. 2016; 5: S1233-S1240

  View details for DOI 10.21037/tcr.2016.11.50

  View details for Web of Science ID 000393328100052

• MINI01.02: Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (pts) with ALK+ NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Horn, L., Wakelee, H., Reckamp, K. L., Blumenschein, G., Infante, J. R., Carter, C. A., Waqar, S. N., Neal, J. W., Harrow, K., Gockerman, J. P., Dukart, G., Liang, C., Gibbons, J. L., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. M. 2016; 11 (11S): S256-S257

  View details for DOI 10.1016/j.jtho.2016.09.017

  View details for PubMedID 27969449

• PS01.22: Novel 3-Dimensional Preclinical Models: Topic: Medical Oncology. Journal of thoracic oncology Salahudeen, A., De La O, S., Padda, S. K., Neal, J. W., Wakelee, H., Kuo, C. 2016; 11 (11S): S282-?

  View details for DOI 10.1016/j.jtho.2016.09.057

  View details for PubMedID 27969489

• PS01.55: IMpower010: Phase III Study of Atezolizumab vs BSC After Adjuvant Chemotherapy in Patients with Completely Resected NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Vallieres, E., Felip, E., Altorki, N., Zhou, C., Zuo, Y., Howland, M., Xia, F., Hoang, T., Sandler, A., Wakelee, H. 2016; 11 (11S): S304-?

  View details for DOI 10.1016/j.jtho.2016.09.090

  View details for PubMedID 27969522

• PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Neal, J. W., Wakelee, H., Padda, S. K., Bertrand, S., Acevedo, B., Holmes Tisch, A., Pagtama, J. Y., Soltys, S. G., Nagpal, S. 2016; 11 (11S): S271-S272

  View details for DOI 10.1016/j.jtho.2016.09.040

  View details for PubMedID 27969472

• PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology. Journal of thoracic oncology Wang, S. X., Zhang, B. M., Wakelee, H., Diehn, M., Kunder, C. A., Neal, J. W. 2016; 11 (11S): S312-S313

  View details for DOI 10.1016/j.jtho.2016.09.102

  View details for PubMedID 27969534

• PS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Han, S., Rivera, G. A., Cheng, I., Gomez, S., Plevritis, S. K., Wakelee, H. 2016; 11 (11S): S319-S320

  View details for DOI 10.1016/j.jtho.2016.09.112

  View details for PubMedID 27969544

• PS01.66: Biomarker Stratification of Outcomes of Third-Generation EGFR TKI Therapy in Patients with Previously-Treated Advanced NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Wakelee, H., Goldman, J. W., Gadgeel, S., Camidge, D. R., Reckamp, K. L., Ou, S. I., Yu, H. A., Solomon, B., Liu, S. V., Pérol, M., Dupuis, N. F., Nickel, A., Karlovich, C., Raponi, M., Yurasov, S., Litten, J., Despain, D., Soria, J., Sequist, L., Carbone, D. 2016; 11 (11S): S311-S312

  View details for DOI 10.1016/j.jtho.2016.09.101

  View details for PubMedID 27969533

• ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1-Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology. Journal of thoracic oncology Wakelee, H., Patel, J. D., Heist, R., Balmanoukian, A., Besse, B., Felip, E., Carcereny Costa, E., Chow, L. Q., Koczywas, M., Garassino, M. C., Christoph, D., Toh, C. K., Johnson, M. L., Chaft, J., Kurata, T., Qiu, J., Kowanetz, M., Coleman, S., Mocci, S., Sandler, A., Gettinger, S. N., Peters, S. 2016; 11 (11S): S251-S252

  View details for DOI 10.1016/j.jtho.2016.09.009

  View details for PubMedID 27969443

• The Burden of Cancer in Asian Americans: A Report of National Mortality Trends by Asian Ethnicity CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Thompson, C. A., Gomez, S. L., Hastings, K. G., Kapphahn, K., Yu, P., Shariff-Marco, S., Bhatt, A. S., Wakelee, H. A., Patel, M. I., Cullen, M. R., Palaniappan, L. P. 2016; 25 (10): 1371-1382

  Abstract

  Asian Americans (AA) are the fastest growing U.S. population, and when properly distinguished by their ethnic origins, exhibit substantial heterogeneity in socioeconomic status, health behaviors, and health outcomes. Cancer is the second leading cause of death in the United States, yet trends and current patterns in the mortality burden of cancer among AA ethnic groups have not been documented.We report age-adjusted rates, standardized mortality ratios, and modeled trends in cancer-related mortality in the following AA ethnicities: Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese, from 2003 to 2011, with non-Hispanic whites (NHW) as the reference population.For most cancer sites, AAs had lower cancer mortality than NHWs; however, mortality patterns were heterogeneous across AA ethnicities. Stomach and liver cancer mortality was very high, particularly among Chinese, Koreans, and Vietnamese, for whom these two cancer types combined accounted for 15% to 25% of cancer deaths, but less than 5% of cancer deaths in NHWs. In AA women, lung cancer was a leading cause of death, but (unlike males and NHW females) rates did not decline over the study period.Ethnicity-specific analyses are critical to understanding the national burden of cancer among the heterogeneous AA population.Our findings highlight the need for disaggregated reporting of cancer statistics in AAs and warrant consideration of tailored screening programs for liver and gastric cancers. Cancer Epidemiol Biomarkers Prev; 25(10); 1371-82. ©2016 AACR.

  View details for DOI 10.1158/1055-9965.EPI-16-0167

  View details for PubMedID 27694108

• Phase I/II Trial of X-396, A Novel ALK Inhibitor, in Patients With ALK plus NSCLC Leal, T., Wakelee, H., Infante, J., Blumenschein, G., Reckamp, K., Carter, C., Waqar, S., Gockerman, J., Lovly, C., Dukart, G., Harrow, K., Liang, C., Gibbons, J., Horn, L. ELSEVIER SCIENCE INC. 2016: S209?S210

  View details for Web of Science ID 000427345100060

• Phase I/II Trial of X-396, a Novel ALK Inhibitor, in Patients With ALK plus NSCLC Leal, T., Wakelee, H., Infante, J., Blumenschein, G., Reckamp, K., Carter, C., Waqar, S., Gockerman, J., Lovly, C., Dukart, G., Harrow, K., Liang, C., Gibbons, J., Horn, L. ELSEVIER SCIENCE INC. 2016: S176?S177

  View details for Web of Science ID 000427345100013

• CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Say, C., Aggarwal, S., Carter, J. N., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2016: S41?S42

  View details for DOI 10.1016/j.ijrobp.2016.06.112

  View details for Web of Science ID 000387655804429

• Phase I/II trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC): Correlation with plasma and tissue genotyping and response to therapy (tx) Horn, L., Wakelee, H., Blumenschein, G., Reckamp, K., Waqar, S., Carter, C. A., Gitlitz, B. J., Infante, J. R., Sanborn, R. E., Neal, J., Gockerman, J. P., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. OXFORD UNIV PRESS. 2016

  View details for Web of Science ID 000393913000302

• Rociletinib-associated cataracts in EGFR-mutant NSCLC Piotrowska, Z., Liu, E., Varga, A., Thakur, M., Narayanan, V., Liu, S. V., Neal, J., Spiegel, M., Solomon, B., Yu, H., Ou, S. I., Papadimitrakopoulou, V. A., Gadgeel, S., Camidge, D. R., Soria, J., Wakelee, H., Goldman, J., Kopani, K., Rolfe, L., Sequist, L. V. OXFORD UNIV PRESS. 2016

  View details for DOI 10.1093/annonc/mdw383.39

  View details for Web of Science ID 000393913000331

• A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma. Journal of thoracic oncology Reckamp, K. L., Melnikova, V. O., Karlovich, C., Sequist, L. V., Camidge, D. R., Wakelee, H., Perol, M., Oxnard, G. R., Kosco, K., Croucher, P., Samuelsz, E., Vibat, C. R., Guerrero, S., Geis, J., Berz, D., Mann, E., Matheny, S., Rolfe, L., Raponi, M., Erlander, M. G., Gadgeel, S. 2016; 11 (10): 1690-1700

  Abstract

  In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible.Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC.Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21.DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.

  View details for DOI 10.1016/j.jtho.2016.05.035

  View details for PubMedID 27468937

• Clinicopathologic Features of Advanced Squamous NSCLC. Journal of thoracic oncology Socinski, M. A., Obasaju, C., Gandara, D., Hirsch, F. R., Bonomi, P., Bunn, P., Kim, E. S., Langer, C. J., Natale, R. B., Novello, S., Paz-Ares, L., Pérol, M., Reck, M., Ramalingam, S. S., Reynolds, C. H., Spigel, D. R., Stinchcombe, T. E., Wakelee, H., Mayo, C., Thatcher, N. 2016; 11 (9): 1411-1422

  Abstract

  Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

  View details for DOI 10.1016/j.jtho.2016.05.024

  View details for PubMedID 27296106

• Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. Journal of thoracic oncology Langer, C. J., Obasaju, C., Bunn, P., Bonomi, P., Gandara, D., Hirsch, F. R., Kim, E. S., Natale, R. B., Novello, S., Paz-Ares, L., Pérol, M., Reck, M., Ramalingam, S. S., Reynolds, C. H., Socinski, M. A., Spigel, D. R., Wakelee, H., Mayo, C., Thatcher, N. 2016

  Abstract

  Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.

  View details for DOI 10.1016/j.jtho.2016.08.138

  View details for PubMedID 27575423

• Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry. Journal of thoracic oncology Burt, B. M., Yao, X., Shrager, J., Antonicelli, A., Padda, S., Reiss, J., Wakelee, H., Su, S., Huang, J., Scott, W. 2016

  Abstract

  Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.

  View details for DOI 10.1016/j.jtho.2016.08.131

  View details for PubMedID 27566187

• Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2. Journal of clinical oncology Crinò, L., Ahn, M., De Marinis, F., Groen, H. J., Wakelee, H., Hida, T., Mok, T., Spigel, D., Felip, E., Nishio, M., Scagliotti, G., Branle, F., Emeremni, C., Quadrigli, M., Zhang, J., Shaw, A. T. 2016; 34 (24): 2866-2873

  Abstract

  Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.

  View details for DOI 10.1200/JCO.2015.65.5936

  View details for PubMedID 27432917

• Pretreatment biopsy for thymic epithelial tumors-does histology subtype matter for treatment strategy? Journal of thoracic disease Padda, S. K., Keijzers, M., Wakelee, H. A. 2016; 8 (8): 1895-1900

  View details for DOI 10.21037/jtd.2016.06.77

  View details for PubMedID 27618984

• Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy. Clinical therapeutics Chuang, J. C., Shrager, J. B., Wakelee, H. A., Neal, J. W. 2016; 38 (7): 1567-1576

  Abstract

  Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.

  View details for DOI 10.1016/j.clinthera.2016.06.005

  View details for PubMedID 27368115

• Statin use and all-cancer survival: prospective results from the Women's Health Initiative BRITISH JOURNAL OF CANCER Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. 2016; 115 (1): 129-135

  Abstract

  This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT).The WHI study enrolled women aged 50-79 years from 1993 to 1998 at 40 US clinical centres. Among 146?326 participants with median 14.6 follow-up years, 23?067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival.Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71-0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74-0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85-1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92-1.001).In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used.British Journal of Cancer advance online publication, 9 June 2016; doi:10.1038/bjc.2016.149 www.bjcancer.com.

  View details for DOI 10.1038/bjc.2016.149

  View details for PubMedID 27280630

• Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7

  Abstract

  Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ?33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.

  View details for DOI 10.1038/ncomms11815

  View details for PubMedID 27283993

• Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization ONCOLOGIST Ali, S. M., Hensing, T., Schrock, A. B., Allen, J., Sanford, E., Gowen, K., Kulkarni, A., He, J., Suh, J. H., Lipson, D., Elvin, J. A., Yelensky, R., Chalmers, Z., Chmielecki, J., Peled, N., Klempner, S. J., Firozvi, K., Frampton, G. M., Molina, J. R., Menon, S., Brahmer, J. R., MacMahon, H., Nowak, J., Ou, S. I., Zauderer, M., Ladanyi, M., Zakowski, M., Fischbach, N., Ross, J. S., Stephens, P. J., Miller, V. A., Wakelee, H., Ganesan, S., Salgia, R. 2016; 21 (6): 762-770

  Abstract

  For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.

  View details for DOI 10.1634/theoncologist.2015-0497

  View details for PubMedID 27245569

• Plasma genotyping of patients enrolled on the expansion phase VII trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC). Horn, L., Wakelee, H. A., Reckamp, K. L., Blumenschein, G. R., Infante, J. R., Carter, C., Waciar, S., Neal, J. W., Gockerman, J. P., Harrow, K., Dukart, G., Liang, C., Gibbons, J. J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9056

  View details for Web of Science ID 000404711506202

• E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC-Outcomes based on chemotherapy subsets. Wakelee, H. A., Dahlberg, S., Keller, S. M., Tester, W. J., Gandara, D. R., Graziano, S. L., Adjei, A. A., Leighl, N. B., Butts, C., Aisner, S. C., Rothman, J. M., Patel, J. D., Sborov, M. D., McDermott, R. S., Perez-Soler, R., Traynor, A. M., Evans, T. L., Horn, L., Ramalingam, S. S., Schiller, J. H. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.8507

  View details for Web of Science ID 000404711505239

• TIGER-3: A phase 3 multinational open-label randomized study of rociletinib vs investigator-choice chemotherapy in patients (pts) with epidermal growth factor receptor mutant-positive (EGFRm) non-small cell lung cancer (NSCLC) progressing on prior EGFR tyrosine kinase inhibitor (TKI) therapy and doublet chemotherapy. Yang, J., Popat, S., Novello, S., Groen, H. M., Perol, M., Felip, E., Griesinger, F., Reckamp, K. L., Lee, J., Smit, E. F., Blakely, C. M., Akerley, W. L., Kim, Y., Bazhenova, L., Califano, R., Hall, R., Georgiou, P., Isaacson, J. D., Golsorkhi, T., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.TPS9106

  View details for Web of Science ID 000404711506252

• Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC. Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D., Chabon, J. J., Scherer, F., Stehr, H., Liu, C., Bratman, S., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500

  View details for Web of Science ID 000404711506257

• Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. Wakelee, H. A., Gadgeel, S. M., Goldman, J., Reckamp, K. L., Karlovich, C., Melnikova, V., Soria, J., Yu, H., Solomon, B. J., Perol, M., Neal, J. W., Liu, S. V., Raponi, M., Despain, D., Erlander, M. G., Matheny, S. L., Yurasov, S., Camidge, D., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9001

  View details for Web of Science ID 000404711506149

• Safety and clinical activity of durvalumab (MEDI4736), an anti-PD-L1 antibody, in treatment-naive patients with advanced non small-cell lung cancer. Antonia, S., Kim, S., Spira, A. I., Ahn, M., Ou, S., Stjepanovic, N., Fasolo, A., Jagert, D., Ottt, P., Wainberg, Z. A., Wakelee, H. A., Goldman, J., Kurland, J., Rebelatto, M. C., Yao, W., Gupta, A., Blake-Haskins, J. A., Segal, N. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9029

  View details for Web of Science ID 000404711506177

• Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib. Chabon, J., Simmons, A., Newman, A. M., Lovejoy, A. F., Esfahani, M. S., Haringsma, H., Kurtz, D., Stehr, H., Scherer, F., Durkin, K. A., Otterson, G., Purcell, W. T., Camidge, D., Goldman, J., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9000

  View details for Web of Science ID 000404711506148

• A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers Sikic, B. I., Lakhani, N., Patnaik, A., Shah, S. A., Chandana, S. R., Rasco, D., Colevas, A., O'Rourke, T., Narayanan, S., Papadopoulos, K., Fisher, G. A., Villalobos, V., Prohaska, S. S., Howard, M., Beeram, M., Chao, M. P., Agoram, B., Chen, J. Y., Huang, J., Axt, M., Liu, J., Volkmer, J., Majeti, R., Weissman, I. L., Takimoto, C. H., Supan, D., Wakelee, H. A., Aoki, R., Pegram, M. D., Padda, S. K. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.3019

  View details for Web of Science ID 000404665404058

• Updated results from TIGER-X, a phase open label study of rociletinib in patients (pts) with advanced, recurrent T790M-positive non-small cell lung cancer (NSCLC). Goldman, J., Soria, J., Wakelee, H. A., Camidge, D., Gadgeel, S. M., Yu, H., Reckamp, K. L., Papadimitrakopoulou, V., Perol, M., Ou, S., Matheny, S. L., Despain, D., Isaacson, J. D., Yurasov, S., Rolfe, L., Sequis, L. V. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9045

  View details for Web of Science ID 000404711506193

• Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686) CLINICAL CANCER RESEARCH Karlovich, C., Goldman, J. W., Sun, J., Mann, E., Sequist, L. V., Konopa, K., Wen, W., Angenendt, P., Horn, L., Spigel, D., Soria, J., Solomon, B., Camidge, D. R., Gadgeel, S., Paweletz, C., Wu, L., Chien, S., O'Donnell, P., Matheny, S., Despain, D., Rolfe, L., Raponi, M., Allen, A. R., Park, K., Wakelee, H. 2016; 22 (10): 2386-2395

  Abstract

  The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ?10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR.

  View details for DOI 10.1158/1078-0432.CCR-15-1260

  View details for PubMedID 26747242

• Scientific Advances in Lung Cancer 2015 JOURNAL OF THORACIC ONCOLOGY Tsao, A. S., Scagliotti, G. V., Bunn, P. A., Carbone, D. P., Warren, G. W., Bai, C., de Koning, H. J., Yousaf-Khan, A. U., McWilliams, A., Tsao, M. S., Adusumilli, P. S., Rami-Porta, R., Asamura, H., Van Schil, P. E., Darling, G. E., Ramalingam, S. S., Gomez, D. R., Rosenzweig, K. E., Zimmermann, S., Peters, S., Ignatius, S., Reungwetwattana, T., Jaenne, P. A., Mok, T. S., Wakelee, H. A., Pirker, R., Mazieres, J., Brahmer, J. R., Zhou, Y., Herbst, R. S., Papadimitrakopoulou, V. A., Redman, M. W., Wynes, M. W., Gandara, D. R., Kelly, R. J., Hirsch, F. R., Pass, H. I. 2016; 11 (5): 613-638

  Abstract

  Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.

  View details for DOI 10.1016/j.jtho.2016.03.012

  View details for PubMedID 27013409

• Association of non-melanoma skin cancer with second non-cutaneous malignancy in the Women's Health Initiative Ransohoff, K., Stefanick, M., Li, S., Kurian, A., Wakelee, H., Wang, A., Hedlin, H., Paskett, E., Han, J., Tang, J. ELSEVIER SCIENCE INC. 2016: S36

  View details for DOI 10.1016/j.jid.2016.02.232

  View details for Web of Science ID 000380028800204

• Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy. Journal of cutaneous pathology Schaberg, K. B., Novoa, R. A., Wakelee, H. A., Kim, J., Cheung, C., Srinivas, S., Kwong, B. Y. 2016; 43 (4): 339-346

  Abstract

  Recent advances in the immunotherapeutic treatment of cancer have led to the development of multiple new directed therapies including monoclonal antibodies that block the immune checkpoint T-cell receptor programmed death 1 (PD-1) and the PD-1 ligand, programmed death ligand 1 (PD-L1). Various immune-related toxicities have been associated with these drugs including, most commonly, skin rashes.Five cases of lichenoid dermatitis, including one case of lichenoid mucositis and one case of lichen sclerosus, associated with anti-PD-L1 and anti-PD1 therapy were compared with three biopsies of non-drug-related lichen planus (LP) and three lichen planus-like keratoses (LPLK) used as controls.Histopathologic and immunophenotypic analysis of these lichenoid lesions demonstrated significantly greater histiocytic infiltrates than observed in control lichenoid reactions (p = 0.0134). We also observed increased spongiosis and epidermal necrosis. No significant differences were seen in expression of CD3, CD4:CD8, CD20, PD-1, CD25, Foxp3, CXCL13 and PD-L1 expression.These findings expand the literature of immune-related toxicities of PD-L1 and PD-1 blockade to include lichenoid dermatitis and lichenoid mucositis. Of note, these cutaneous side effects were amenable to topical treatment, without the need for medication dose reduction or discontinuation.

  View details for DOI 10.1111/cup.12666

  View details for PubMedID 26762844

• Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene. Clinical lung cancer Myall, N. J., Neal, J. W., Cho-Phan, C. D., Zhou, L. Y., Stehr, H., Zhou, L., Diehn, M., Wakelee, H. A. 2016; 17 (2): e17-21

  View details for DOI 10.1016/j.cllc.2015.12.001

  View details for PubMedID 26776917

• Lung Cancer Survival Among Chinese Americans, 2000 to 2010. Journal of global oncology Gomez, S. L., Yang, J., Lin, S., McCusker, M., Sandler, A., Patel, M., Cheng, I., Wakelee, H. A., Clarke, C. A. 2016; 2 (1): 30?38

  Abstract

  PURPOSE: Despite being the leading cause of cancer death, no prior studies have characterized survival patterns among Chinese Americans diagnosed with lung cancer. This study was conducted to identify factors associated with survival after lung cancer in a contemporary cohort of Chinese patients with lung cancer.METHODS: The study design is a prospective descriptive analysis of population-based California Cancer Registry data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall mortality. Participants were Chinese American residents diagnosed with first primary invasive lung cancer from 2000 to 2010 (2,216 men and 1,616 women).RESULTS: Among Chinese men, decreased mortality was associated with care at a National Cancer Institute cancer center (HR, 0.85; 95% CI, 0.73 to 0.99) and adenocarcinoma versus small-cell carcinoma (HR, 0.78; 95% CI, 0.65 to 0.92). Women had better survival compared with men (HR, 0.82; 95% CI, 0.75 to 0.89), with mortality associated with never married versus currently married status (HR, 1.36; 95% CI, 1.11 to 1.66), lower versus higher neighborhood socioeconomic status (HR, 1.38; 95% CI, 1.10 to 1.72 comparing lowest to highest quintile), care at a cancer center (HR, 0.80; 95% CI, 0.67 to 0.96), and squamous cell relative to small-cell carcinoma (HR, 1.60; 95% CI, 1.04 to 2.48).CONCLUSION: Focusing on factors associated with marital status, community socioeconomic status, and characteristics unique to National Cancer Institute-designated cancer centers may help to identify potential strategies for improving the length of survival for Chinese Americans.

  View details for DOI 10.1200/JGO.2015.000539

  View details for PubMedID 28717680

• Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK plus non-small cell lung cancer (NSCLC) Reckamp, K. L., Infante, J. R., Blumenschein, G. R., Wakelee, H., Carter, C. A., Gockerman, J. P., Lovly, C., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Horn, L. ELSEVIER SCIENCE INC. 2016: S36?S37

  View details for Web of Science ID 000427344900061

• Differences in Active and Passive Smoking Exposures and Lung Cancer Incidence Between Veterans and Non-Veterans in the Women's Health Initiative GERONTOLOGIST Bastian, L. A., Gray, K. E., Derycke, E., Mirza, S., Gierisch, J. M., Haskell, S. G., Magruder, K. M., Wakelee, H. A., Wang, A., Ho, G. Y., LaCroix, A. Z. 2016; 56: S102-S111

  Abstract

  Women Veterans may have higher rates of both active and passive tobacco exposure than their civilian counterparts, thereby increasing their risk for lung cancer.To compare differences in active and passive smoking exposure and lung cancer incidence among women Veterans and non-Veterans using prospective data from the Women's Health Initiative (WHI).We used data from the WHI, which collected longitudinal demographic, clinical, and laboratory data on 161,808 postmenopausal women. We employed linear and multinomial regression and generalized linear models to compare active and passive smoking exposure between Veterans and non-Veterans and Cox proportional hazards models to estimate differences in lung cancer incidence rates.After adjustment, Veterans had 2.54 additional pack years of smoking compared with non-Veterans (95% confidence interval [CI] 1.68, 3.40). Veterans also had a 1% increase in risk of any passive smoking exposure (95% CI 1.00, 1.02) and a 9% increase in risk of any workplace exposure (95% CI 1.07, 1.11) compared with non-Veterans. After adjustment for age and smoking exposures, Veterans did not have a higher risk of lung cancer compared with non-Veterans (relative risk = 1.06 95% CI 0.86, 1.30).Women Veterans had higher rates of tobacco use and exposure to passive smoking, which were associated with a higher risk for lung cancer compared with non-Veterans. Clinicians who care for Veterans need to be aware that older women Veterans have more exposures to risk factors for lung cancer.

  View details for DOI 10.1093/geront/gnv664

  View details for PubMedID 26768384

• Resistance to Therapy. Cancer treatment and research Rivera, G., Wakelee, H. A. 2016; 170: 183-202

  Abstract

  Identification of driver mutations in adenocarcinoma of the lung has revolutionized the treatment of this disease. It is now standard of care to look for activating mutations in epidermal growth factor receptor (EGFR), and translocations in anaplastic lymphoma kinase (ALK) or ROS1 in all newly diagnosed adenocarcinoma of the lung, and in many patients with squamous cell carcinoma as well. Recognition of multiple other lung cancer driver mutations has also expanded treatment options. Targeted treatments of these mutations lead to rapid and prolonged responses, but resistance inevitably develops. Until recently, traditional chemotherapy was the only alternative at that time, but better understanding of resistance mechanisms has lead to additional therapeutic options. These mechanisms of resistance and treatments are the focus of this chapter. Understanding of mechanisms of chemotherapy resistance is touched upon, along with a brief discussion of immune checkpoint inhibitors.

  View details for DOI 10.1007/978-3-319-40389-2_9

  View details for PubMedID 27535395

• Efficacy of Rociletinib (CO-1686) in Centrally Confirmed T790M-positive and T790M-negative Non-small Cell Lung Cancer (NSCLC) Patients (Pts) Sequist, L. V., Goldman, J. W., Wakelee, H., Camidge, D. R., Gadgeel, S., Yu, H. A., Varga, A., Solomon, B., Oxnard, G. R., Ou, S. I., Papadimitrakopoulou, V., Liu, S. V., Reckamp, K. L., Spira, A. I., Despain, D., Karlovich, C. A., Yurasov, S., Soria, J. KARGER. 2016: 121

  View details for Web of Science ID 000371353700392

• Association of non-melanoma skin cancer with second non-cutaneous malignancy in the Women's Health Initiative. The British journal of dermatology Ransohoff, K. J., Stefanick, M. L., Li, S., Kurian, A. W., Wakelee, H., Wang, A., Paskett, E., Han, J., Tang, J. Y. 2016

  Abstract

  Non-melanoma skin cancer (NMSC), the most prevalent cancer in the US,(1) has been associated with increased risk of non-cutaneous malignancies, including breast cancer, lung cancer, and lymphoma. (2-7) In the Women's Health Initiative (WHI) Observational Study (OS), women with NMSC history at baseline were more likely to report history of another cancer (Odds ratio [OR] = 2.3, 95% CI = 2.18 -2.44.(6) Subsequently, Nurses Health Study (NHS) prospective analyses found increased risk of developing breast cancer, lung cancer, and melanoma in women with NMSC.(7) We sought to replicate these prospective findings in the large WHI cohort, for which important potential confounders, e.g. smoking and body mass index, and rich phenotypic data are available. This article is protected by copyright. All rights reserved.

  View details for PubMedID 27229371

• Estrogen Plus Progestin and Lung Cancer: Follow-up of the Women's Health Initiative Randomized Trial CLINICAL LUNG CANCER Chlebowski, R. T., Wakelee, H., Pettinger, M., Rohan, T., Liu, J., Simon, M., Tindle, H., Messina, C., Johnson, K., Schwartz, A., Gass, M., Wactawski-Wende, J. 2016; 17 (1): 10-?

  Abstract

  In the Women's Health Initiative (WHI) estrogen plus progestin trial, after 5.6 years' intervention and 8 years' median follow-up, more women died from lung cancer in the hormone therapy group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.16-2.52; P = .01). Now after 14 years' median follow-up, we reexamined combined hormone therapy effects on lung cancer mortality.In the WHI placebo-controlled trial, 16,608 postmenopausal women aged 50 to 79 years and with an intact uterus were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Incidence and mortality rates for lung cancer were assessed from multivariant proportional hazard models.After 14 years' cumulative follow-up, there were 219 lung cancers (0.19% per year) in the estrogen plus progestin group and 184 (0.17%) in the placebo group (HR, 1.12; 95% CI, 0.92-1.37; P = .24). While there were more deaths from lung cancer with combined hormone therapy (153 [0.13%] vs. 132 [0.12%], respectively), the difference was not statistically significant (HR, 1.09; 95% CI, 0.87-1.38; P = .45). The statistically significant increase in deaths from lung cancer observed during intervention in women assigned to estrogen plus progestin was attenuated after discontinuation of study pills (linear trend over time, P = .042).The increased risk of death from lung cancer observed during estrogen plus progestin use was attenuated after discontinuation of combined hormone therapy.

  View details for DOI 10.1016/j.cllc.2015.09.004

  View details for Web of Science ID 000367538900002

• Survival among Never-Smokers with Lung Cancer in the Cancer Care Outcomes Research and Surveillance Study. Annals of the American Thoracic Society Clément-Duchêne, C., Stock, S., Xu, X., Chang, E. T., Gomez, S. L., West, D. W., Wakelee, H. A., Gould, M. K. 2016; 13 (1): 58-66

  Abstract

  Differences in patient characteristics and outcomes have been observed among current, former, and never-smokers with lung cancer, but most prior studies included few never-smokers and were not prospective.We used data from a large, prospective study of lung cancer care and outcomes in the United States to compare characteristics of never-smokers and smokers with lung cancer and to examine survival among the never-smokers.Smoking status at diagnosis was determined by self-report and survival was determined from medical records and cancer registries, with follow-up through June 2010 or later. Cox regression was used to examine the association between smoking and survival, and to identify predictors of survival among never-smokers.Among 3,410 patients with lung cancer diagnosed between September 1, 2003 and October 14, 2005 who completed a baseline patient survey, there were 274 never-smokers (8%), 1,612 former smokers (47%), 1,496 current smokers or smokers who quit recently (44%), and 28 with missing information about smoking status (<1%). Never-smokers appeared more likely than former and current/recent smokers to be female and of Asian or Hispanic race/ethnicity, and to have adenocarcinoma histology, fewer comorbidities, private insurance, and higher income and education. Compared with never-smokers, the adjusted hazard of death from any cause was 29% higher among former smokers (hazard ratio, 1.29; 95% confidence interval, 1.08-1.55), and 39% higher among current/recent smokers (hazard ratio, 1.39; 95% confidence interval, 1.16-1.67). Factors predicting worse overall survival among never-smokers included Hispanic ethnicity, severe comorbidity, undifferentiated histology, and regional or distant stage. Never-smoking Hispanics appeared more likely to have regional or advanced disease at diagnosis and less likely to undergo surgical resection, although these differences were not statistically significant.Never-smokers with lung cancer are more likely than ever-smokers to be female, Asian or Hispanic, and more advantaged socioeconomically, suggesting possible etiologic differences in lung cancer by smoking status. Among never-smokers, Hispanics with lung cancer had worse survival than non-Hispanic whites.

  View details for DOI 10.1513/AnnalsATS.201504-241OC

  View details for PubMedID 26730864

• Lung Cancer in Never Smokers. Advances in experimental medicine and biology Rivera, G. A., Wakelee, H. 2016; 893: 43-57

  Abstract

  Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000-26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.

  View details for DOI 10.1007/978-3-319-24223-1_3

  View details for PubMedID 26667338

• Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions EXPERT OPINION ON PHARMACOTHERAPY Chuang, J. C., Salahudeen, A. A., Wakelee, H. A. 2016; 17 (7): 989-993

  Abstract

  Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms.EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression on rociletinib, and future directions.It is important to note that there are other 3(rd) generation EGFR TKIs with activity against T790M already approved by the US FDA (osimertinib) and many others in development. Future research will focus on figuring out which patients can benefit the most from a particular medication with minimal side effects, and further resistance mechanisms after rociletinib.

  View details for DOI 10.1517/14656566.2016.1162786

  View details for PubMedID 26950414

• Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens JOURNAL OF THORACIC ONCOLOGY Paz-Ares, L., Hirsh, V., Zhang, L., De Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y., Novello, S., Juhasz, E., Aren, O., Sun, Y., Schmelter, T., Ong, T. J., Pena, C., Smit, E. F., Mok, T. S. 2015; 10 (12): 1745-1753

  Abstract

  Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

  View details for DOI 10.1097/JTO.0000000000000693

  View details for Web of Science ID 000365575100015

• MISSION Trial - A phase III, multi-center, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly non-squamous NSCLC after 2 or 3 previous treatment regimens. Journal of thoracic oncology Paz-Ares, L., Hirsh, V., Zhang, L., De Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y., Novello, S., Juhász, E., Arén, O., Sun, Y., Schmelter, T., Ong, T. J., Peña, C., Smit, E. F., Mok, T. S. 2015: -?

  Abstract

  Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled MISSION trial randomized patients with advanced relapsed/refractory NSCLC, following 2 or 3 prior treatment regimens, to sorafenib 400 mg bid (n=353) or matching placebo (n=353) plus best supportive care. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and time-to-progression (TTP). EGFR and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Median PFS (2.8 versus 1.4 mo; HR 0.61; 95% CI 0.51-0.72, p<0.0001) and TTP (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with EGFR mutations, OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

  View details for PubMedID 26551592

• Pruritus as a Paraneoplastic Symptom of Thymoma JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Shrager, J. B., Riess, J. W., Pagtama, J. Y., Tisch, A. J., Kwong, B. Y., Liang, Y., Schwartz, E. J., Loo, B. W., Neal, J. W., Hardy, R., Wakelee, H. A. 2015; 10 (11): E110-E112

  View details for DOI 10.1097/JTO.0000000000000623

  View details for PubMedID 26536199

• Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose-Escalation Trial Modlin, L. A., Choi, C. H., Gibbs, I. C., Wakelee, H. A., Neal, J., Pinder-Schenck, M. C., Chang, S. D., Adler, J. R., Harsh, G. R., Soltys, S. G. ELSEVIER SCIENCE INC. 2015: S178

  View details for DOI 10.1016/j.ijrobp.2015.07.425

  View details for Web of Science ID 000373215302104

• Adjuvant therapy for EGFR mutant and ALK positive NSCLC: Current data and future prospects. Lung cancer Chuang, J. C., Neal, J. W., Niu, X., Wakelee, H. A. 2015; 90 (1): 1-7

  Abstract

  Tyrosine kinase inhibitors (TKIs) against targetable mutations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are highly effective in treating advanced stage lung cancers harboring such mutations. Questions remain, however, about whether these agents can improve cure rates for early stage lung cancers in the adjuvant setting. Here, we examine the current data and ongoing trials addressing this issue.

  View details for DOI 10.1016/j.lungcan.2015.07.016

  View details for PubMedID 26275476

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

  Abstract

  To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.Retrospective observational case series.Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG).Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction LUNG CANCER Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280-286

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for DOI 10.1016/j.lungcan.2015.06.011

  View details for Web of Science ID 000360513200010

• Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 Wakelee, H. A., Dahlberg, S. E., Keller, S. M., Tester, W. J., Gandara, D. R., Graziano, S. L., Adjei, A., Leighl, N., Aisner, S. C., Rothman, J. M., Patel, J., Sborov, M. D., Mcdermott, S. R., Perez-Soler, R., Traynor, A. M., Butts, C., Evans, T., Horn, L., Ramalingam, S. S., Schiller, J. ELSEVIER SCIENCE INC. 2015: S796

  View details for Web of Science ID 000370365103677

• Rociletinib treatment and outcomes in non-small cell lung cancer (NSCLC) patients with negative central testing for T790M Solomon, B., Wakelee, H., Sequist, L. V., Gadgeel, S., Soria, J. C., Goldman, J. W., Yu, H., Camidge, D. R., Papadimitrakopoulou, V., Matheny, S., Despain, D., Besse, B. ELSEVIER SCI LTD. 2015: S636

  View details for DOI 10.1016/S0959-8049(16)31745-2

  View details for Web of Science ID 000361887403062

• Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X Wakelee, H. A., Sequist, L. V., Gadgeel, S., Soria, J., Goldman, J. W., Yu, H., Camidge, D. R., Solomon, B. J., Matheny, S., Despain, D., Papadimitrakopoulou, V. ELSEVIER SCIENCE INC. 2015: S271?S272

  View details for Web of Science ID 000370365101030

• Activity of rociletinib in EGFR mutant NSCLC patients with a history of CNS involvement Varga, A., Camidge, D. R., Sequist, L. V., Wakelee, H., Ou, S. H., Goldman, J. W., Papadimitrakopoulou, V., Gadgeel, S., Mekhail, T., Oxnard, G. R., Socinski, M., Solomon, B., Yu, H., Matheny, S., Despain, D., Soria, J. C. ELSEVIER SCI LTD. 2015: S598

  View details for DOI 10.1016/S0959-8049(16)31654-9

  View details for Web of Science ID 000361887402546

• Dose Optimization of Rociletinib for EGFR Mutated NSCLC Goldman, J. W., Wakelee, H. A., Gadgeel, S., Camidge, D. R., Solomon, B. J., Yu, H., Oxnard, G. R., Ou, S., Papadimitrakopoulou, V., Perol, M., Reckamp, K., Soria, J., Varga, A., Dziadziuszko, R., Despain, D., Matheny, S., Sequist, L. V. ELSEVIER SCIENCE INC. 2015: S318?S319

  View details for Web of Science ID 000370365101174

• Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement Camidge, D. R., Sequist, L. V., Soria, J., Wakelee, H. A., Ou, S., Goldman, J. W., Papadimitrakopoulou, V., Gadgeel, S., Mekhail, T., Oxnard, G. R., Socisnki, M. A., Solomon, B. J., Varga, A., Matheny, S., Despain, D., Yu, H. ELSEVIER SCIENCE INC. 2015: S319

  View details for Web of Science ID 000370365101175

• Efficacy of rociletinib (co-1686) in EGFR-mutant non-small cell lung cancer (NSCLC) patients (pts) assessed with a plasma EGFR test Gadgeel, S., Soria, J. C., Goldman, J. W., Wakelee, H., Camidge, D. R., Yu, H., Varga, A., Solomon, B., Oxnard, G. R., Ou, S. H., Papadimitrakopoulou, V., Liu, S. V., Reckamp, K., Spira, A., Piotrowska, Z., Despain, D., Karlovich, C., Yurasov, S., Sequist, L. V. ELSEVIER SCI LTD. 2015: S628

  View details for DOI 10.1016/S0959-8049(16)31729-4

  View details for Web of Science ID 000361887403046

• Ceritinib in ALK plus NSCLC Metastatic to Brain and/or Leptomeninges: The ASCEND-7 Study Chow, L. Q., Barlesi, F., Bertino, E. M., Kim, D., Van Den Bent, M. J., Wakelee, H. A., Wen, P. Y., Arratia, P., Shen, J., Branle, F. ELSEVIER SCIENCE INC. 2015: S550?S551

  View details for Web of Science ID 000370365102484

• Dose optimization of rociletinib for EGFR mutated NSCLC: Benefit/risk analysis from the TIGER-X trial Soria, J. C., Goldman, J. W., Wakelee, H., Gadgeel, S., Camidge, D. R., Solomon, B., Yu, H., Oxnard, G. R., Ou, S. H., Papadimitrakopoulou, V., Perol, M., Reckamp, K., Varga, A., Dziadziuszko, R., Chouaid, C., Cortot, A., Do, P., Moro-Sibilot, D., Poudenx, M., Sequist, L. V. ELSEVIER SCI LTD. 2015: S637

  View details for DOI 10.1016/S0959-8049(16)31746-4

  View details for Web of Science ID 000361887403063

• Symptoms and QOL with Ceritinib in ALK plus NSCLC Patients with/without Brain Metastases Crino, L., Ahn, M., De Marinis, F., Groen, H. M., Wakelee, H. A., Hida, T., Mok, T., Shaw, A., Felip, E., Nishio, M., Scagliotti, G. V., Branle, F., Emeremni, C., Sutradhar, S., Quadrigli, M., Zhang, J., Spigel, D. ELSEVIER SCIENCE INC. 2015: S379

  View details for Web of Science ID 000370365101353

• TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC Yang, J., Popat, S., Bazhenova, L., Blakely, C. M., Dichman, R., Felip, E., Griesinger, F., Groen, H. M., Gurubhagavatula, S., Leach, J. W., Novello, S., Perol, M., Patel, R., Reckamp, K., Georgiou, P., Miyamoto, E., Isaacson, J., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S430

  View details for Web of Science ID 000370365102086

• Lung Cancer Incidence by Histology, Gender, Race/Ethnicity and Socioeconomic Status Patel, M. I., Mckinley, M., Cheng, I., Wakelee, H. A., Gomez, S. ELSEVIER SCIENCE INC. 2015: S460?S461

  View details for Web of Science ID 000370365102182

• An Update on Clinical Trials: Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC? Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S94?S95

  View details for Web of Science ID 000370365100061

• A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 Neal, J. W., Dahlberg, S. E., Wakelee, H. A., Aisner, S. C., Bowden, M., Carbone, D. P., Ramalingam, S. S. ELSEVIER SCIENCE INC. 2015: S373

  View details for Web of Science ID 000370365101334

• Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies Wakelee, H. A., Padda, S. K., Burns, M., Spittler, A. J., Riess, J. W., San Pedro-Salcedo, M., Ramchandran, K. J., Gubens, M. A., Neal, J. W., Loehrer, P. J. ELSEVIER SCIENCE INC. 2015: S195

  View details for Web of Science ID 000370365100271

• VeriStrat (R) and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib plus /- Erlotinib in Non-Small Cell Lung Cancer Padda, S. K., Lara, P., Gettinger, S. N., Engelman, J. A., Jaenne, P. A., West, H., Zhou, L. Y., Subramaniam, D. S., Leach, J. W., Wax, M. B., Neal, J. W., Clary, D. O., Goodman, L. J., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S291

  View details for Web of Science ID 000370365101080

• Case Series of HER2 Mutated Metastatic Lung Adenocarcinoma and Response to HER2 Targeted Therapies Chuang, J., Neal, J. W., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S549

  View details for Web of Science ID 000370365102479

• Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma Padda, S. K., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Berry, M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S196

  View details for Web of Science ID 000370365100273

• Overcoming Resistance Without the Risk of Reaction: Use of Afatinib and Panitumumab in Two Cases of Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer With T790M Mutations CLINICAL LUNG CANCER Castellanos, E. H., Rivera, G., Wakelee, H., Horn, L. 2015; 16 (5): E97-E99

  View details for DOI 10.1016/j.cllc.2015.02.005

  View details for PubMedID 25842367

• Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Liang, Y., Wakelee, H. A., Neal, J. W. 2015; 16 (5): 366-373

  Abstract

  Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.

  View details for DOI 10.1016/j.cllc.2014.12.009

  View details for Web of Science ID 000360182100017

  View details for PubMedCentralID PMC4490141

• Incidence Trends of Lung Cancer by Immigration Status among Chinese Americans CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gomez, S. L., Yang, J., Lin, S., McCusker, M., Sandler, A., Cheng, I., Wakelee, H. A., Patel, M., Clarke, C. A. 2015; 24 (8): 1157-1164

  Abstract

  Lung cancer is the leading cause of cancer-related death among Chinese Americans. A detailed examination of incidence trends by immigration status and histology may inform the etiology of lung cancer in this growing population.California Cancer Registry data were enhanced with data on patient nativity. Lung cancer incidence rates for Chinese males and females were computed for the years 1990-2010, and rates by immigration status and histology were computed for 1990-2004. Trends were assessed with annual percentage change (APC) statistics (two-sided P values) based on linear regression.A total of 8,167 lung cancers were diagnosed among California Chinese from 1990 to 2010. Overall incidence increased nonstatistically among U.S.-born males (APC, 2.1; 95% CI, -4.9 to 9.7), but decreased significantly among foreign-born (APC, -1.7; 95% CI, -2.9 to -0.6). Statistically significant decreasing trends were observed for non-small cell lung cancer (NSCLC), specifically the squamous cell and large cell carcinoma subtypes among foreign-born males. Among females, incidence decreased nonsignificantly among U.S.-born (APC, -2.8; 95% CI, -9.1 to 4.0) but was stable among foreign-born (APC, -0.4; 95% CI, -1.7 to 1.0). A statistically significant decreasing trend was observed for squamous cell among foreign-born females.These data provide critical evidence base to inform screening, research, and public health priorities in this growing population.Given the low smoking prevalence among Chinese Americans, especially females, and few known lung cancer risk factors in U.S. never-smoker populations, additional research of etiologic genetic or biologic factors may elucidate knowledge regarding lung cancer diagnosed in never smokers. Cancer Epidemiol Biomarkers Prev; 24(8); 1157-64. ©2015 AACR.

  View details for DOI 10.1158/1055-9965.EPI-15-0123

  View details for Web of Science ID 000359320500002

  View details for PubMedID 25990553

• COPD and risk of lung cancer in post-menopausal women: findings from the Women's Health Initiative Cote, M. L., Lehman, A., Chlebowski, R., Haynes, B., Ho, G., Patel, M., Sakoda, L., Simon, M., Wakelee, H., Schwartz, A. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-835

  View details for Web of Science ID 000371578501288

• Pretreatment and serial plasma assessments of EGFR mutations in NSCLC patients treated with rociletinib (CO-1686) Goldman, J. W., Karlovich, C., Mann, E., Rolfe, L., Matheny, S., Despain, D., Angenendt, P., Stamm, C., Wakelee, H. A., Soria, J., Solomon, B., Camidge, D. R., Dziadziuszko, R., Horn, L., Gadgeel, S., Raponi, M., Allen, A. R., Sequist, L. V. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-927

  View details for Web of Science ID 000371578501378

• Treatment, overall survival, and costs in patients with ALK-positive non-small-cell lung cancer after crizotinib monotherapy CURRENT MEDICAL RESEARCH AND OPINION Guerin, A., Sasane, M., Wakelee, H., Zhang, J., Culver, K., Dea, K., Nitulescu, R., Galebach, P., Macalalad, A. R. 2015; 31 (8): 1587-1597

  Abstract

  Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden.To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation.This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population.A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P?=?0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P?

  View details for DOI 10.1185/03007995.2015.1057115

  View details for Web of Science ID 000361264300016

  View details for PubMedID 26029864

• Hormone Use, Reproductive History, and Risk of Lung Cancer The Women's Health Initiative Studies JOURNAL OF THORACIC ONCOLOGY Schwartz, A. G., Ray, R. M., Cote, M. L., Abrams, J., Sokol, R. J., Hendrix, S. L., Chen, C., Chlebowski, R. T., Hubbell, F. A., Kooperberg, C., Manson, J. E., O'Sullivan, M. J., Rohan, T., Stefanick, M. L., Wactawski-Wende, J., Wakelee, H., Simon, M. S. 2015; 10 (7): 1004-1013

  Abstract

  Results from the Women's Health Initiative clinical trials demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy (HT). We conducted a joint analysis of the Women's Health Initiative observational study data and clinical trials data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk.Reproductive history, oral contraceptive use, and postmenopausal HT were evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2467 incident lung cancer cases were ascertained, with median follow-up of 14 years.For all lung cancers, women with previous use of estrogen plus progestin of less than 5 years (hazard ratio = 0.84; 95% confidence interval = 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend toward decreased risk with increasing age at menopause (ptrend = 0.04) and a trend toward increased risk with increasing number of live births (ptrend = 0.03). Reduced risk of non-small-cell lung cancer was associated with age 20-29 years at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy.Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with estrogen receptor expression in the lung should continue as a role for estrogen cannot be ruled out and may hold potential for prevention and treatment strategies.

  View details for DOI 10.1097/JTO.0000000000000558

  View details for PubMedID 25852020

• Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer discovery Piotrowska, Z., Niederst, M. J., Karlovich, C. A., Wakelee, H. A., Neal, J. W., Mino-Kenudson, M., Fulton, L., Hata, A. N., Lockerman, E. L., Kalsy, A., Digumarthy, S., Muzikansky, A., Raponi, M., Garcia, A. R., Mulvey, H. E., Parks, M. K., DiCecca, R. H., Dias-Santagata, D., Iafrate, A. J., Shaw, A. T., Allen, A. R., Engelman, J. A., Sequist, L. V. 2015; 5 (7): 713-722

  Abstract

  Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required.This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713-22. ©2015 AACR.See related commentary by Ichihara and Lovly, p. 694.This article is highlighted in the In This Issue feature, p. 681.

  View details for DOI 10.1158/2159-8290.CD-15-0399

  View details for PubMedID 25934077

• A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies LUNG CANCER Gubens, M. A., Burns, M., Perkins, S. M., Pedro-Salcedo, M. S., Althouse, S. K., Loehrer, P. J., Wakelee, H. A. 2015; 89 (1): 57-60

  Abstract

  Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy.Patients with unresectable thymic malignancy were treated with saracatinib 175mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%.21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated.Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population (NCT00718809).

  View details for DOI 10.1016/j.lungcan.2015.04.008

  View details for PubMedID 26009269

• ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer CANCER EPIDEMIOLOGY Guerin, A., Sasane, M., Zhang, J., Macalalad, A. R., Galebach, P., Jarvis, J., Kageleiry, A., Culver, K., Wu, E. Q., Wakelee, H. 2015; 39 (3): 307-312

  Abstract

  Approximately 2-8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists' experience with ALK testing in the US.US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing.27 oncologists provided data on 273 ALK+ NSCLC patients. Patients' median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers.In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics.

  View details for DOI 10.1016/j.canep.2015.04.005

  View details for PubMedID 25914136

• Cabozantinib (C), erlotinib (E) or the combination (E plus C) as second-or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCLC): A randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512). Neal, J. W., Dahlberg, S., Wakelee, H. A., Aisner, S. C., Bowden, M., Carbone, D., Ramalingam, S. S. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901716

• Recreational activity and sedentary behavior in relation to lung cancer incidence and mortality in the Women's Health Initiative Wang, A., Qin, F., Hedlin, H., Desai, M., Chlebowski, R. T., Gomez, S., Eaton, C., Johnson, K., Qi, L., Wactawski-Wende, J., Womack, C., Wakelee, H. A., Stefanick, M. L. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036900386

• Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). Sequist, L. V., Goldman, J., Wakelee, H. A., Camidge, D., Yu, H., Varga, A., Solomon, B., Oxnard, G. R., Ou, S., Papadimitrakopoulou, V., Chao, B. H., Liu, S. V., Reckamp, K. L., Spira, A. I., Piotrowska, Z., Despain, D., Karlovich, C., Yurasov, S., Soria, J. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901714

• ASCEND-2: A single-arm, open-label, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged (ALK plus ) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ). Mok, T., Spigel, D., Felip, E., deMarinis, F., Ahn, M., Groen, H. M., Wakelee, H. A., Hida, T., Crino, L., Nishio, M., Scagliotti, G. V., Branle, F., Emeremni, C., Quadrigli, M., Zhang, J., Shaw, A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901771

• TIGER-3: A phase 3, open-label, randomized study of rociletinib vs cytotoxic chemotherapy in patients (pts) with mutant EGFR non-small cell lung cancer (NSCLC) progressing on prior EGFR TKI therapy and doublet chemotherapy. Yang, J., Popat, S., Georgiou, P., Miyamoto, E., Isaacson, J. D., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904858

• Statin use and all-cancer mortality: Prospective results from the Women's Health Initiative Wang, A., Aragaki, A. K., Tang, J. Y., Kurian, A. W., Manson, J. E., Chlebowski, R. T., Simon, M. S., Desai, P. M., Wassertheil-Smoller, S., Liu, S., Kritchevsky, S., Wakelee, H. A., Stefanick, M. L. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036900373

• Phase II trial of single agent amrubicin (A) in patients (pts) with previously treated advanced thymic malignancies (TM). Wakelee, H. A., Padda, S., Burns, M., Spittler, A., Riess, J., San Pedro-Salcedo, M., Ramchandran, K., Gubens, M. A., Neal, J. W., Loehrer, P. J. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901710

• Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer NEW ENGLAND JOURNAL OF MEDICINE Sequist, L. V., Soria, J., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., SOLOMON, B. J., Oxnard, G. R., Dziadziuszko, R., Aisner, D. L., Doebele, R. C., Galasso, C., Garon, E. B., Heist, R. S., Logan, J., Neal, J. W., Mendenhall, M. A., Nichols, S., Piotrowska, Z., Wozniak, A. J., Raponi, M., Karlovich, C. A., Jaw-Tsai, S., Isaacson, J., Despain, D., Matheny, S. L., Rolfe, L., Allen, A. R., Camidge, D. R. 2015; 372 (18): 1700-1709

  Abstract

  Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

  View details for DOI 10.1056/NEJMoa1413654

  View details for PubMedID 25923550

• GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

  Abstract

  Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

  View details for PubMedID 25667444

• GLI1, CTNNB1 and NOTCH1 Protein Expression in a Thymic Epithelial Malignancy Tissue Microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

  Abstract

  Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

  View details for PubMedID 25667444

• Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer Liang, Y., Padda, S. K., Riess, J. W., West, R. B., Neal, J. W., Wakelee, H. A. 2015; 87 (1): 34-38

  Abstract

  Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies.Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis.A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months).This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases.

  View details for DOI 10.1016/j.lungcan.2014.11.006

  View details for PubMedID 25443273

• Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non--Small-Cell Lung Cancer. Clinical lung cancer Liang, Y., Wakelee, H. A., Neal, J. W. 2015; 16 (5): 366?73

  Abstract

  Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.

  View details for PubMedID 25665893

• Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Paz-Ares, L., Hirsh, V., Zhang, L., de Marinis, F., Yang, J. C., Wakelee, H. A., Seto, T., Wu, Y. L., Novello, S., Juhász, E., Arén, O., Sun, Y., Schmelter, T., Ong, T. J., Peña, C., Smit, E. F., Mok, T. S. 2015; 10 (12): 1745?53

  Abstract

  Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

  View details for PubMedID 26743856

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction. Lung cancer (Amsterdam, Netherlands) Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280?86

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for PubMedID 26149476

• Novel Treatments for Thymoma and Thymic Carcinoma. Frontiers in oncology Rajan, A., Wakelee, H., Giaccone, G. 2015; 5: 267-?

  View details for DOI 10.3389/fonc.2015.00267

  View details for PubMedID 26649279

• Are Patients With Thoracic Malignancies at Risk for Uncontrolled Symptoms? Journal of oncology practice / American Society of Clinical Oncology Patel, M. I., Williams, D. C., Wohlforth, C., Fisher, G., Wakelee, H. A., Blayney, D. W. 2015; 11 (1): e98-e102

  Abstract

  Patients with cancer often develop symptoms and contact their oncologists and care teams after normal clinic operating hours. Better understanding of these after-hours telephone calls can inform efforts to improve cancer care and to reduce health care spending. We sought to evaluate after-hours calls at Stanford Cancer Institute (SCI) Thoracic Oncology Clinic.We retrospectively analyzed content of telephone call notes made to SCI during weekends and from 5 pm to 8 am on weekdays. Chief complaint, caller and patient demographics, patient diagnosis, advice given, and disposition were analyzed. ?(2) tests were used to analyze differences in proportions.There were a total of 263 after-hours telephone calls during the 6 months of the study. After exclusions, there were 241 telephone calls for analysis. The majority of calls occurred between 5 pm to 11 pm (n = 175 [73%]; P < .001), followed by daytime calls on weekends (n = 157 [65%]; P < .001). Common symptoms were cough (28%) and dyspnea (27%). Of the calls, 62% (150 patients) resulted in emergency department (ED) referral, and 77% of patients (115 of 150) evaluated in the ED were admitted to the hospital.Most after-hours telephone calls from patients with lung cancer are related to symptoms. Many patients were referred to the ED and subsequently required hospitalization. Analysis of call content and prior events leading to after-hours calls may predict hospital admissions in this group of patients and can inform development of proactive interventions to improve quality of care and patient-centered outcomes.

  View details for DOI 10.1200/JOP.2014.001502

  View details for PubMedID 25271246

• Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative Observational Study prospective cohort?. Annals of oncology Wang, A., Kubo, J., Luo, J., Desai, M., Hedlin, H., Henderson, M., Chlebowski, R., Tindle, H., Chen, C., Gomez, S., Manson, J. E., Schwartz, A. G., Wactawski-Wende, J., Cote, M., Patel, M. I., Stefanick, M. L., Wakelee, H. A. 2015; 26 (1): 221-230

  Abstract

  Lung cancer is the leading cause of worldwide cancer deaths. While smoking is its leading risk factor, few prospective cohort studies have reported on the association of lung cancer with both active and passive smoking. This study aimed to determine the relationship between lung cancer incidence with both active and passive smoking (childhood, adult at home, and at work).The Women's Health Initiative Observational Study (WHI-OS) was a prospective cohort study conducted at 40 US centers that enrolled postmenopausal women from 1993 to 1999. Among 93 676 multiethnic participants aged 50-79, 76 304 women with complete smoking and covariate data comprised the analytic cohort. Lung cancer incidence was calculated by Cox proportional hazards models, stratified by smoking status.Over 10.5 mean follow-up years, 901 lung cancer cases were identified. Compared with never smokers (NS), lung cancer incidence was much higher in current [hazard ratio (HR) 13.44, 95% confidence interval (CI) 10.80-16.75] and former smokers (FS; HR 4.20, 95% CI 3.48-5.08) in a dose-dependent manner. Current and FS had significantly increased risk for all lung cancer subtypes, particularly small-cell and squamous cell carcinoma. Among NS, any passive smoking exposure did not significantly increase lung cancer risk (HR 0.88, 95% CI 0.52-1.49). However, risk tended to be increased in NS with adult home passive smoking exposure ?30 years, compared with NS with no adult home exposure (HR 1.61, 95% CI 1.00-2.58).In this prospective cohort of postmenopausal women, active smoking significantly increased risk of all lung cancer subtypes; current smokers had significantly increased risk compared with FS. Among NS, prolonged passive adult home exposure tended to increase lung cancer risk. These data support continued need for smoking prevention and cessation interventions, passive smoking research, and further study of lung cancer risk factors in addition to smoking.NCT00000611.

  View details for DOI 10.1093/annonc/mdu470

  View details for PubMedID 25316260

• Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC. Translational lung cancer research Das, M., Wakelee, H. 2014; 3 (6): 397-399

  Abstract

  In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.

  View details for DOI 10.3978/j.issn.2218-6751.2014.09.05

  View details for PubMedID 25806332

• Ultrasensitive Detection of Circulating Tumor DNA in Non-Small Cell Lung Cancer by Deep Sequencing Diehn, M., Bratman, S. V., Newman, A. M., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. ELSEVIER SCIENCE INC. 2014: S75

  View details for DOI 10.1016/j.ijrobp.2014.08.315

  View details for Web of Science ID 000346413500167

• Racial/Ethnic Variations in Lung Cancer Incidence and Mortality, Adjusted for Smoking Behavior: Results From the Women's Health Initiative Patel, M. I., Wang, A., Kapphahn, K., Kubo, J., Desai, M., Chlebowski, R., Simon, M., Bird, C., Corbie-Smith, G., Gomez, S., Adams-Campbell, L., Cote, M., Stefanick, M., Wakelee, H. ELSEVIER SCIENCE INC. 2014: S56

  View details for DOI 10.1016/j.ijrobp.2014.08.263

  View details for Web of Science ID 000346413500122

• Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Nonsquamous Non-Small Cell Lung Cancer (nsNSCLC): Results From a Phase 2, Placebo-Controlled Study (GO27821) Wakelee, H. A., Zvirbule, Z., De Braud, F., Kingsley, C. D., Mekhail, T., Schuette, W., Lena, H., Lawler, W., Braiteh, F., Cosgriff, T., Kaen, D., Boyer, M., Hsu, J., Phan, S., Novello, S. ELSEVIER SCIENCE INC. 2014: S37?S38

  View details for DOI 10.1016/j.ijrobp.2014.08.216

  View details for Web of Science ID 000346413500079

• Description of ALK plus NSCLC Patient Characteristics and ALK Testing Patterns Wakelee, H. A., Sasane, M., Zhang, J., Macalalad, A. R., Galebach, P., Jarvis, J., Kageleiry, A., Huang, Q., Culver, K., Wu, E. Q., Guerin, A. ELSEVIER SCIENCE INC. 2014: S60?S61

  View details for DOI 10.1016/j.ijrobp.2014.08.276

  View details for Web of Science ID 000346413500132

• A Phase 1 Trial of X-396, a Novel ALK Inhibitor, in Patients With Advanced Solid Tumors Horn, L., Blumenscheine, G., Wakelee, H. A., Arkenau, T. H., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Lovly, C. M., Infante, J. R. ELSEVIER SCIENCE INC. 2014: S52?S53

  View details for DOI 10.1016/j.ijrobp.2014.08.251

  View details for Web of Science ID 000346413500112

• Randomized Phase 2 Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Single-Agent Chemotherapy in Previously Treated KRAS Mutant Advanced Non-Small Cell Lung Cancer (NSCLC) Gerber, D. E., Socinski, M. A., Neal, J. W., Wakelee, H. A., Shirai, K., Sequist, L. V., Rosovsky, R., Lilenbaum, R., Bastos, B. R., Huang, C., Johnson, M. L., Hasketh, P. J., Subramaniam, D. S., Chai, F., Kazakin, J., Schwartz, B. E., Schiller, J. H., Brahmer, J. R. ELSEVIER SCIENCE INC. 2014: S36

  View details for Web of Science ID 000346413500076

• Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990-2010 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cheng, I., Le, G. M., Noone, A., Gali, K., Patel, M., Haile, R. W., Wakelee, H. A., Gomez, S. L. 2014; 23 (11): 2250-2265

  Abstract

  Lung cancer is one of the leading cancer sites diagnosed among Asian Americans, Pacific Islanders, and Native Hawaiians (AANHPI). To better understand the patterns of lung cancer incidence among AANHPIs, we examined the incidence trends of five histologic cell types of lung cancer across ten AANHPI populations in comparison with non-Hispanic Whites.Lung cancer incidence data from 1990 through 2010 were obtained from 13 U.S. population-based cancer registries. Age-adjusted histologic cell-type-specific incidence rates and 95% confidence intervals were calculated. Joinpoint regression models and annual percentage change (APC) statistics were used to characterize the magnitude and direction of trends.From 1990 through 2010, incidence rates of adenocarcinoma increased significantly for Filipino and Korean women with a 2.6% and 3.0% annual percentage increase, respectively. More recently, a significant rise in the incidence of adenocarcinoma was observed for Chinese men (1996-2010; APC = 1.3%). Squamous cell carcinoma (SCC) increased 2.4% per year among Japanese women. For SCC, small cell lung carcinoma, large cell and other specified carcinoma, and unspecified types, stable or decreasing trends were observed in most AANHPI groups and non-Hispanic Whites.AANHPIs demonstrate a range in the burden of lung cancer across histologies and specific populations.These findings illustrate the importance of disaggregating AANHPIs into their specific populations. The rise in incidence of adenocarcinoma and SCC among certain AANHPIs demonstrates the need for research into non-tobacco associated risk factors for these populations and targeted efforts for tobacco prevention.

  View details for DOI 10.1158/1055-9965.EPI-14-0493

  View details for Web of Science ID 000345279600007

  View details for PubMedCentralID PMC5738466

• Interim phase 2 results of study CO-1686-008: A phase 1/2 study of the irreversible, mutant selective, EGFR inhibitor rociletinib (CO-1686) in patients with advanced non small cell lung cancer Soria, J., Sequist, L. V., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Yu, H. A., Solomon, B. J., Ou, S. H., Papadimitrakopoulou, V., Oxnard, G. R., Horn, L., Dziadziuszko, R., Chao, B., Spira, A. I., Liu, S., Mekhail, T., Matheny, S., Litten, J., Camidge, R. D. ELSEVIER SCI LTD. 2014: 199

  View details for DOI 10.1016/S0959-8049(14)70731-2

  View details for Web of Science ID 000347755700606

• Review of the current targeted therapies for non-small-cell lung cancer. World journal of clinical oncology Nguyen, K. H., Neal, J. W., Wakelee, H. 2014; 5 (4): 576-587

  Abstract

  The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

  View details for DOI 10.5306/wjco.v5.i4.576

  View details for PubMedID 25302162

• Review of the current targeted therapies for non-small-cell lung cancer WORLD JOURNAL OF CLINICAL ONCOLOGY Nguyen, K. H., Neal, J. W., Wakelee, H. 2014; 5 (4): 576?87

  View details for DOI 10.5306/wjco.v5.i4.576

  View details for Web of Science ID 000439080800003

• Development of the International Thymic Malignancy Interest Group International Database: An Unprecedented Resource for the Study of a Rare Group of Tumors JOURNAL OF THORACIC ONCOLOGY Huang, J., Ahmad, U., Antonicelli, A., Catlin, A. C., Fang, W., Gomez, D., Loehrer, P., Lucchi, M., Marom, E., Nicholson, A., Ruffini, E., Travis, W., Van Schil, P., Wakelee, H., Yao, X., Detterbeck, F. 2014; 9 (10): 1573-1578

  Abstract

  Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors.A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included.Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10-1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4-20.3) for thymoma, 6.8 years (95% CI, 5.5-7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5-8.5) for thymic carcinoid.The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors.

  View details for DOI 10.1097/JTO.0000000000000269

  View details for PubMedID 25521402

• Serial monitoring of EGFR mutations in plasma and evaluation of EGFR mutation status in matched tissue and plasma from NSCLC patients treated with CO-1686 Dziadziuszko, R., Karlovich, C., Wen, W., Sun, J., Chien, S., Mann, E., O'Donnell, P., Angenendt, P., Wakelee, H., Horn, L., Spigel, D., Sequist, L., Soria, J., Solomon, B., Camidge, D., Goldman, J., Gadgeel, S., Raponi, M., Allen, A., Wu, L., Park, K. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-5587

  View details for Web of Science ID 000349910205001

• Circulating Tumor DNA Concentrations Reflect Metabolic Tumor Volume in NSCLC Modlin, L. A., Bratman, S. V., Newman, A. M., Eclov, N. W., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2014: S812

  View details for DOI 10.1016/j.ijrobp.2014.05.2342

  View details for Web of Science ID 000342331403138

• PROGRAMMED DEATH RECEPTOR LIGAND-1 (PD-L1) EXPRESSION IN A THYMOMA TISSUE MICROARRAY (TMA) Padda, S., Riess, J. W., Schwartz, E., Tian, L., Kohrt, H., Neal, J. W., West, R., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S212

  View details for Web of Science ID 000344627500002

• PEMETREXED IN PATIENTS WITH THYMIC MALIGNANCIES PREVIOUSLY TREATED WITH CHEMOTHERAPY Liang, Y., Padda, S., Riess, J. W., West, R., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S226

  View details for Web of Science ID 000344627500020

• COMPUTED TOMOGRAPHY (CT) CHARACTERISTICS ASSOCIATED WITH MASAOKA-KOGA PATHOLOGIC STAGE IN THYMOMA Padda, S., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Hoang, C. D., Burt, B. M., Leung, A. N., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S222

  View details for Web of Science ID 000344627500014

• PRURITUS AS A PARANEOPLASTIC SYMPTOM OF THYMOMA Padda, S., Pagtama, J. Y., Tisch, A. H., Neal, J. W., Riess, J. W., Loo, B. W., Hardy, R., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S240?S241

  View details for Web of Science ID 000344627500044

• A multicenter randomized phase II trial of erlotinib with and without hydroxychloroquine (HCQ) in TKI-naive patients (pts) with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) Neal, J. W., Wakelee, H. A., Feliciano, J., Goldberg, S. B., Morgensztern, D., Das, M., Heist, R., Lennes, I., Muzikansky, A., Edelman, M. J., Gettinger, S. N., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204150

• Racial/ethnic variations in lung cancer incidence and mortality, adjusted for smoking behavior: Results from the Women's Health Initiative. Patel, M. I., Wang, A., Kapphahn, K., Kubo, J., Desai, M., Chlebowski, R. T., Simon, M. S., Bird, C. E., Corble-Smith, G., Gomez, S., Adams-Campbell, L. L., Cote, M. L., Stefanick, M. L., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613202580

• A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. Horn, L., Infante, J. R., Blumenschein, G. R., Wakelee, H. A., Arkenau, H., Dukart, G., Liang, C., Harrow, K., Gibbons, J., Lovly, C., Pao, W. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204095

• Description of ALK plus NSCLC patient characteristics and ALK testing patterns Wakelee, H. A., Sasane, M., Zhang, J., Macalalad, A. R., Galebach, P. J., Jarvis, J., Kageletry, A., Huang, Q., Culver, K. W., Wu, E., Guerin, A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204125

• A population-based study of incidence and survival trends of 1,261 thymic malignancies (TM): Results from the California Cancer Registry (CCR). Riess, J., Chen, Y., Lara, P., Wakelee, H. A., Gubens, M. A., Cress, R. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613202635

• First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M) Sequist, L. V., Soria, J., Gadgeel, S. M., Wakelee, H. A., Camidge, D., Varga, A., Solomon, B. J., Papadimitrakopoulou, V., Jaw-Tsai, S. S., Caunt, L., Kaur, P., Rolfe, L., Allen, A. R., Goldman, J. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204075

• Programmed death receptor ligand-1 (PD-L1) expression in a thymoma (T) tissue microarray (TMA) Padda, S., Riess, J., Schwartz, E., Tian, L., Kohrt, H., Neal, J. W., Natkunam, Y., West, R. B., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204064

• SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. Pennell, N. A., Neal, J. W., Chaft, J. E., Azzoli, C. G., Janne, P. A., Govindan, R., Evans, T. L., Costa, D., Rosovsky, R., Wakelee, H. A., Heist, R., Shaw, A., Temel, J. S., Shapiro, M. A., Muzikansky, A., Lanuti, M., Lynch, T., Kris, M. G., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613203950

• Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing. Bratman, S., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204749

• Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clinical lung cancer Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2014; 15 (3): 202-206

  Abstract

  Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.

  View details for DOI 10.1016/j.cllc.2013.12.009

  View details for PubMedID 24524822

• TREATMENT AND SURVIVAL PATTERNS AMONG ALK plus NSCLC PATIENTS FOLLOWING CRIZOTINIB DISCONTINUATION Guerin, A., Wakelee, H., Sasane, M., Zhang, J., Galebach, P., Jarvis, J., Kageleiry, A., Huang, Q., Culver, K., Wu, E. Q., Macalalad, A. R. ELSEVIER SCIENCE INC. 2014: A73

  View details for DOI 10.1016/j.jval.2014.03.428

  View details for Web of Science ID 000341082000398

• An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 548-554

  Abstract

  Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ?0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

  View details for DOI 10.1038/nm.3519

  View details for PubMedID 24705333

• An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage NATURE MEDICINE Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 552-558

  Abstract

  Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ?0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

  View details for DOI 10.1038/nm.3519

  View details for Web of Science ID 000335710700028

• Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients. Immunopharmacology and immunotoxicology Riess, J. W., Bhattacharya, N., Blenman, K. R., Neal, J. W., Hwang, G., Pultar, P., San-Pedro Salcedo, M., Engleman, E., Lee, P. P., Malik, R., Wakelee, H. A. 2014; 36 (2): 182-186

  Abstract

  Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.Talactoferrin was administered orally at 1.5?g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.

  View details for DOI 10.3109/08923973.2013.864671

  View details for PubMedID 24494587

• FIRST-IN-HUMAN EVALUATION OF CO-1686, AN IRREVERSIBLE, HIGHLY SELECTIVE TYROSINE KINASE INHIBITOR OF MUTATIONS OF EGFR (ACTIVATING AND T790M) Wakelee, H., Soria, J., Camidge, R., Gadgeel, S., Goldman, J., Varga, A., Solomon, B., Papadimitrakopoulou, V., Kaur, P., Sequist, L. V. LIPPINCOTT WILLIAMS & WILKINS. 2014: S38

  View details for Web of Science ID 000341688500093

• A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer. British journal of cancer Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Riess, J. W., Kuo, C. J., Liu, L., Gao, B., DiCioccio, A. T., Adjei, A. A., Wakelee, H. A. 2014; 110 (3): 602-608

  Abstract

  Background:This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).Methods:This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6?mg?kg(-1), pemetrexed 500?mg?m(-2), and cisplatin 75?mg?m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.Results:The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.Conclusion:Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

  View details for DOI 10.1038/bjc.2013.735

  View details for PubMedID 24292447

• Early-stage non-small cell lung cancer: surgery, stereotactic radiosurgery, and individualized adjuvant therapy. Seminars in oncology Padda, S. K., Burt, B. M., Trakul, N., Wakelee, H. A. 2014; 41 (1): 40-56

  Abstract

  Despite cures in early stage (IA-IIB) non-small cell lung cancer (NSCLC), the 5-year survival rate is only 36%-73%. Surgical resection via lobectomy is the treatment of choice in early-stage NSCLC, with the goal being complete anatomic resection of the tumor and mediastinal lymph node evaluation. Newer technologies, including the minimally invasive thoracoscopic approach and the many techniques available to stage the mediastinum, have introduced advantages over traditional approaches in achieving this goal. The advent of stereotactic ablative radiotherapy (SABR) has changed how we treat those patients who cannot undergo surgery secondary to comorbidities or patient preference. SABR allows for precise radiation delivery in a short course and at high doses. Adjuvant cisplatin-based chemotherapy is the standard of care for completely resected high-risk stage IB and stage II NSCLC based on a ~5% improvement in 5-year overall survival. The concept of customized adjuvant chemotherapy is emerging, and we will explore the potential value of targeting tumor mutations with available drugs (ie, epidermal growth factor receptor [EGFR] mutations with erlotinib), a strategy that for the moment should be restricted to clinical trials.

  View details for DOI 10.1053/j.seminoncol.2013.12.011

  View details for PubMedID 24565580

• [Chemotherapy definitions and policies for thymic malignancies]. Zhongguo fei ai za zhi = Chinese journal of lung cancer Girard, N., Lal, R., Wakelee, H., Riely, G. J., Loehrer, P. J. 2014; 17 (2): 116-121

  View details for DOI 10.3779/j.issn.1009-3419.2014.02.09

  View details for PubMedID 24581162

• 50 Years of progress in the systemic therapy of non-small cell lung cancer. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting Wakelee, H., Kelly, K., Edelman, M. J. 2014: 177?89

  Abstract

  Non-small cell lung cancer constitutes 85% to 90% of lung cancer and is the most common cause of cancer death. Over the past 50 years, substantial progress has been made in all aspects of lung cancer including screening, diagnostic evaluation, surgery, radiation therapy, and chemotherapy. This review focuses on the advances in systemic therapy during this half century.

  View details for PubMedID 24857075

• Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips LAB ON A CHIP Earhart, C. M., Hughes, C. E., Gaster, R. S., Ooi, C. C., Wilson, R. J., Zhou, L. Y., Humke, E. W., Xu, L., Wong, D. J., Willingham, S. B., Schwartz, E. J., Weissman, I. L., Jeffrey, S. S., Neal, J. W., Rohatgi, R., Wakeleebe, H. A., Wang, S. X. 2014; 14 (1): 78-88

  View details for DOI 10.1039/c3lc50580d

  View details for Web of Science ID 000327669000008

• Lung cancer incidence trends by histology type among Asian American, Native Hawaiian, and Pacific Islander populations in the United States, 1990-2010. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Cheng, I., Le, G. M., Noone, A. M., Gali, K., Patel, M., Haile, R. W., Wakelee, H. A., Gomez, S. L. 2014; 23 (11): 2250?65

  Abstract

  Lung cancer is one of the leading cancer sites diagnosed among Asian Americans, Pacific Islanders, and Native Hawaiians (AANHPI). To better understand the patterns of lung cancer incidence among AANHPIs, we examined the incidence trends of five histologic cell types of lung cancer across ten AANHPI populations in comparison with non-Hispanic Whites.Lung cancer incidence data from 1990 through 2010 were obtained from 13 U.S. population-based cancer registries. Age-adjusted histologic cell-type-specific incidence rates and 95% confidence intervals were calculated. Joinpoint regression models and annual percentage change (APC) statistics were used to characterize the magnitude and direction of trends.From 1990 through 2010, incidence rates of adenocarcinoma increased significantly for Filipino and Korean women with a 2.6% and 3.0% annual percentage increase, respectively. More recently, a significant rise in the incidence of adenocarcinoma was observed for Chinese men (1996-2010; APC = 1.3%). Squamous cell carcinoma (SCC) increased 2.4% per year among Japanese women. For SCC, small cell lung carcinoma, large cell and other specified carcinoma, and unspecified types, stable or decreasing trends were observed in most AANHPI groups and non-Hispanic Whites.AANHPIs demonstrate a range in the burden of lung cancer across histologies and specific populations.These findings illustrate the importance of disaggregating AANHPIs into their specific populations. The rise in incidence of adenocarcinoma and SCC among certain AANHPIs demonstrates the need for research into non-tobacco associated risk factors for these populations and targeted efforts for tobacco prevention.

  View details for PubMedID 25368400

• Commentary: highlights in NSCLC from the 15th World Conference on Lung Cancer. Clinical advances in hematology & oncology : H&O Wakelee, H. A. 2014; 12 Suppl 3 (1): 17?21

  View details for PubMedID 25856508

• Commentary: Highlights in NSCLC From the 15th World Conference on Lung Cancer CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY Wakelee, H. A. 2014; 12 (1): 17?21

  View details for PubMedID 24852399

• Anti-angiogenic Agents in Metastatic NSCLC LUNG CANCER,4TH EDITION Das, M., Wakelee, H., Roth, J. A., Hong, W. K., Komaki, R. U., Tsao, A. S., Chang, J. Y., Blackmon, S. H. 2014: 527?40

  View details for Web of Science ID 000354798900035

• Response. Chest Xu, Y., Zheng, M., Khuong, A., Merritt, R. E., Shrager, J. B., Wakelee, H. A., Kratzke, R. A., Hoang, C. D. 2013; 144 (6): 1971-1972

  View details for DOI 10.1378/chest.13-1931

  View details for PubMedID 24297135

• Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips. Lab on a chip Earhart, C. M., Hughes, C. E., Gaster, R. S., Ooi, C. C., Wilson, R. J., Zhou, L. Y., Humke, E. W., Xu, L., Wong, D. J., Willingham, S. B., Schwartz, E. J., Weissman, I. L., Jeffrey, S. S., Neal, J. W., Rohatgi, R., Wakelee, H. A., Wang, S. X. 2013; 14 (1): 78-88

  Abstract

  Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients.

  View details for DOI 10.1039/c3lc50580d

  View details for PubMedID 23969419

• miR-1 Induces Growth Arrest and Apoptosis in Malignant Mesothelioma CHEST Xu, Y., Zheng, M., Merritt, R. E., Shrager, J. B., Wakelee, H. A., Kratzke, R. A., Hoang, C. D. 2013; 144 (5): 1632-1643

  Abstract

  We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells.microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative PCR. Representative cell lines H513 and H2052 were used in functional analyses of microRNA-1.In addition to several novel MPM-associated microRNAs, we observed that the expression level of microRNA-1 was significantly lower in tumors as compared to normal pleural specimens. Subsequently, pre-mir of microRNA-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of microRNA-1. Early and late apoptosis was increased markedly in microRNA-1-transfected cell lines. Taken together, these data suggested that overexpression of microRNA-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related genes, pro-apoptotic and anti-apoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype.Thus, further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/ or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found microRNA-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance.

  View details for DOI 10.1378/chest.12-2770

  View details for PubMedID 23828229

• Serial monitoring of EGFR mutations in plasma and evaluation of EGFR mutation status in matched tissue and plasma from NSCLC patients treated with CO-1686. Sun, J., Karlovich, C., Wen, W., Wakelee, H., Chien, S., Mann, E., O'Donne, P., Angenendt, P., Dziadziuszko, R., Horn, L., Spige, D. R., Sequist, L., Soria, J., Solomon, B., Camidge, D., Goldman, J., Gadgeel, S. M., Raponi, M., Wu, L., Park, K. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1535-7163.TARG-13-B25

  View details for Web of Science ID 000209496800248

• SERIAL MONITORING OF PLASMA EGFR T790M LEVELS AND EVALUATION OF EGFR MUTATIONAL STATUS IN MATCHED TISSUE AND PLASMA FROM NSCLC PATIENTS TREATED WITH CO-1686 Wakelee, H. A., Karlovich, C. A., Wen, W., Sun, J., Chien, S., Mann, E., Donnell, P. O., Angenendt, P., Dziadziusko, R., Horn, L., Spigel, D., Sequist, L. V., Solomon, B., Soria, J., Camidge, D., Goldman, J., Gadgeel, S., Raponi, M., Wu, L., Park, K. LIPPINCOTT WILLIAMS & WILKINS. 2013: S388?S389

  View details for Web of Science ID 000339624901279

• Using Fiber Array Scanning Technology (FAST) Platform for sensitive detection and analysis of circulating tumor cells with a hybrid epithelial/mesenchymal phenotype from non-small cell lung cancer. Liu, X., Ly, J. C., Kara, L., Wakelee, H., Collins, N., Laderoute, K., Sambucetti, L. C. AMER ASSOC CANCER RESEARCH. 2013

  View details for DOI 10.1158/1535-7163.TARG-13-A199

  View details for Web of Science ID 000209496800143

• Are patients' needs being met after hours? An evaluation of phone calls made after hours for patients with thoracic malignancies. Patel, M. I., Moore, D., Milstein, A., Wakelee, H. A., Blayney, D. W. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for DOI 10.1200/jco.2013.31.31_suppl.46

  View details for Web of Science ID 000335565500047

• ARE PATIENTS' NEEDS BEING MET AFTER-HOURS? AN EVALUATION OF PHONE CALLS MADE AFTER HOURS FOR PATIENTS WITH THORACIC MALIGNANCIES. Patel, M. I., Williams, D., Wohlforth, C., Fisher, G. A., Blayney, D., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S709

  View details for Web of Science ID 000339624903178

• LUNG CANCER INCIDENCE TRENDS AMONG ASIAN-AMERICAN ETHNIC POPULATIONS IN THE UNITED STATES, 1990-2010 Gomez, S., Cheng, I., Gali, K., Patel, M. I., Haile, R., Noone, A., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2013: S233

  View details for Web of Science ID 000339624901043

• INCREASED GALECTIN-1 EXPRESSION IN A THYMIC EPITHELIAL TUMOR TISSUE MICROARRAY (TMA) AND GALECTIN-1 KNOCKDOWN STUDIES IN A THYMOMA CELL LINE Riess, J. W., Kuo, P., Kong, C., Wakelee, H. A., West, R., Quynh Le LIPPINCOTT WILLIAMS & WILKINS. 2013: S269

  View details for Web of Science ID 000339624901100

• ARE THERE DISPARITIES IN LUNG CANCER INCIDENCE TRENDS AMONG HISPANICS AND AFRICAN AMERICANS? AN ANALYSIS OF THE SURVEILLANCE EPIDEMIOLOGY AND END RESULTS DATABASE 1992-2010 Patel, M. I., Cheng, I., Gomez, S., Gali, K., Haile, R., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1293

  View details for Web of Science ID 000339624906153

• GLI1, NOTCH1 AND CTNNB1 EXPRESSION BY AUTOMATED QUANTITATIVE IMMUNOFLUORESCENCE (AQUA) IN A THYMIC MALIGNANCY TISSUE MICROARRAY (TMA) Riess, J. W., West, R., Padda, S. K., Dean, M., Klimowicz, A., Huong, C., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S944

  View details for Web of Science ID 000339624904251

• PALLIATIVE CARE AND ANTI-CANCER CARE INTEGRATION: DESCRIPTION OF THREE MODELS OF CARE DELIVERY AT A TERTIARY MEDICAL CENTER Ramchandran, K. J., Fronk, J., Trieu, S., Wakelee, H. A., Das, M., Neal, J. W., Harman, S., Dwyer, P., Bosch, J., Shaw, H., Safari, S., Oden, R., Morrison, T., Blayney, D. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1324

  View details for Web of Science ID 000339624906208

• VIETNAMESE NON-SMALL CELL LUNG CANCER PATIENTS IN CALIFORNIA: MOLECULAR PROFILES AND CLINICAL CHARACTERISTICS Nguyen, K. H., Das, M., Ramchandran, K., Shrager, J., Merritt, R. E., Hoang, C., Burt, B., Tisch, A., Pagtama, J., Zehnder, J., Berry, G., Wakelee, H. A., Anh-Hoa Nguyen, Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: S208?S209

  View details for Web of Science ID 000339624901009

• FIRST-IN-HUMAN EVALUATION OF CO-1686, AN IRREVERSIBLE, HIGHLY, SELECTIVE TYROSINE KINASE INHIBITOR OF MUTATIONS OF EGFR (ACTIVATING AND T790M) Soria, J., Sequist, L. V., Gadgeel, S., Goldman, J., Wakelee, H., Varga, A., Fidias, P., Wozniak, A. J., Neal, J. W., Doebele, R. C., Garon, E. B., Jaw-Tsai, S., Caunt, L., Kaur, P., Rolfe, L., Camidge, D., Allen, A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S141?S142

  View details for Web of Science ID 000339624900168

• STAGE 1 RESULTS OF A 2-STAGE PHASE II TRIAL OF SINGLE AGENT AMRUBICIN IN PATIENTS WITH PREVIOUSLY TREATED THYMIC MALIGNANCIES Wakelee, H. A., Riess, J. W., San Pedro-Salcedo, M., Padda, S. K., Ramchandran, K., Gubens, M. A., Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: S731

  View details for Web of Science ID 000339624903218

• CORRELATIVE ANALYSIS OF CIRCULATING BIOMARKERS FROM A PHASE 1B/2 TRIAL OF CABOZANTINIB (C) WITH OR WITHOUT ERLOTINIB (E) IN PATIENTS (PTS) WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) Padda, S. K., Rosenberg-Hasson, Y., Neal, J. W., Gettinger, S. N., Engelman, J. A., Jaenne, P. A., West, H. L., Subramaniam, D., Leach, J. W., Lara, P. N., Wax, M. B., Wakelee, H. A., Clary, D. O., Zhou, L. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1072?S1073

  View details for Web of Science ID 000339624905131

• ENERGY METABOLISM IN LUNG ADENOCARCINOMA Hoang, C., Xu, Y., Shi, Z., Lin, Y., Merritt, R. E., Shrager, J., Das, M., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1036?S1037

  View details for Web of Science ID 000339624905063

• ERLOTINIB (E) AND DOVITINIB (TKI258) (D) IN PATIENTS (PTS) WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A SIGNIFICANT PHARMACOKINETIC (PK) INTERACTION Das, M., Padda, S. K., Zhou, L., Frymoyer, A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1185?S1186

  View details for Web of Science ID 000339624905335

• How do social factors explain outcomes in non-small-cell lung cancer among hispanics in california? Explaining the Hispanic paradox. Journal of clinical oncology Patel, M. I., Schupp, C. W., Gomez, S. L., Chang, E. T., Wakelee, H. A. 2013; 31 (28): 3572-3578

  Abstract

  Hispanics in the United States have lower age-adjusted mortality resulting from non-small-cell lung cancer (NSCLC) compared with non-Hispanic whites (NHWs). The purpose of this study was to evaluate individual, clinical, and neighborhood factors in survival among Hispanics with NSCLC.We performed a retrospective analysis of NHWs and Hispanics with NSCLC between 1998 and 2007 in the California Cancer Registry (follow-up to December 2009). Kaplan-Meier curves depict survival by nativity for Hispanics with NSCLC. Cox proportional hazards models estimated hazard of mortality by race with adjustment for individual (age, sex, marital status), clinical (histologic grade, surgery, irradiation, chemotherapy), and neighborhood factors (neighborhood socioeconomic status, ethnic enclave).We included 14,280 Hispanic patients with NSCLC. Foreign-born Hispanics had 15% decreased risk of disease-specific mortality resulting from NSCLC compared with NHWs (hazard ratio [HR], 0.85; 95% CI, 0.83 to 0.88) after adjustment for individual, clinical, and neighborhood factors. After adjustment for individual factors, compared with US-born Hispanics, foreign-born Hispanics had 10% decreased risk of disease-specific mortality (HR, 0.90; 95% CI, 0.87 to 0.96). Clinical and neighborhood factors slightly moderated the survival benefit for foreign-born patients. A modestly more pronounced survival advantage was seen for foreign-born Hispanics living in low socioeconomic and high Hispanic enclave neighborhoods as compared with US-born Hispanics (HR, 0.86; 95% CI, 0.81 to 0.90).Foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with NHWs and US-born Hispanics with NSCLC. Neighborhood factors slightly moderate this survival advantage. This survival advantage is slightly more pronounced in lower socioeconomic and higher Hispanic enclave neighborhoods.

  View details for DOI 10.1200/JCO.2012.48.6217

  View details for PubMedID 23960183

• How do social factors explain outcomes in non-small-cell lung cancer among Hispanics in California? Explaining the Hispanic paradox. Journal of clinical oncology Patel, M. I., Schupp, C. W., Gomez, S. L., Chang, E. T., Wakelee, H. A. 2013; 31 (28): 3572-3578

  Abstract

  Hispanics in the United States have lower age-adjusted mortality resulting from non-small-cell lung cancer (NSCLC) compared with non-Hispanic whites (NHWs). The purpose of this study was to evaluate individual, clinical, and neighborhood factors in survival among Hispanics with NSCLC.We performed a retrospective analysis of NHWs and Hispanics with NSCLC between 1998 and 2007 in the California Cancer Registry (follow-up to December 2009). Kaplan-Meier curves depict survival by nativity for Hispanics with NSCLC. Cox proportional hazards models estimated hazard of mortality by race with adjustment for individual (age, sex, marital status), clinical (histologic grade, surgery, irradiation, chemotherapy), and neighborhood factors (neighborhood socioeconomic status, ethnic enclave).We included 14,280 Hispanic patients with NSCLC. Foreign-born Hispanics had 15% decreased risk of disease-specific mortality resulting from NSCLC compared with NHWs (hazard ratio [HR], 0.85; 95% CI, 0.83 to 0.88) after adjustment for individual, clinical, and neighborhood factors. After adjustment for individual factors, compared with US-born Hispanics, foreign-born Hispanics had 10% decreased risk of disease-specific mortality (HR, 0.90; 95% CI, 0.87 to 0.96). Clinical and neighborhood factors slightly moderated the survival benefit for foreign-born patients. A modestly more pronounced survival advantage was seen for foreign-born Hispanics living in low socioeconomic and high Hispanic enclave neighborhoods as compared with US-born Hispanics (HR, 0.86; 95% CI, 0.81 to 0.90).Foreign-born Hispanics with NSCLC have a decreased risk of disease-specific mortality compared with NHWs and US-born Hispanics with NSCLC. Neighborhood factors slightly moderate this survival advantage. This survival advantage is slightly more pronounced in lower socioeconomic and higher Hispanic enclave neighborhoods.

  View details for DOI 10.1200/JCO.2012.48.6217

  View details for PubMedID 23960183

• Adjuvant chemotherapy of completely resected early stage non-small cell lung cancer (NSCLC) TRANSLATIONAL LUNG CANCER RESEARCH Liang, Y., Wakelee, H. A. 2013; 2 (5): 403?10

  Abstract

  Surgery is regarded as the primary treatment modality for early stage non-small cell lung cancer (NSCLC), but even after complete resection, a substantial percentage of these patients eventually develop local recurrence or distant metastases. Therefore more effective treatment strategies to reduce lung cancer mortality and recurrence rate are needed. Only recently has the use of adjuvant chemotherapy become standard in early stage NSCLC, at least for stage II and resected IIIA NSCLC. Controversies remain about the benefit for stage I patients. Five-year survival improvements of 5% to 10% have been reported with cisplatin-based adjuvant chemotherapy from multiple large randomized phase III clinical trials and meta-analyses. Questions remain as to which patients benefit and which regimens are best. In this paper, important clinical research in the field of adjuvant chemotherapy of NSCLC is reviewed.

  View details for PubMedID 25806259

  View details for PubMedCentralID PMC4367729

• Management of early stage non-small cell lung cancer TRANSLATIONAL LUNG CANCER RESEARCH Wakelee, H. 2013; 2 (5): 315

  View details for PubMedID 25806250

  View details for PubMedCentralID PMC4367724

• Noninvasive and Ultrasensitive Quantitation of Circulating Tumor DNA by Hybrid Capture and Deep Sequencing Bratman, S. V., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H., Shrager, J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2013: S92

  View details for DOI 10.1016/j.ijrobp.2013.06.237

  View details for Web of Science ID 000324503600224

• A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non-Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements. Clinical lung cancer Riess, J. W., Padda, S. K., Bangs, C. D., Das, M., Neal, J. W., Adrouny, A. R., Cherry, A., Wakelee, H. A. 2013; 14 (5): 592-595

  View details for DOI 10.1016/j.cllc.2013.04.008

  View details for PubMedID 23810364

• INCREASED GALECTIN-1 EXPRESSION IN A THYMIC EPITHELIAL TUMOR TISSUE MICROARRAY (TMA) Riess, J., Kuo, P., Kong, C., West, R., Padda, S., Wakelee, H., Le, Q. LIPPINCOTT WILLIAMS & WILKINS. 2013: 25?26

  View details for Web of Science ID 000339623500028

• GLI1, NOTCH1 AND CTNNB1 EXPRESSION BY AUTOMATED QUANTITATIVE IMMUNOFLUORESCENCE (AQUA) IN A THYMIC MALIGNANCY TISSUE MICROARRAY (TMA) Riess, J., West, R., Padda, S., Dean, M., Klimowicz, A., Huong, C., Neal, J., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2013: 25

  View details for Web of Science ID 000339623500027

• STAGE 1 RESULTS OF A 2-STAGE PHASE II TRIAL OF SINGLE AGENT AMRUBICIN IN PATIENTS WITH PREVIOUSLY TREATED THYMIC MALIGNANCIES Wakelee, H., Riess, J., Pedro-Salcedo, M., Padda, S., Ramchandran, K., Gubens, M., Neal, J. LIPPINCOTT WILLIAMS & WILKINS. 2013: 22?23

  View details for Web of Science ID 000339623500024

• Phase I and pharmacokinetic study of bexarotene in combination with gefitinib in the third-line treatment of non-small-cell lung cancer: brief report. Anti-cancer drugs Padda, S. K., Chhatwani, L., Zhou, L., Jacobs, C. D., Lopez-Anaya, A., Wakelee, H. A. 2013; 24 (7): 731-735

  Abstract

  Gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and bexarotene (a rexinoid) affect similar oncogenic pathways and are both metabolized through cytochrome P450 CYP3A4. We studied the combination of bexarotene and gefitinib in the third-line treatment of advanced non-small-cell lung cancer to examine pharmacokinetic interactions and establish the maximum tolerated dose. This was a single-institution, nonrandomized, open-label, phase I clinical trial with a standard 3+3 dose escalation. Three patients were enrolled at each dose level on the basis of pharmacokinetic analysis with dose level 1 including gefitinib (Iressa) 250 mg oral daily and bexarotene (Targretin) 400 mg/m oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m oral daily. Patients received gefitinib alone for 2 weeks to allow for steady state and thereafter, bexarotene was added. In dose level 1, two of three patients had undetectable gefitinib levels at day 15 for unknown reasons. However, the peak levels on day 29 for all three patients receiving 250 mg of gefitinib with bexarotene are lower than published peak levels. Among the three patients in dose level +1, ?40% lower gefitinib plasma concentrations were noted on day 29 compared with day 15 along with a mean 44% reduction in area under the plasma concentration-time curve from 0 to 24 h (AUC0-24). Bexarotene appears to lower the Cmax and AUC0-24 of gefitinib through cytochrome P450 CYP3A4. Our results have pharmacokinetic implications for ongoing trials that combine bexarotene with other small molecules in the era of personalized cancer therapy.

  View details for DOI 10.1097/CAD.0b013e32836100d7

  View details for PubMedID 23552470

• First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M. Sequist, L. V., Soria, J., Gadgeel, S. M., Wakelee, H. A., Camidge, D., Varga, A., Fidias, P., Wozniak, A. J., Neal, J. W., Doebele, R., Garon, E. B., Jaw-Tsai, S. S., Stern, J. C., Allen, A. R., Goldman, J. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419601042

• Active and passive smoking in relation to lung cancer incidence in the Women's Health Initiative prospective cohort study. Wang, A., Kubo, J., Luo, J., Desai, M., Henderson, M. T., Chlebowski, R. T., Tindle, H., Chen, C., Manson, J. E., Schwartz, A. G., Cote, M. L., Wactawski-Wende, J., Gomez, S., Patel, M. I., Stefanick, M. L., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419600564

• Are needs of stakeholders in cancer care being met? A novel approch to assessing needs to improve value in cancer care Patel, M. I., Moore, D., Randolph, S., Wakelee, H. A., Blayney, D. W., Milstein, A. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419602297

• Smoking and estrogen plus progestin (E plus P) and lung cancer incidence and mortality. Chlebowski, R. T., Wakelee, H. A., Rohan, T. E., Liu, J., Simon, M. S., Tindle, H., Messina, C. R., Wactawski-Wende, J., Johnson, K., Schwartz, A. G., Gass, M. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419600583

• A Patient With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer With Development of Leptomeningeal Carcinomatosis While on Targeted Treatment With Crizotinib JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Riess, J. W., Nagpal, S., Neal, J. W., Wake, H. A. 2013; 11 (4): 389-394

  Abstract

  Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

  View details for PubMedID 23584342

• A case series of NSCLC patients with different molecular characteristics and choroidal metastases: improvement in vision with treatment including pemetrexed and bevacizumab. Journal of thoracic oncology Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): e17-8

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for PubMedID 23328555

  View details for PubMedCentralID PMC3552378

• A Case Series of NSCLC Patients with Different Molecular Characteristics and Choroidal Metastases Improvement in Vision with Treatment Including Pemetrexed and Bevacizumab JOURNAL OF THORACIC ONCOLOGY Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): E17-E18

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for Web of Science ID 000316204900003

  View details for PubMedID 23328555

  View details for PubMedCentralID PMC3552378

• Aflibercept in lung cancer EXPERT OPINION ON BIOLOGICAL THERAPY Neal, J. W., Wakelee, H. A. 2013; 13 (1): 115-120

  Abstract

  Angiogenesis, the recruitment and growth of blood vessels, is a process central to the growth of solid tumors. One of the key mediators of angiogenesis is the vascular endothelial growth factor (VEGF) family of ligands. An antibody to VEGF-A, bevacizumab, has demonstrated a survival benefit in conjunction with platinum-based doublet chemotherapy in non-small-cell lung cancer (NSCLC). Aflibercept (VEGF Trap) is a recombinant VEGF receptor-antibody protein fusion with higher affinity for VEGF-A than bevacizumab, plus affinity for VEGF-B and placental growth factor (PlGF). AREAS COVERED: This article reviews recent clinical trials investigating the role of aflibercept in the treatment of lung cancer, both published in the literature and those for which preliminary data have been presented at major scientific meetings. EXPERT OPINION: Aflibercept has proven Phase III efficacy in metastatic colorectal cancer, but in lung cancer, large clinical trials have not yielded positive results. There remains hope that identification of biomarkers of response will one day help select patients most likely to benefit from antiangiogenesis therapy.

  View details for DOI 10.1517/14712598.2013.745847

  View details for PubMedID 23199019

• Treatment of Leptomeningeal Spread of NSCLC: A Continuing Challenge CURRENT TREATMENT OPTIONS IN ONCOLOGY Nagpal, S., Riess, J., Wakelee, H. 2012; 13 (4): 491-504

  Abstract

  OPINION STATEMENT: Leptomeningeal metastasis is a serious and frequently fatal complication of non-small cell lung cancer. Curative treatment remains elusive, but careful use of radiation, systemic chemotherapy, intrathecal chemotherapy, and symptoms management can greatly improve quality of life and survival. For most patients, we recommend a combination of skull-based radiation with focal radiation to any symptomatic spinal segments followed by systemic chemotherapy. For patients with EGFR mutations, erlotinib may be used as first-line therapy in a daily or high-dose regimen. Pemetrexed has promise for use in patients with brain and leptomeningeal metastases. Patients with multiple comorbidities or low performance status may tolerate intrathecal therapy better than systemic chemotherapy. The most commonly used intrathecal chemotherapies are methotrexate and liposomal cytarabine, although newer agents, such as topotecan and mafosfamide, may be more effective. Elevated intracranial pressure, which causes headaches, vertigo, nausea, and vomiting, should be treated with dexamethasone and acetazolamide. In select patients, cerebrospinal fluid shunting may be considered. The use of antidepressants, central nervous system stimulants, benzodiazepines, antiemetics, and pain medications can increase quality of life in patients with leptomeningeal metastases.

  View details for DOI 10.1007/s11864-012-0206-4

  View details for Web of Science ID 000311292500006

  View details for PubMedID 22836285

• MET inhibitors in combination with other therapies in non-small cell lung cancer TRANSLATIONAL LUNG CANCER RESEARCH Padda, S., Neal, J. W., Wakelee, H. A. 2012; 1 (4): 238?53

  View details for DOI 10.3978/j.issn.2218-6751.2012.10.08

  View details for Web of Science ID 000218783300003

• Anti-angiogenic agents in Non-Small-Cell Lung Cancer (NSCLC): a perspective on the MONET1 (Motesanib NSCLC Efficacy and Tolerability) study JOURNAL OF THORACIC DISEASE Das, M., Wakelee, H. 2012; 4 (6): 558-561

  View details for DOI 10.3978/j.issn.2072-1439.2012.10.02

  View details for Web of Science ID 000314790400004

  View details for PubMedID 23205278

  View details for PubMedCentralID PMC3506785

• MET inhibitors in combination with other therapies in non-small cell lung cancer. Translational lung cancer research Padda, S., Neal, J. W., Wakelee, H. A. 2012; 1 (4): 238-253

  Abstract

  MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.

  View details for DOI 10.3978/j.issn.2218-6751.2012.10.08

  View details for PubMedID 25806189

• Angiogenesis inhibitors. Journal of thoracic oncology Das, M., Wakelee, H. 2012; 7 (16): S397-8

  View details for DOI 10.1097/JTO.0b013e31826df227

  View details for PubMedID 23160332

• PRIMARY CHEMOTHERAPY FOR THYMIC MALIGNANCIES Wakelee, H. ELSEVIER SCIENCE INC. 2012: S412

  View details for Web of Science ID 000428093300005

• BIOMARKERS FOR ANTI-ANGIOGENIC THERAPY Das, M., Wakelee, H. ELSEVIER SCIENCE INC. 2012: S442?S443

  View details for Web of Science ID 000428093300114

• A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer LUNG CANCER Clement-Duchene, C., Natale, R. B., Jahan, T., Krupitskaya, Y., Osarogiagbon, R., Sanborn, R. E., Bernstein, E. D., Dudek, A. Z., Latz, J. E., Shi, P., Wakelee, H. A. 2012; 78 (1): 57-62

  Abstract

  Regardless of epidermal growth factor receptor (EGFR) mutation status, erlotinib improves survival for patients with advanced non-small cell lung cancer (NSCLC) after one or more chemotherapy regimens. Enzastaurin is an oral serine/threonine kinase inhibitor. This phase II study was designed to evaluate the efficacy and safety of erlotinib and enzastaurin in NSCLC, a combination with promise to overcome EGFR resistance based on preclinical models.Eligible patients with advanced NSCLC (IIIB or IV) who had failed one or two prior systemic treatment regimen(s) were enrolled and received erlotinib 150 mg/day and enzastaurin 500 mg/day (after a 1125-mg loading dose on day 1, cycle 1), both orally in 28-day cycles. The primary endpoint was progression-free survival (PFS).From January 2008 to July 2009, 49 patients were enrolled: 29 (59%) men and 20 (41%) women; 8 (16%) were non-smokers. The median PFS was 1.7 months (one-sided 90% CI: 1.5-NA) and median overall survival (OS) was 8.3 months (95% CI: 5.3-14.3). Five patients had partial response, for an overall response rate of 10.2%; the disease control rate was 30.6% (responders+10 patients with stable disease). Grade 3-4 drug-related adverse events in ?5% of patients were diarrhea, acne, and nausea. One possibly drug-related death due to interstitial lung disease occurred during the study.In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.

  View details for DOI 10.1016/j.lungcan.2012.06.003

  View details for PubMedID 22809813

• A Double-Blind Randomized Discontinuation Phase-II Study of Sorafenib (BAY 43-9006) in Previously Treated Non-Small-Cell Lung Cancer Patients Eastern Cooperative Oncology Group Study E2501 JOURNAL OF THORACIC ONCOLOGY Wakelee, H. A., Lee, J., Hanna, N. H., Traynor, A. M., Carbone, D. P., Schiller, J. H. 2012; 7 (10): 1574-1582

  Abstract

  Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (? 2 prior therapies) used a randomized discontinuation design.Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization.There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected.The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.

  View details for DOI 10.1097/JTO.0b013e31826149ba

  View details for PubMedID 22982658

• Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Trakul, N., Chang, C. N., Harris, J., Chapman, C., Rao, A., Shen, J., Quinlan-Davidson, S., Filion, E. J., Wakelee, H. A., Colevas, A. D., Whyte, R. I., Dieterich, S., Maxim, P. G., Hristov, D., Tran, P., Quynh-Thu Le, Q. T., Loo, B. W., Diehn, M. 2012; 84 (1): 231-237

  Abstract

  Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy.We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume ?12 mL) received multifraction regimens with BED ?100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2).The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02).A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  View details for DOI 10.1016/j.ijrobp.2011.10.071

  View details for PubMedID 22381907

• A RANDOMIZED, PHASE II, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF ONARTUZUMAB (METMAB) WITH EITHER BEVACIZUMAB plus PLATINUM plus PACLITAXEL OR PEMETREXED plus PLATINUM AS FIRST-LINE TREATMENT FOR PATIENTS (PTS) WITH STAGE IIIB OR IV NON-SQUAMOUS NON-SMALL CELL LUNG CANCER (NSCLC) Wakelee, H., Yu, W., Rittweger, K., Paton, V. E. OXFORD UNIV PRESS. 2012: 445

  View details for Web of Science ID 000309409002297

• Prolonged Survival in Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Metastases (LM) in the Modern Treatment Era Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S243?S243

  View details for Web of Science ID 000317035000106

• How Do Social Factors Explain Outcomes In Non-small Cell Lung Cancer Among Hispanic/latinos In California? Patel, M. I., Chang, E., Gomez, S., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S216?S216

  View details for Web of Science ID 000317035000036

• A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours BRITISH JOURNAL OF CANCER Diaz-Padilla, I., Siu, L. L., San Pedro-Salcedo, M., Razak, A. R., Colevas, A. D., Shepherd, F. A., Leighl, N. B., Neal, J. W., Thibault, A., Liu, L., Lisano, J., Gao, B., Lawson, E. B., Wakelee, H. A. 2012; 107 (4): 604-611

  Abstract

  To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75?mg?m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ? 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

  View details for DOI 10.1038/bjc.2012.319

  View details for Web of Science ID 000307770300005

  View details for PubMedID 22805331

  View details for PubMedCentralID PMC3419963

• ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy. Lung cancer Das, M., Riess, J. W., Frankel, P., Schwartz, E., Bennis, R., Hsieh, H. B., Liu, X., Ly, J. C., Zhou, L., Nieva, J. J., Wakelee, H. A., Bruce, R. H. 2012; 77 (2): 421-426

  Abstract

  To utilize a novel circulating tumor cell (CTC) technology to quantify ERCC1 expression on CTCs and determine whether ERCC1 expression levels predict efficacy of platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC).ERCC1 expression was measured in 17 metastatic NSCLC patients who received platinum-based therapy and had ?2 intact CTCs with acceptable ERCC1 expression assay results. ERCC1 levels were determined from average expression on individual CTCs in each sample. Progression-free survival (PFS) was calculated from the date of therapy initiation.PFS decreased with increasing ERCC1 expression (p<0.04, F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days versus 172 days, log-rank, p<0.02) in a Kaplan-Meier analysis using ERCC expression level of 1 as a cutoff (range 0-30). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p<0.02, log-rank). PFS was also observed to decrease with increased cytokeratin (CK) expression (p<0.01 long-rank (Cox regression) and F-test (linear regression)). The hazard ratio is 4.38 (95% CI 1.76-10.9) for each log-change in CK value until progression was noted on imaging.Low expression of ERCC1 on CTCs correlates with PFS in patients with metastatic NSCLC receiving platinum-based therapy.

  View details for DOI 10.1016/j.lungcan.2012.04.005

  View details for PubMedID 22555222

• ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy LUNG CANCER Das, M., Riess, J. W., Frankel, P., Schwartz, E., Bennis, R., Ben Hsieh, H., Liu, X., Ly, J. C., Zhou, L., Nieva, J. J., Wakelee, H. A., Bruce, R. H. 2012; 77 (2): 421-426

  Abstract

  To utilize a novel circulating tumor cell (CTC) technology to quantify ERCC1 expression on CTCs and determine whether ERCC1 expression levels predict efficacy of platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC).ERCC1 expression was measured in 17 metastatic NSCLC patients who received platinum-based therapy and had ?2 intact CTCs with acceptable ERCC1 expression assay results. ERCC1 levels were determined from average expression on individual CTCs in each sample. Progression-free survival (PFS) was calculated from the date of therapy initiation.PFS decreased with increasing ERCC1 expression (p<0.04, F-test, linear regression). Lack of ERCC1 expression was associated with longer PFS (266 days versus 172 days, log-rank, p<0.02) in a Kaplan-Meier analysis using ERCC expression level of 1 as a cutoff (range 0-30). The difference in survival was statistically significant with a hazard ratio of 4.20 (95% CI 1.25-14.1, p<0.02, log-rank). PFS was also observed to decrease with increased cytokeratin (CK) expression (p<0.01 long-rank (Cox regression) and F-test (linear regression)). The hazard ratio is 4.38 (95% CI 1.76-10.9) for each log-change in CK value until progression was noted on imaging.Low expression of ERCC1 on CTCs correlates with PFS in patients with metastatic NSCLC receiving platinum-based therapy.

  View details for DOI 10.1016/j.lungcan.2012.04.005

  View details for Web of Science ID 000307036500030

• Differential effect of age on survival in advanced NSCLC in women versus men: Analysis of recent Eastern Cooperative Oncology Group (ECOG) studies, with and without bevacizumab LUNG CANCER Wakelee, H. A., DAHLBERG, S. E., Brahmer, J. R., Schiller, J. H., Perry, M. C., Langer, C. J., Sandler, A. B., Belani, C. P., Johnson, D. H. 2012; 76 (3): 410-415

  Abstract

  The impact of age on prognosis in advanced stage non-small cell lung cancer (NSCLC) may differ by sex.Eligible patients (N=1590) from E1594, a 4-arm platinum-based chemotherapy trial, and E4599 (carboplatin/paclitaxel ± bevacizumab) chemotherapy arm were divided into male and female cohorts and separated into age groups of <60 or ?60 years old. Eligible E4599 patients (N=850) were similarly separated by age and sex and by treatment (± bevacizumab). Survival was calculated separately for each cohort.The median survival time (MST) for women ?60 years old treated with chemotherapy alone on E1594 and E4599 was 11.6 months versus 9.0 months for women <60 (p=0.03). MST was 7.4 and 8.3 months for men ?60 and <60 years old respectively (NS). In E4599 the age <60 by bevacizumab treatment interaction was statistically significant (p=0.03) for women (younger had greater benefit), with no age effect in men.In this unplanned, exploratory subgroup analysis of advanced stage NSCLC ECOG trials, women ?60 years old treated with chemotherapy live longer than men and younger women. In contrast, bevacizumab survival benefit was more pronounced in men of any age and in younger women on E4599.

  View details for DOI 10.1016/j.lungcan.2011.12.006

  View details for PubMedID 22266041

• How do social factors explain outcomes in non-small cell lung cancer among Hispanics/Latinos in California? 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Patel, M. I., Chang, E. T., Gomez, S. L., Schupp, C., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801334

• Correlation of ERCC1 expression on circulating tumor cells with progression-free survival in metastatic non-small cell lung cancer patients treated with platinum-based chemotherapy 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Riess, J., Das, M. S., Frankel, P. H., Schwartz, E., Bennis, R., Ben Hsieh, H., Liu, X., Ly, J., Zhou, L. Y., Nieva, J. J., Bruce, R., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009800395

• A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Liu, L., Lisano, J. M., Adjei, A. A., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009804215

• Utility of 18F FDG PET/CT in patients with advanced thymic neoplasms Davidzon, G., Wakelee, H., Neal, J., Mittra, E., Quon, A., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2012

  View details for Web of Science ID 000443680202308

• Metastatic non-small cell lung cancer management: novel targets and recent clinical advances. Clinical advances in hematology & oncology : H&O Riess, J. W., Wakelee, H. A. 2012; 10 (4): 226-234

  Abstract

  Lung cancer continues to be the most common cause of cancer-related mortality in the United States and other developed countries. The most common subtype is non-small cell lung cancer (NSCLC). Within NSCLC, we are discovering remarkable molecular heterogeneity. Most current actionable mutations have been identified in patients with adenocarcinoma histology, but now new mutations are being discovered in squamous cell histology patients as well. This molecular heterogeneity provides an opportunity for clinical trials to exploit various candidate oncogene-addicted pathways in NSCLC. This article focuses on 2 shifting paradigms in NSCLC management: the recent advances in targeted therapy and maintenance treatment.

  View details for PubMedID 22706483

• Targeting VEGF in lung cancer EXPERT OPINION ON THERAPEUTIC TARGETS Das, M., Wakelee, H. 2012; 16 (4): 395-406

  Abstract

  VEGF promotes tumor angiogenesis and is an important target in various malignancies, including NSCLC. AREAS COVERED: Here, the authors review the data that led to the approval of bevacizumab, a monoclonal antibody against VEGF, in the treatment of lung cancer. The authors also review the key results from a number of Phase II and Phase III trials involving other anti-angiogenic agents being studied in NSCLC, including small-molecule tyrosine kinase inhibitors against the VEGF-receptor and vascular-disrupting agents (VDAs). EXPERT OPINION: Results from ongoing studies and the identification of reliable biomarkers remain critical goals in understanding the exact role of these anti-angiogenic agents in the treatment paradigm of NSCLC.

  View details for DOI 10.1517/14728222.2012.669752

  View details for PubMedID 22439677

• A phase I dose-escalation and pharmacokinetic study of enzastaurin and erlotinib in patients with advanced solid tumors CANCER CHEMOTHERAPY AND PHARMACOLOGY Padda, S. K., Krupitskaya, Y., Chhatwani, L., Fisher, G. A., Colevas, A. D., Pedro-Salcedo, M. S., Decker, R., Latz, J. E., Wakelee, H. A. 2012; 69 (4): 1013-1020

  Abstract

  Enzastaurin, an oral serine/threonine kinase inhibitor, targets the protein kinase C and AKT pathways with anti-tumor and anti-angiogenic effects. Erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, has activity in solid tumors. Based on the promising combination of EGFR inhibitors and anti-angiogenic agents, this phase I trial was initiated.This single-institution, open-label, non-randomized trial used a standard 3 + 3 dose-escalation model in patients with advanced solid malignancies including non-small-cell lung cancer (NSCLC). Two dose levels of enzastaurin (with loading doses) were explored: 250 mg daily and 500 mg daily. Erlotinib was given at 150 mg daily.Sixteen patients were enrolled in this study (median age, 64 years). Most patients were heavily pre-treated, female, and Caucasian and had NSCLC. The highest dose of enzastaurin, 500 mg daily, was tolerated with no unexpected adverse events and no alteration in the pharmacokinetics of either drug at this dose level. The mean clearance was 5.75 L/h for erlotinib and 53.8 L/h for enzastaurin. The most common possibly drug-related grade 3-4 adverse events included diarrhea (25.0%), neurologic symptoms (18.8%), and vomiting (18.8%). Activity was noted, with a partial response in one patient and prolonged disease stability for >12 cycles in three patients.The combination of enzastaurin 500 mg daily and erlotinib 150 mg daily is well tolerated and does not alter the pharmacokinetics of the individual drugs, with clinical activity seen. A phase II trial of this combination has been initiated in patients with advanced-stage NSCLC.

  View details for DOI 10.1007/s00280-011-1792-8

  View details for PubMedID 22160298

• A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Middleton, G., Dunlop, D., Ramlau, R., Leighl, N., Hao, D., Lopez-Anaya, A., Zatloukal, P., Jacobs, C. D. 2012; 69 (3): 815-824

  Abstract

  This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

  View details for DOI 10.1007/s00280-011-1771-0

  View details for PubMedID 22057854

• Maintenance Bevacizumab is Associated With Increased Hemoglobin in Patients With Advanced, Nonsquamous, Non-Small Cell Lung Cancer CANCER INVESTIGATION Riess, J. W., Logan, A. C., Krupitskaya, Y., Padda, S., Clement-Duchene, C., Ganjoo, K., Colevas, A. D., San Pedro-Salcedo, M., Kuo, C. J., Wakelee, H. A. 2012; 30 (3): 231-235

  Abstract

  We retrospectively analyzed hematologic parameters in 22 patients with advanced, nonsquamous, NSCLC undergoing VEGF inhibition on a phase II clinical trial of bevacizumab, carboplatin, and gemcitabine. We also examined TTP in relation to hemoglobin changes. Median hemoglobin increased significantly from a 12.9 g/dL pretreatment to 13.8 g/dL (p =.01) after the second cycle of maintenance bevacizumab until the first off cycle measurement. There was no difference in TTP in patients who achieved a rise in hemoglobin compared with patients who did not (median 238 days vs. 268 days, p =.38.) Maintenance bevacizumab is associated with increased hemoglobin in advanced, nonsquamous, NSCLC patients.

  View details for DOI 10.3109/07357907.2012.656862

  View details for PubMedID 22360362

• A phase I pharmacokinetic study of bexarotene with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC) CANCER CHEMOTHERAPY AND PHARMACOLOGY Rodon, J., Jacobs, C. D., Chu, Q., Rowinsky, E. K., Lopez-Anaya, A., Takimoto, C. H., Wakelee, H. A. 2012; 69 (3): 825-834

  Abstract

  Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer.Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene).An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment.The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.

  View details for DOI 10.1007/s00280-011-1770-1

  View details for Web of Science ID 000302325600026

  View details for PubMedID 22057853

• The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer CANCER CHEMOTHERAPY AND PHARMACOLOGY Wakelee, H. A., Takimoto, C. H., Lopez-Anaya, A., Chu, Q., Middleton, G., Dunlop, D., Ramlau, R., Leighl, N., Rowinsky, E. K., Hao, D., Zatloukal, P., Jacobs, C. D., Rodon, J. 2012; 69 (2): 563-571

  Abstract

  Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents.Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene).Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions.A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

  View details for DOI 10.1007/s00280-011-1772-z

  View details for PubMedID 22057855

• Metabolic Tumor Volume is an Independent Prognostic Factor in Patients Treated Definitively for Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Lee, P., Bazan, J. G., Lavori, P. W., Weerasuriya, D. K., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Graves, E. E., Loo, B. W. 2012; 13 (1): 52-58

  Abstract

  Fluorine-18 flurodeoxyglucose positron emission tomography (FDG-PET) imaging has rapidly become the standard of care for staging patients with lung cancer. We evaluated the prognostic value of metabolic tumor volume (MTV), a measure of tumor burden on FDG-PET imaging, in patients with non-small-cell lung cancer (NSCLC) treated definitively.A retrospective review identified 61 patients with NSCLC who underwent FDG-PET imaging for pretreatment staging. Metabolically active tumor regions were segmented on the PET scans semiautomatically to calculate the total body MTV. We determined the relationship of overall survival (OS) and progression-free survival (PFS) with MTV in the entire cohort, and in the subgroup treated definitively.The estimated median PFS and OS for the entire cohort were 11.1 months and 18.9 months. Higher MTV was significantly associated with worse OS (P = 0.00075) and PFS (P = 0.00077). For definitively treated patients, when MTV was analyzed as a binary value above or below the median value, 2-year PFS was 60% versus 39.7% (median PFS 34.9 vs. 11.9 months) and 2-year OS was 79.7% versus 33.3% (median OS 41.9 vs. 18.9 months), respectively (log-rank P = 0.12 for PFS and P = 0.066 for OS). When MTV was analyzed as a continuous variable, multivariate Cox proportional hazards analysis demonstrated a trend to worse PFS (hazard ratio [HR] = 1.31; P = 0.12) and significantly worse OS (HR = 1.53; P = 0.018) with increasing MTV after controlling for known prognostic variables.Tumor burden as assessed by MTV yields prognostic information on survival beyond that of established prognostic factors in patients with NSCLC treated definitively.

  View details for DOI 10.1016/j.cllc.2011.05.001

  View details for PubMedID 21703935

• Adjuvant Chemotherapyfor Early-Stage Non-Small Cell Lung Cancer LUNG CANCER Patel, M. I., Wakelee, H. A., Argiris, A. 2012; 3 (1): 129?40

  View details for DOI 10.5003/2151-4194.3.1.129

  View details for Web of Science ID 000318660600009

• XL647-A Multitargeted Tyrosine Kinase Inhibitor Results of a Phase II Study in Subjects with Non-small Cell Lung Cancer Who Have Progressed after Responding to Treatment with Either Gefitinib or Erlotinib JOURNAL OF THORACIC ONCOLOGY Pietanza, M. C., Lynch, T. J., Lara, P. N., Cho, J., Yanagihara, R. H., Vrindavanam, N., Chowhan, N. M., Gadgeel, S. M., Pennell, N. A., Funke, R., Mitchell, B., Wakelee, H. A., Miller, V. A. 2012; 7 (1): 219-226

  Abstract

  Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M.Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ?12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA.Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations.The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.

  View details for DOI 10.1097/JTO.0b013e31822eebf9

  View details for Web of Science ID 000300305600032

  View details for PubMedID 22011666

• Current Management of Small Cell Lung Cancer CLINICS IN CHEST MEDICINE Neal, J. W., Gubens, M. A., Wakelee, H. A. 2011; 32 (4): 853-?

  Abstract

  Confined to one side of the chest, limited stage small cell lung cancer is treated with a combination of chemotherapy and radiotherapy, yet has a long-term survival rate of only 15%. Extensive stage disease has initial response rates to chemotherapy exceeding 70%. However, the disease almost invariably progresses and becomes fatal. Many recent clinical trials have failed to show superiority of newer chemotherapeutics or targeted therapies compared with the standard chemotherapy backbone of platinum plus etoposide. Numerous promising targeted therapies and other agents are still in development.

  View details for DOI 10.1016/j.ccm.2011.07.002

  View details for PubMedID 22054891

• Angiogenesis Inhibitors JOURNAL OF THORACIC ONCOLOGY Das, M., Wakelee, H. 2011; 6 (11): S1801-S1802

  View details for DOI 10.1097/01.JTO.0000407564.91781.ab

  View details for PubMedID 22005536

• Results from a Single Institution Phase II Trial of Concurrent Docetaxel/Carboplatin/Radiotherapy Followed by Surgical Resection and Consolidation Docetaxel/Carboplatin in Stage III Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Das, M., Donington, J. S., Murphy, J., Kozak, M., Eclov, N., Whyte, R. I., Hoang, C. D., Zhou, L., Le, Q., Loo, B. W., Wakelee, H. 2011; 12 (5): 280-285

  Abstract

  The optimal treatment of locally advanced non-small-cell lung cancer (NSCLC) remains controversial. We hypothesized that using a trimodality approach in selected patients with stage IIIA/IIIB disease would be both feasible and efficacious with reasonable toxicity.We enrolled 13 patients with resectable stage III NSCLC on a prospective phase II trial of trimodality therapy. Induction treatment consisted of weekly docetaxel 20 mg/m(2) and weekly carboplatin at an area under curve (AUC) of 2 concurrent with 45 Gy thoracic radiotherapy. Resection was performed unless felt to be unsafe or if patients had progressive disease. Postoperative consolidation consisted of docetaxel 75 mg/m(2) and carboplatin at an AUC of 6 every 3 weeks for 3 cycles with growth factor support.All patients responded to induction chemoradiotherapy as measured by total gross tumor volume reductions of 43% on average (range, 27%-64%). Twelve patients underwent resection of the tumor and involved nodes, yielding a resectability rate of 92%. The primary endpoint of 2-year overall survival (OS) was 72% (95% confidence interval [CI], 36%-90%), and 2-year progression-free survival (PFS) was 36% (95% CI, 9%-64%). The maximal toxicity observed per patient was grade II in 5 patients (38%); grade III in 7 patients (54%); grade IV in 1 patient (8%); and grade V in none.This trimodality approach resulted in promising outcomes with reasonable toxicity in carefully selected patients with stage III NSCLC at a single institution.

  View details for DOI 10.1016/j.cllc.2011.06.003

  View details for PubMedID 21752720

• Chemotherapy Definitions and Policies for Thymic Malignancies JOURNAL OF THORACIC ONCOLOGY Girard, N., Lal, R., Wakelee, H., Riely, G. J., Loehrer, P. J. 2011; 6 (7): S1749-S1755

  View details for Web of Science ID 000292277900011

  View details for PubMedID 21847058

• MAINTENANCE BEVACIZUMAB MONOTHERAPY INCREASES HEMOGLOBIN (HGB) IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG ADENOCARCINOMA (NSCLC-AD) Riess, J. W., Logan, A., Krupitskaya, Y., Clement-Duchene, C., Kuo, C., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: S962?S963

  View details for Web of Science ID 000291769800090

• MID-RADIATION THERAPY PET CORRELATES WITH SURVIVAL IN LOCALLY ADVANCED NSCLC Loo, B. W., Chang, C., Hong, J., Wakelee, H., Quynh Thu Le, Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Diehn, M., Olson, M. LIPPINCOTT WILLIAMS & WILKINS. 2011: S694?S695

  View details for Web of Science ID 000208855803108

• INTERIM REPORT OF ON-STUDY DEMOGRAPHICS AND TOXICITY FROM EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) E1505, A PHASE III RANDOMIZED TRIAL OF ADJUVANT CHEMOTHERAPY WITH OR WITHOUT BEVACIZUMAB FOR COMPLETELY RESECTED EARLY STAGE NON-SMALL CELL LUNG CANCER (NSCLC) Wakelee, H. A., Dahlberg, S. E., Keller, S. M., Gandara, D. R., Graziano, S., Leighl, N. B., Adjei, A. A., Schiller, J. LIPPINCOTT WILLIAMS & WILKINS. 2011: S464

  View details for Web of Science ID 000208855802191

• A POOLED ANALYSIS OF ADVANCED NONSQUAMOUS NSCLC PATIENTS WITH STABLE TREATED BRAIN METASTASES IN TWO PHASE II TRIALS RECEIVING BEVACIZUMAB AND PEMETREXED AS SECOND-LINE THERAPY Gubens, M., Akerley, W., Lynch, T., Langer, C. J., Socinski, M. A., Colevas, A., Clement-Duchene, C., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: S1224?S1225

  View details for Web of Science ID 000291769801052

• American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients With Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy JOURNAL OF CLINICAL ONCOLOGY Keedy, V. L., Temin, S., Somerfield, M. R., Beasley, M. B., Johnson, D. H., McShane, L. M., Milton, D. T., Strawn, J. R., Wakelee, H. A., Giaccone, G. 2011; 29 (15): 2121-2127

  Abstract

  An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the clinical utility of using epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer (NSCLC) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor (TKI). CLINICAL CONTEXT: Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib. In the United States, approximately 15% of patients with adenocarcinoma of the lung harbor activating EGFR mutations. EGFR mutation testing is widespread at academic medical centers and in some locales in community practice. As of yet, there is no evidence of an overall survival (OS) benefit from selecting treatment based on performing this testing. RECENT DATA: One large phase III trial (the Iressa Pan-Asia Study [IPASS] trial), three smaller phase III randomized controlled trials using progression-free survival as the primary end point, and one small phase III trial with OS as the primary end point, all involving first-line EGFR TKIs and chemotherapy doublets, form the basis of this PCO. PROVISIONAL CLINICAL OPINION: On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.

  View details for DOI 10.1200/JCO.2010.31.8923

  View details for Web of Science ID 000290716900044

  View details for PubMedID 21482992

• Interim report of on-study demographics and toxicity from E1505, a phase III randomized trial of adjuvant (adj) chemotherapy (chemo) with or without bevacizumab (B) for completely resected early-stage non-small cell lung cancer (NSCLC). Wakelee, H. A., Dahlberg, S. E., Keller, S. M., Gandara, D. R., Graziano, S. L., Leighl, N. B., Adjei, A. A., Schiller, J. H., Eastern Cooperative Oncology Grp AMER SOC CLINICAL ONCOLOGY. 2011

  View details for Web of Science ID 000208880302153

• Safety, pharmacokinetics (PK), and pharmacodynamics (PD) of HGS1029, an inhibitor of apoptosis protein (IAP) inhibitor, in patients (Pts) with advanced solid tumors: Results of a phase I study. Sikic, B. I., Eckhardt, S. G., Gallant, G., Burris, H. A., Camidge, D. R., Colevas, A. D., Jones, S. F., Messersmith, W. A., Wakelee, H. A., Li, H., Kaminker, P. G., Morris, S., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.3008

  View details for Web of Science ID 000208880301437

• Tumor Volume as a Potential Imaging-Based Risk-Stratification Factor in Trimodality Therapy for Locally Advanced Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Kozak, M. M., Murphy, J. D., Schipper, M. L., Donington, J. S., Zhou, L., Whyte, R. I., Shrager, J. B., Hoang, C. D., Bazan, J., Maxim, P. G., Graves, E. E., Diehn, M., Hara, W. Y., Quon, A., Quynh-Thu Le, Q. T., Wakelee, H. A., Loo, B. W. 2011; 6 (5): 920-926

  Abstract

  The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials.We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment.All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R² = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV ? median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival.Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.

  View details for DOI 10.1097/JTO.0b013e31821517db

  View details for PubMedID 21774104

• Survival following Non-Small Cell Lung Cancer among Asian/Pacific Islander, Latina, and Non-Hispanic White Women Who Have Never Smoked CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gomez, S. L., Chang, E. T., Shema, S. J., Fish, K., Sison, J. D., Reynolds, P., Clement-Duchene, C., Wrensch, M. R., Wiencke, J. L., Wakelee, H. A. 2011; 20 (3): 545-554

  Abstract

  Lung cancer is the leading cause of cancer death among U.S. Asian/Pacific Islander (API) and Latina women despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS).Women diagnosed with lung cancer from 1998 to 2003 and 2005 to 2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic (NH) white, 23 U.S.-born Latina, 32 foreign-born Latina, 30 U.S.-born API, and 190 foreign-born API never-smokers diagnosed with lung cancer and followed through 2008.All-cause survival was poorer among APIs [HR=1.7 (95% CI: 1.0-2.8) among U.S.-born APIs and HR=1.2 (95% CI: 0.9-1.5) among foreign-born APIs] and Latinas [HR=2.1 (95% CI: 1.2-3.6) among U.S.-born Latinas; HR=1.4 (95% CI: 0.9-2.3) among foreign-born Latinas] relative to NH whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors.Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations as possible explanations for these striking racial/ethnic differences.Latina and API female never-smokers diagnosed with lung cancer were up to two times more likely to die than NH whites, highlighting the need for additional research to identify the underlying reasons for the disparities and heightened clinical awareness.

  View details for DOI 10.1158/1055-9965.EPI-10-0965

  View details for Web of Science ID 000288067200017

  View details for PubMedID 21239685

  View details for PubMedCentralID PMC3070404

• Changes in FDG-PET/CT Parameters on Serial Pre-radiotherapy Scans Predict Disease Progression and Survival in Patients with Non-small Cell Lung Cancer Bazan, J. G., Chung, M. P., Eastham, D. V., Wakelee, H., Hara, W. Y., Maxim, P. G., Graves, E., Le, Q. T., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2011: S579?S580

  View details for Web of Science ID 000296411701268

• Stage IIIB and IV NSCLC: Primary Therapy LUNG CANCER: A MULTIDISCIPLINARY APPROACH TO DIAGNOSIS AND MANAGEMENT Das, M., Wakelee, H., Kernstine, K., Reckamp, K. 2011: 183?95

  View details for Web of Science ID 000283895900015

• Adjuvant chemotherapy for early stage non-small cell lung cancer. Frontiers in oncology Patel, M. I., Wakelee, H. A. 2011; 1: 45-?

  Abstract

  For many years adjuvant chemotherapy has been a standard treatment after complete resection in malignancies such as breast and colon but only recently has its use become standard in early stage non-small cell lung cancer (NSCLC). Although surgery is regarded as the best possible treatment for early stage NSCLC, only 20-25% of patients have resectable disease at presentation. Despite optimal surgical treatment, 5-year survival rates for NSCLC remain 50-60% for stage IB, 40-50% for stage II, and 20-30% for stage III (Kohler et al., 2011; Siegel et al., 2011). Adjuvant chemotherapy provides additional survival benefit in resected NSCLC but questions remain as to how to select patients for therapy and which regimen is best. Other than work with tegafur/uracil in Japan, the positive adjuvant trials have all utilized a cisplatin backbone, but the drug(s) to pair with cisplatin are a matter of debate and will be discussed further in this manuscript.

  View details for DOI 10.3389/fonc.2011.00045

  View details for PubMedID 22655247

• A Quantitative Assay of ERCC1 Expression in Circulating Tumor Cells (CTCs) in Non-small Cell Lung Cancer (NSCLC): A Potential Predictor of Treatment Response Das, M., Hsieh, B. H., Krivacic, R. T., Lazarus, N., Bennis, R., Ly, J., Schwartz, E., Zhou, L., Bruce, R. H., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2010: S535?S535

  View details for Web of Science ID 000284994100090

• Vascular Disrupting Agents JOURNAL OF THORACIC ONCOLOGY Das, M., Wakelee, H. 2010; 5 (12): S482-S483

  View details for PubMedID 21102249

• A Phase II Study Of Saracatinib (AZD0530), A Src Inhibitor, Administered Orally Daily To Patients With Advanced Thymic Malignancies Wakelee, H. A., Gubens, M. A., Burns, M., Barbeau, S. L., Perkins, S., Pedo-Salcedo, M. G., Loehrer, P. J. LIPPINCOTT WILLIAMS & WILKINS. 2010: S528?S528

  View details for Web of Science ID 000284994100072

• A Phase II First-Line Study of Gemcitabine, Carboplatin, and Bevacizumab in Advanced Stage Nonsquamous Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., McMillan, A., Kumar, A., Zhao, G., Padda, S., Zhou, L., San Pedro-Salcedo, M., Colevas, A. D., Wakelee, H. A. 2010; 5 (11): 1821-1825

  Abstract

  Bevacizumab improves responses and progression-free survival when added to first-line paclitaxel/carboplatin or cisplatin/gemcitabine for patients with advanced nonsquamous non-small cell lung cancer. This study was designed to evaluate toxicities and efficacy of gemcitabine/carboplatin/bevacizumab.Patients with untreated advanced nonsquamous non-small cell lung cancer, with no evidence of brain metastases and not on anticoagulation were eligible. Patients received gemcitabine 1000 mg/m on days 1 and 8; carboplatin area under the curve 5 day 1; and bevacizumab 15 mg/kg day 1 every 3 weeks for up to six cycles. Bevacizumab was then continued every 3 weeks until disease progression or unacceptable toxicity.From July 2006 to December 2008, 48 patients were enrolled: 23 (48%) men, 25 (52%) women, and 19 (40%) never smokers. One patient never received therapy and is not included in the analysis. Median cycle number was 8 (1-42) with 37 patients (78.7%) completing ?4 cycles of three drugs. Dose reductions occurred in 34 (72.3%) patients. Grade 3/4 toxicities included neutropenia (47%/15%), thrombocytopenia (11%/15%), anemia (6%/0%), dyspnea (6%/2%), bacterial pneumonia (4%/0%), and hypertension (4%/2%). No neutropenic fevers occurred. One patient died of hemoptysis. Grade 3 bleeding occurred in three other patients. There were seven (14.9%) partial responses. Median time to first event (progression/death/toxicity requiring discontinuation) was 6.4 months (95% confidence interval: 4.8-7.9 months). The median overall survival (OS) was 12.8 months (95% confidence interval: 10.0-16.5). The OS is 57% at 1 year and 10% at 2 years.Although perhaps skewed by a high proportion of nonsmokers and women, treatment with gemcitabine/carboplatin/bevacizumab has an acceptable toxicity profile with promising median OS despite a low response rate.

  View details for DOI 10.1097/JTO.0b013e3181f1d23c

  View details for PubMedID 20881641

• Lung Cancer Among Postmenopausal Women Treated With Estrogen Alone in the Women's Health Initiative Randomized Trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Chlebowski, R. T., Anderson, G. L., Manson, J. E., Schwartz, A. G., Wakelee, H., Gass, M., Rodabough, R. J., Johnson, K. C., Wactawski-Wende, J., Kotchen, J. M., Ockene, J. K., O'Sullivan, M. J., Hubbell, F. A., Chien, J. W., Chen, C., Stefanick, M. L. 2010; 102 (18): 1413-1421

  Abstract

  In the Women's Health Initiative (WHI) randomized controlled trial, use of estrogen plus progestin increased lung cancer mortality. We conducted post hoc analyses in the WHI trial evaluating estrogen alone to determine whether use of conjugated equine estrogen without progestin had a similar adverse influence on lung cancer.The WHI study is a randomized, double-blind, placebo-controlled trial conducted in 40 centers in the United States. A total of 10?739 postmenopausal women aged 50-79 years who had a previous hysterectomy were randomly assigned to receive a once-daily 0.625-mg tablet of conjugated equine estrogen (n = 5310) or matching placebo (n = 5429). Incidence and mortality rates for all lung cancers, small cell lung cancers, and non-small cell lung cancers in the two randomization groups were compared by use of hazard ratios (HRs) and 95% confidence intervals (CIs) that were estimated from Cox proportional hazards regression analyses. Analyses were by intention to treat, and all statistical tests were two-sided.After a mean of 7.9 years (standard deviation = 1.8 years) of follow-up, 61 women in the hormone therapy group were diagnosed with lung cancer compared with 54 in the placebo group (incidence of lung cancer per year = 0.15% vs 0.13%, respectively; HR of incidence = 1.17, 95% CI = 0.81 to 1.69, P = .39). Non-small cell lung cancers were of comparable number, stage, and grade in both groups. Deaths from lung cancer did not differ between the two groups (34 vs 33 deaths in estrogen and placebo groups, respectively; HR of death = 1.07, 95% CI = 0.66 to 1.72, P = .79).Unlike use of estrogen plus progestin, which increased deaths from lung cancer, use of conjugated equine estrogen alone did not increase incidence or death from lung cancer.

  View details for DOI 10.1093/jnci/djq285

  View details for Web of Science ID 000282176600010

  View details for PubMedID 20709992

  View details for PubMedCentralID PMC2943522

• AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer CURRENT OPINION IN MOLECULAR THERAPEUTICS Neal, J., Wakelee, H. 2010; 12 (4): 487-495

  Abstract

  The VEGF/VEGFR and angiopoietin/Tie-2 signaling pathways are important in the process of vascular endothelial growth (angiogenesis) and in the maintenance of tumor-associated blood vessels. While there are several agents targeting the VEGF/VEGFR signaling pathway, there are none available that target the angiopoietin/Tie-2 signaling pathway. The first such agent to reach clinical trials is AMG-386 (2xCon4C), being developed by Amgen Inc and licensed in Japan to Takeda Bio Development Center Ltd. AMG-386 is an anti-angiopoietin peptibody comprising a peptide with angiopoietin-binding properties that is fused to the Fc (crystallizable fragment) region of an antibody and inhibits the interaction between the ligands angiopoietin-1 and angiopoietin-2 with the Tie-2 receptor. AMG-386 significantly inhibited the growth of tumors in a variety of mouse xenograft models. In phase I trials of AMG-386 as a monotherapy or in combination with chemotherapy in patients with advanced solid tumors, AMG-386 demonstrated only mild toxicities, and one complete response and several partial responses were achieved in patients. Phase II trials of AMG-386 in combination with chemotherapy were ongoing in a variety of solid tumors, including breast, ovarian, colorectal, gastric and renal cell cancers. If safe and effective, AMG-386 could be an exciting addition to other antiangiogenic therapies in solid tumors.

  View details for PubMedID 20677100

• A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC). Wakelee, H. A., Gettinger, S. N., Engelman, J. A., Janne, P. A., West, H. J., Subramaniam, D. S., Leach, J. W., Wax, M. B., Yaron, Y., Lara, P. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for Web of Science ID 000208852003222

• Thymic malignancies (TM) in the United States: A population-based study of incidence and survival trends Gubens, M. A., Clement-Duchene, C., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.1606

  View details for Web of Science ID 000208852002773

• Survival among never and ever smokers with lung cancer in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study Clement-Duchene, C., Xu, X., Gomez, S. L., Chang, E. T., West, D. W., Wakelee, H. A., Gould, M. K. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.1595

  View details for Web of Science ID 000208852002762

• Phase I study evaluating the safety, tolerability, and pharmacokinetics (PK) of HGS1029, a small-molecule inhibitor of apoptosis protein (IAP), in patients (pts) with advanced solid tumors. Eckhardt, S. G., Gallant, G., Sikic, B. I., Camidge, D. R., Burris, H. A., Wakelee, H. A., Messersmith, W. A., Jones, S. F., Colevas, A. D., Infante, J. R. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for Web of Science ID 000208852003171

• A phase I study of aflibercept, pemetrexed (P), and cisplatin (C) in patients with advanced solid tumors. Townsley, C. A., Siu, L. L., Pedro-Salcedo, M., Liu, L., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2010

  View details for DOI 10.1200/jco.2010.28.15_suppl.2536

  View details for Web of Science ID 000208852003127

• Estrogen Alone and Lung Cancer in Postmenopausal Women Chlebowski, R., Anderson, G., Manson, J., Schwartz, A., Wakelee, H., Gass, M., Rodabough, R., Johnson, K., Wactawski-Wende, J., Stefanick, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: 394?94

  View details for Web of Science ID 000277538600050

• Voreloxin, a First-in-Class Anticancer Quinolone Derivative, in Relapsed/Refractory Solid Tumors: A Report on Two Dosing Schedules CLINICAL CANCER RESEARCH Advani, R. H., Hurwitz, H. I., Gordon, M. S., Ebbinghaus, S. W., Mendelson, D. S., Wakelee, H. A., Hoch, U., Silverman, J. A., Havrilla, N. A., Berman, C. J., Fox, J. A., Allen, R. S., Adelman, D. C. 2010; 16 (7): 2167-2175

  Abstract

  Voreloxin, a novel replication-dependent DNA-damaging agent, intercalates DNA and inhibits topoisomerase II. Voreloxin induces site-selective DNA double-strand breaks and apoptosis. We report the phase 1 experience of voreloxin in patients with relapsed/refractory solid tumors, including dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, and clinical activity.Two dose-escalation studies evaluated voreloxin administered i.v. every 3 weeks (SPO-0001) or weekly for 3 weeks every 28 days (SPO-0002). In SPO-0001, patients were classified as heavily pretreated (HP) or minimally pretreated (MP) based on therapeutic history.In the SPO-0001 study, 41 patients (24 HP/17 MP) were treated in eight dose cohorts (3-75 mg/m(2)). At 60 mg/m(2), four HP patients experienced DLTs: grade 4 neutropenia (n = 3, one with fever) and grade 3 febrile neutropenia/pneumonia (n = 1). At 75 mg/m(2), two MP patients experienced DLTs: grade 4 neutropenia/thrombocytopenia (n = 1) or grade 2 oral thrush for >29 days (n = 1). Therefore, the MTD was 48 mg/m(2) (HP patients) and 60 mg/m(2) (MP patients). In the SPO-0002 study, 21 patients were treated in six dose cohorts (3-24 mg/m(2)). At 18 mg/m(2), two patients experienced DLTs: grade 3 neutropenia, one with pleural effusion (>14 days each). The MTD was 15 mg/m(2). Voreloxin exhibited low clearance (2 L/h/m(2)), a long terminal half-life (22 hours), and dose-proportional exposure. Overall, 31 of 62 patients had stable disease and 1 patient (ovarian cancer) had a partial response per Rustin criteria.Voreloxin showed an acceptable safety profile with clinical activity in patients with relapsed/refractory solid tumors. The MTD was schedule-dependent. Voreloxin is currently in clinical studies of ovarian cancer and acute myeloid leukemia.

  View details for DOI 10.1158/1078-0432.CCR-09-2236

  View details for PubMedID 20233886

• Anti-angiogenesis drugs in lung cancer RESPIROLOGY Lee, S., Baas, P., Wakelee, H. 2010; 15 (3): 387?92

  Abstract

  In the last years much attention has been given to the implementation of the so-called targeted drugs. One of the targets of tumours is the vasculature and this has led to the development of anti-angiogenic drugs. In lung cancer the use of these drugs has resulted in both positive and negative studies. In this paper the pros and cons are presented. We hope that this information will help the physician in making a proper treatment choice.

  View details for DOI 10.1111/j.1440-1843.2010.01715.x

  View details for Web of Science ID 000276036400003

  View details for PubMedID 20337999

• Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors ANNALS OF ONCOLOGY Wakelee, H. A., Patnaik, A., Sikic, B. I., Mita, M., Fox, N. L., Miceli, R., Ullrich, S. J., Fisher, G. A., Tolcher, A. W. 2010; 21 (2): 376-381

  Abstract

  Lexatumumab (HGS-ETR2) is a fully human agonistic mAb to the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 that activates the extrinsic apoptosis pathway and has potent preclinical antitumor activity. Materials and methods: This phase 1, dose escalation study assessed the safety, tolerability, pharmacokinetics (PKs) and immunogenicity of lexatumumab administered i.v. every 14 days in patients with advanced solid tumors.Thirty-one patients received lexatumumab over five dose levels (0.1-10 mg/kg). Most (26 of 31) received four or more cycles of treatment. One patient at 10 mg/kg experienced a possibly related dose-limiting toxicity of grade 3 hyperamylasemia. Nine patients achieved stable disease. One patient with chemotherapy-refractive Hodgkin's disease experienced a mixed response. Lexatumumab PKs were linear up to 10 mg/kg. At the 10 mg/kg dose, the mean (+/-standard deviation) t(1/2b) was 13.67 +/- 4.07 days, clearance was 4.95 +/- 1.93 ml/day/kg, V(1) was 45.55 ml/kg and V(ss) was 79.08 ml/kg, indicating that lexatumumab distributes outside the plasma compartment. No human antihuman antibodies were detected.Lexatumumab can be safely administered every 14 days at 10 mg/kg. The PK profile supports this schedule. Further evaluation of lexatumumab at this dose schedule is warranted, including combination trials with other agents.

  View details for DOI 10.1093/annonc/mdp292

  View details for PubMedID 19633048

• Lung cancer and hormone replacement therapy reply LANCET Chlebowski, R. T., Schwartz, A. G., Wakelee, H., Anderson, G. L. 2010; 375 (9709): 118?19

  View details for DOI 10.1016/S0140-6736(10)60042-6

  View details for Web of Science ID 000273664500019

• Antiangiogenic Agents and Vascular Disrupting Agents for the Treatment of Lung Cancer A Review JOURNAL OF THORACIC ONCOLOGY Clement-Duchene, C., Wakelee, H. 2010; 5 (1): 129-139

  Abstract

  Although lung cancer therapy has slowly improved with standard cytotoxic chemotherapy drugs, we have reached an efficacy plateau. The addition of targeted agents, such as those with antiangiogenesis activity, to chemotherapy can improve response and survival outcomes. The first of these agents to gain approval in lung cancer in October 2006 was the antivascular endothelial growth factor antibody, bevacizumab. Small molecule tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor also have proven activity and are under active investigation. Vascular disrupting agents target existing tumor vasculature leading to tumor necrosis, and are being studied in solid tumors, including lung cancer, both as single agents and in combination with chemotherapy. This article will review these new targeted antiangiogenic and antivascular agents with a focus on their use as lung cancer therapeutics.

  View details for Web of Science ID 000273496000022

  View details for PubMedID 19952799

• Lung Cancer Sex Differences FEMALE SEX HORMONES AND CANCERS Hsu, J. Y., Wakelee, H. A., Chen, G. G. 2010: 149?70

  View details for Web of Science ID 000284351500009

• Docetaxel in the treatment of non-small cell lung carcinoma: an update and analysis. Lung Cancer (Auckland, N.Z.) Gubens, M. A., Wakelee, H. A. 2010; 1: 63-76

  Abstract

  Docetaxel, a semisynthetic taxane, was the first agent to show efficacy in the second-line treatment of non-small cell lung cancer (NSCLC), and has since become a mainstay of NSCLC therapy. We review its mode of action, pharmacology, toxicity and efficacy and describe both its established role in the treatment of NSCLC and future directions in research. Docetaxel works primarily by promoting microtubule assembly and polymerization, and through this hyperstabilization, causes cell cycle arrest and death. The primary toxicity of docetaxel is neutropenia, which can be mitigated by weekly administration in selected patients. Less common toxicities are peripheral edema, which can be reduced by appropriate premedication and interstitial pneumonitis. Hypersensitivity reactions are less frequent than with paclitaxel. Docetaxel has shown a survival and quality of life advantage as a single agent first- and second-line versus placebo, as well as first-line in a platinum-based doublet therapy compared to a single agent. Increasingly docetaxel has also been used effectively in adjuvant regimens in earlier stages of the disease. Future areas of research include combinations with novel targeted therapies, and a greater understanding of biomarkers that might help predict efficacy and personalize therapy.

  View details for PubMedID 28210107

• Marked Tumor Response and Fatal Hemoptysis During Radiation for Lung Cancer in a Human Immunodeficiency Virus-Positive Patient Taking Nelfinavir JOURNAL OF THORACIC ONCOLOGY Chapman, C. H., Shen, J., Filion, E. J., Tran, P. T., Hara, W., Asuncion, A., Marko, D., Wakelee, H., Berry, G. J., Dimmick, K. W., Loo, B. W., Green, J. 2009; 4 (12): 1587-1589

  View details for PubMedID 20009915

• Cooperative Group Research Efforts in Thoracic Malignancies 2009: A Review From the 10th Annual International Lung Cancer Congress CLINICAL LUNG CANCER Wakelee, H., Loo, B. W., Kernstine, K. H., Putnam, J. B., Edelman, M. J., Vokes, E. E., Schiller, J. H., Baas, P., Saijo, N., Adjei, A., Goss, G., Choy, H., Gandara, D. R. 2009; 10 (6): 395-404

  Abstract

  Critical advances in the treatment of patients with lung cancer have occurred in the past few years. The cooperative groups in North America and internationally have played crucial roles in these advances. The leaders of the groups meet on a regular basis to review the progress of their trials. However, they rarely have a chance to discuss all ongoing and planned trials, except at the annual Lung Cancer Congress held each June. This article captures this exchange from the 10th Annual Lung Cancer Congress held in June 2009. Exciting efforts are ongoing for all stages of non-small-cell lung cancer, small-cell lung cancer, and mesothelioma. A major focus of the groups at this time is a push toward more personalized medicine, as reflected in the selection criteria for many of the trials, along with planned correlates to better define populations most likely to benefit. Agents targeting the vascular endothelial growth factor (VEGF) pathway, including many tyrosine kinase inhibitors against the VEGF receptor, and those targeting the epidermal growth factor receptor pathway, are under extensive development with many combination trials ongoing.

  View details for DOI 10.3816/CLC.2009.n.075

  View details for PubMedID 19900856

• Vascular Endothelial Growth Factor Pathway JOURNAL OF THORACIC ONCOLOGY Krupitskaya, Y., Wakelee, H. 2009; 4 (11): S1071?S1073

  View details for PubMedID 19861922

• Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial LANCET Chlebowski, R. T., Schwartz, A. G., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Rodabough, R. J., Chien, J. W., Wactawski-Wende, J., Gass, M., Kotchen, J. M., Johnson, K. C., O'Sullivan, M. J., Ockene, J. K., Chen, C., Hubbell, F. A. 2009; 374 (9697): 1243-1251

  Abstract

  In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period.The WHI study was a randomised, double-blind, placebo-controlled trial undertaken in 40 centres in the USA. 16 608 postmenopausal women aged 50-79 years with an intact uterus were randomly assigned by a computerised, stratified, permuted block algorithm to receive a once-daily tablet of 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (n=8506) or matching placebo (n=8102). We assessed incidence and mortality rates for all lung cancer, small-cell lung cancer, and non-small-cell lung cancer by use of data from treatment and post-intervention follow-up periods. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00000611.After a mean of 5.6 years (SD 1.3) of treatment and 2.4 years (0.4) of additional follow-up, 109 women in the combined hormone therapy group had been diagnosed with lung cancer compared with 85 in the placebo group (incidence per year 0.16%vs 0.13%; hazard ratio [HR] 1.23, 95% CI 0.92-1.63, p=0.16). 96 women assigned to combined therapy had non-small-cell lung cancer compared with 72 assigned to placebo (0.14%vs 0.11%; HR 1.28, 0.94-1.73, p=0.12). More women died from lung cancer in the combined hormone therapy group than in the placebo group (73 vs 40 deaths; 0.11%vs 0.06%; HR 1.71, 1.16-2.52, p=0.01), mainly as a result of a higher number of deaths from non-small-cell lung cancer in the combined therapy group (62 vs 31 deaths; 0.09%vs 0.05%; HR 1.87, 1.22-2.88, p=0.004). Incidence and mortality rates of small-cell lung cancer were similar between groups.Although treatment with oestrogen plus progestin in postmenopausal women did not increase incidence of lung cancer, it increased the number of deaths from lung cancer, in particular deaths from non-small-cell lung cancer. These findings should be incorporated into risk-benefit discussions with women considering combined hormone therapy, especially those with a high risk of lung cancer.National Heart, Lung and Blood Institute, National Institutes of Health.

  View details for DOI 10.1016/S0140-6736(09)61526-9

  View details for Web of Science ID 000270852500030

  View details for PubMedID 19767090

• A phase II first line study of gemcitabine, carboplatin and bevacizumab in advanced stage non-squamous non-small cell lung cancer Clement-Duchene, C., Krupitskaya, Y., Ganjoo, K., Lavori, P., Kumar, A., Zhao, G., Padda, S., San Pedro-Salcedo, M., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2009: S674?S674

  View details for Web of Science ID 000269496002133

• A randomized discontinuation phase II study of sorafenib vs placebo in patients with non-small cell lung cancer (NSCLC) who failed at least two prior chemotherapy regimens: E2501 Schiller, J., Lee, J., Hanna, N. H., Traynor, A. M., Wakelee, H., Carbone, D. P. LIPPINCOTT WILLIAMS & WILKINS. 2009: S355?S356

  View details for Web of Science ID 000269496001086

• Angiogenesis in lung cancer: role of anti-angiogenic TKI's Wakelee, H. A., Clement-Duchene, C. LIPPINCOTT WILLIAMS & WILKINS. 2009: S24?S26

  View details for Web of Science ID 000269496000021

• Survival after non-small cell lung cancer in never-smoking Asian/Pacific Islander and Latina women Wakelee, H. A., Chang, E. T., Shema, S., Reynolds, P., Clement-Duchene, C., Wiencke, J., Gomez, S. L. LIPPINCOTT WILLIAMS & WILKINS. 2009: S310

  View details for Web of Science ID 000269496001004

• A single arm phase 2 study of enzastaurin in combination with erlotinib, both administered orally daily, to patients with advanced non-small cell lung cancer (NSCLC) Wakelee, H. A., Dubey, S., Krupitskaya, Y., Osarogiagbon, R. U., Sanborn, R. E., Bernstein, E. D., Dudek, A. Z., Latz, J. E., Yuan, Z., Natale, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2009: S445?S445

  View details for Web of Science ID 000269496001254

• Mid-treatment PET predicts progression in hypofractionated accelerated radiation therapy for lung tumors Chang, C. N., Fillion, E., Chapman, C., Rao, A., Wakelee, H., Ganjoo, K., Le, Q., Maxim, P., Quon, A., Graves, E. E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S939?S939

  View details for Web of Science ID 000269496002721

• Excellent early local control with tumor volume adapted dosing of stereotactic body radiation therapy for pulmonary tumors Chang, C. N., Zhou, L. Y., MacFarlane, G., Tran, P., Rao, A., Chapman, C., Le, Q., Wakelee, H., Colevas, A. D., Whyte, R., Hristov, D., Dieterich, S., Maxim, P., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S938?S939

  View details for Web of Science ID 000269496002720

• Quantification of pre-treatment metabolic tumor growth rate in lung cancer Eastham, D., Chapman, C. H., Rao, A. K., Balasubramanian, N., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, D. A., Maxim, P. A., Graves, E., Loo, B. W. LIPPINCOTT WILLIAMS & WILKINS. 2009: S733?S733

  View details for Web of Science ID 000269496002262

• Uncovering Disparities in Survival after Non-Small-Cell Lung Cancer among Asian/Pacific Islander Ethnic Populations in California CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chang, E. T., Shema, S. J., Wakelee, H. A., Clarke, C. A., Gomez, S. L. 2009; 18 (8): 2248-2255

  Abstract

  Asians may have better survival after non-small-cell lung cancer (NSCLC) than non-Asians. However, it is unknown whether survival varies among the heterogeneous U.S. Asian/Pacific Islander (API) populations. Therefore, this study aimed to quantify survival differences among APIs with NSCLC. Differences in overall and disease-specific survival were analyzed in the California Cancer Registry among 16,577 API patients diagnosed with incident NSCLC between 1988 and 2007. Adjusted hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression models with separate baseline hazards by disease stage. Despite better overall and disease-specific survival among APIs compared with non-Hispanic Whites, differences were evident across API populations. Among women, Japanese (overall survival HR, 1.16; 95% CI, 1.06-1.27) and APIs other than those in the six largest ethnic groups (other APIs; HR, 1.19; 95% CI, 1.07-1.33) had significantly poorer overall and disease-specific survival than Chinese. By contrast, South Asian women had significantly better survival than Chinese (HR, 0.79; 95% CI, 0.63-0.97). Among men, Japanese (HR, 1.15; 95% CI, 1.07-1.24), Vietnamese (HR, 1.07; 95% CI, 1.00-1.16), and other APIs (HR, 1.18; 95% CI, 1.08-1.28) had significantly poorer overall and disease-specific survival than Chinese. Other factors independently associated with poorer survival were lower neighborhood socioeconomic status, involvement with a non-university hospital, unmarried status, older age, and earlier year of diagnosis. APIs have significant ethnic differences in NSCLC survival that may be related to disparate lifestyles, biology, and especially health care access or use. To reduce the nationwide burden of lung cancer mortality, it is critical to identify and ameliorate hidden survival disparities such as those among APIs.

  View details for DOI 10.1158/1055-9965.EPI-09-0332

  View details for Web of Science ID 000268958600016

  View details for PubMedID 19622719

  View details for PubMedCentralID PMC2764550

• Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women's Health Initiative randomized clinical trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chlebowski, R. T., Schwartz, A., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Chien, J. W., Chen, C., Wactawski-Wende, J., Gass, M. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276607000022

• Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer CURRENT OPINION IN INVESTIGATIONAL DRUGS Krupitskaya, Y., Wakelee, H. A. 2009; 10 (6): 597-605

  Abstract

  Angiogenesis is essential for tumor growth, invasion and metastasis, and is mediated, at least in part, by a large family of VEGF ligands and receptors. Ramucirumab, which is being developed by ImClone Systems Inc, is a fully human mAb that binds human VEGFR-2, thus blocking VEGF binding and inhibiting angiogenesis. Proof-of-concept preclinical studies with the mouse mAb DC-101 supported this hypothesis, and ramucirumab inhibited cell proliferation in vitro, as well as tumor progression in mouse xenograft models of human cancer. Ramucirumab was well tolerated on weekly and fortnightly schedules in phase I clinical trials in patients with advanced cancers; mechanism-related DLTs were hypertension and deep venous thrombosis. Stable disease was also observed in several patients treated on either schedule, and several patients on the weekly schedule exhibited partial responses. At the time of publication, ramucirumab was undergoing assessment in phase II trials as a monotherapy in hepatocellular, renal cell and ovarian carcinomas. Ramucirumab was also in phase II trials in combination with dacarbazine in melanoma, with mitoxantrone/prednisone in prostate cancer, with carboplatin/paclitaxel in NSCLC and with oxaliplatin/folinic acid/5-fluorouracil in colorectal cancer. A phase III trial in combination with docetaxel in breast cancer was also ongoing. Pending results from these trials, ramucirumab may be a useful addition to current antiangiogenic therapies. The results are awaited with interest.

  View details for PubMedID 19513949

• A phase II first-line study of gemcitabine, carboplatin, and bevacizumab (GCB) in advanced (adv) stage non-squamous non-small cell lung cancer (NSCLC) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Krupitskaya, Y., Ganjoo, K., Lavori, P. W., Kumar, A., Clement-Duchene, C., Zhao, G., Padda, S., San Pedro-Salcedo, M., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605334

• Non-small cell lung cancer and estrogen plus progestin use in postmenopausal women in the Women's Health Initiative randomized clinical trial 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chlebowski, R. T., Schwartz, A., Wakelee, H., Anderson, G. L., Stefanick, M. L., Manson, J. E., Chien, J. W., Chen, C., Wactawski-Wende, J., Gass, M. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606602097

• Gemcitabine and pemetrexed administered in rapid sequence as front-line chemotherapy for advanced non-small-cell lung cancer: a phase II clinical trial ANNALS OF ONCOLOGY West, H. L., Wakelee, H. A., Perry, M. C., Belt, R. J., Chen, R., Obasaju, C. 2009; 20 (5): 850-856

  Abstract

  Previous studies of the gemcitabine-pemetrexed combination in patients with late-stage non-small-cell lung cancer (NSCLC) utilized a 90-min delay between gemcitabine and pemetrexed administration. This phase II study evaluated activity when these agents were administered in rapid succession.Chemonaive patients with late-stage NSCLC received gemcitabine 1250 mg/m(2) on days 1 and 8, with pemetrexed 500 mg/m(2) immediately following day 8 gemcitabine every 21 days for six cycles, folic acid, B(12), and steroid prophylaxis.Fifty-four enrolled patients (53 treated) completed a median of four cycles. Median dose intensity was 84% (gemcitabine) and 83% (pemetrexed); 68% of patients required dose adjustments. Response was as follows: complete response, 0; partial response, 7 (13%); stable disease, 29 (54%); progressive disease, 9 (17%); and unknown/unavailable, 9 (17%). Median progression-free and overall survival was 4.6 and 12.4 months, respectively. Common grade 3 or 4 toxic effects were as follows: neutropenia (40%); fatigue and dyspnea (21% each); pneumonia (17%); febrile neutropenia and thrombocytopenia (11% each); and anemia (6%).The gemcitabine-pemetrexed combination is minimally active in late-stage NSCLC, with a high incidence of grade 3 or 4 toxic effects requiring frequent dose adjustments. A gemcitabine dose <1250 mg/m(2) warrants consideration for future trials exploring this doublet. Administering day 8 pemetrexed immediately after gemcitabine does not appear to negatively impact therapeutic index.

  View details for DOI 10.1093/annonc/mdn715

  View details for Web of Science ID 000265739700008

  View details for PubMedID 19150937

• Y Quantification of multiple biomarker expression in circulating tumor cells Hsieh, H., Bethel, K., Curry, D., Jeffrey, S., Krivacic, R., Kuhn, P., Lazarus, N., Marrinucci, D., Nieva, J., Schwartz, E., Somlo, G., Wakelee, H., Bruce, R. AMER ASSOC CANCER RESEARCH. 2009

  View details for Web of Science ID 000209701805127

• Osteoblastic Bone Flare on F18-FDG PET in Non-small Cell Lung Cancer (NSCLC) Patients Receiving Bevacizumab in Addition to Standard Chemotherapy JOURNAL OF THORACIC ONCOLOGY Krupitskaya, Y., Eslamy, H. K., Nguyen, D. D., Kumar, A., Wakelee, H. A. 2009; 4 (3): 429-431

  Abstract

  Positron emission tomography (PET) is used routinely to follow therapeutic response in patients treated for non-small cell lung cancer (NSCLC). In responding patients it is generally expected that the observed decrease in fluorodeoxyglucose uptake should be similar in all lesions. In other disease entities though, isolated cases have been documented of asynchronous increases in activity in metastatic bone lesions ("bone flare") despite evidence of therapeutic response or stability in other lesions. Here, we describe four NSCLC cases in which the results of interim PET scans were misleading due to osteoblastic flare phenomenon. In all four cases, patients were treated with bevacizumab in addition to standard chemotherapy. All four patients developed isolated worsening of their skeletal metastases on PET/CT (computed tomography) analysis (increase in fluorodeoxyglucose activity) despite apparent response or stable disease elsewhere. Subsequent scans confirmed that the "worsening" was transient, consistent with a flare response. Awareness of the phenomena is important for physicians treating NSCLC patients, particularly with bevacizumab.

  View details for PubMedID 19247091

• Monoclonal Antibodies Targeting Vascular Endothelial Growth Factor Current Status and Future Challenges in Cancer Therapy BIODRUGS Hsu, J. Y., Wakelee, H. A. 2009; 23 (5): 289-304

  Abstract

  The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma. Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common. Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.

  View details for PubMedID 19754219

• Does Pre-treatment Metabolic Tumor Growth Rate (MTGR) Predict Progression in Lung Cancer? 51st Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Eastham, D. V., Chapman, C. H., Rao, A. K., Narasimhan, B., Quon, A., Vasanawala, M. S., Wakelee, H., Le, Q., Colevas, A. D., Loo, B. W. ELSEVIER SCIENCE INC. 2009: S446?S446

  View details for Web of Science ID 000270573601456

• Systemic VEGF Inhibition Induces Hepatic EPO Production and Erythrocytosis Via HIF-2a-Dependent and -Independent Mechanisms 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Wei, K., Logan, A. C., Wakelee, H., Simon, M. C., Kuo, C. J. AMER SOC HEMATOLOGY. 2008: 183?84

  View details for Web of Science ID 000262104700483

• Cooperative Group Research Efforts in Lung Cancer 2008: Focus on Advanced-Stage Non-Small-Cell Lung Cancer CLINICAL LUNG CANCER Wakelee, H., Kernstine, K., Vokes, E., Schiller, J., Baas, P., Saijo, N., Adjei, A., Goss, G., Gaspar, L., Gandara, D. R., Choy, H., Putnam, J. ". 2008; 9 (6): 346-351

  Abstract

  Clinical trials performed within the cooperative group system play a substantial role in the advancing of lung cancer therapy. Interactions between the leaders of the cooperative groups are critical and occur regularly throughout the year, but the annual Lung Cancer Congress provides a unique forum for representatives from each group to present ongoing and planned studies in an interactive forum. Herein, we highlight discussion from the 9th annual Lung Cancer Congress in June 2008, focused on advanced-stage non-small-cell lung cancer (NSCLC). Many studies are looking at the addition of targeted agents such as bevacizumab, cetuximab, vascular endothelial growth factor receptor inhibitors, and apoptosis-inducing agents to chemotherapy. Personalizing therapy by better selection of patients for particular drugs is also being emphasized, most notably epidermal growth factor receptor fluorescence in situ hybridization overexpression and other predictions of response with cetuximab. Future articles in this series will address early and locally advanced NSCLC as well as other thoracic malignancies such as small-cell lung cancer and mesothelioma. Ongoing trials within the cooperative groups are an essential component of the persistent improvement in the treatment of lung cancer.

  View details for DOI 10.3816/CLC.2008.n.050

  View details for PubMedID 19073517

• Adjuvant chemotherapy for resected non-small cell lung cancer. Seminars in thoracic and cardiovascular surgery Wakelee, H., Chhatwani, L. 2008; 20 (3): 198-203

  Abstract

  Surgery remains the mainstay of therapy for early stage non-small cell lung cancer (NSCLC), but even for stage IA, disease relapse rates remain as high as 30%. Patients with completely resected (R0) N1 disease have about a 50% chance of relapse. In the past 5 years, the benefit of adjuvant chemotherapy has finally been demonstrated for patients with lung cancer. Improvements of 5% to 10% 5-year survival have been reported with cisplatin-based chemotherapy. Still, cure rates have significant room for improvement and ongoing trials with "targeted" agents such as those active against the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), and vaccine therapy will hopefully further increase the odds for patients with resected disease. Other studies looking at tumor gene and protein expression will lead us toward better identification of patients most likely to benefit from therapy.

  View details for DOI 10.1053/j.semtcvs.2008.09.001

  View details for PubMedID 19038728

• A phase I study of enzastaurin (ENZ), an oral PKC inhibitor, in combination with erlotinib (ERL) administered orally daily to patients with advanced solid malignancies Wakelee, H. A., Padda, S. K., Chhatwani, L., Pedro-Salcedo, M., Krupitskaya, Y., Musib, L., Latz, J. E. PERGAMON-ELSEVIER SCIENCE LTD. 2008: 126

  View details for DOI 10.1016/S1359-6349(08)72335-8

  View details for Web of Science ID 000261221200400

• PEMETREXED DISODIUM FOR THE TREATMENT OF NSCLC: AN UPDATE DRUGS OF TODAY Hsu, J. Y., Wakelee, H. 2008; 44 (9): 669-678

  Abstract

  Pemetrexed disodium is a multitargeted antifolate cytotoxic chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) initially for the treatment of malignant pleural mesothelioma, and in August 2004 for second-line treatment of non-small cell lung cancer (NSCLC). In September 2008, the FDA also approved pemetrexed and cisplatin as first-line therapy for NSCLC. Pemetrexed is also no longer recommended for treatment of NSCLC with squamous cell carcinoma histology. Pemetrexed is currently being tested in clinical trials as part of second-line combination, first-line, adjuvant and maintenance therapies.

  View details for DOI 10.1358/dot.2008.44.9.1250412

  View details for PubMedID 19137122

• Sex differences in lung-cancer susceptibility: a smoke screen? LANCET ONCOLOGY Wakelee, H. A., Gomez, S. L., Chang, E. T. 2008; 9 (7): 609-610

  View details for Web of Science ID 000257527400006

  View details for PubMedID 18598927

• Summary statement - Novel Agents in the Treatment of Lung Cancer: Fifth Cambridge Conference assessing opportunities for combination therapy JOURNAL OF THORACIC ONCOLOGY Lynch, T. J., Blumenschein, G. R., Engelman, J. A., Espinoza-Delgado, I., Govindan, R., Hanke, J., Hanna, N. H., Heymach, J. V., Hirsch, F. R., Janne, P. A., Lilenbaum, R. C., Natale, R. B., Riely, G. J., Sequist, L. V., Shapiro, G. T., Shaw, A., Shepherd, F. A., Socinski, M., Sorensen, A. G., Wakelee, H. A., Weitzman, A. 2008; 3 (6): S107-S112

  Abstract

  The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective "drugs" for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1-2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.

  View details for Web of Science ID 000256828300001

  View details for PubMedID 18520291

• Antibodies to vascular endothelial growth factor in non-small cell lung cancer JOURNAL OF THORACIC ONCOLOGY Wakelee, H. 2008; 3 (6): S113-S118

  Abstract

  Angiogenesis, formation of new vasculature, is critical to cancer growth. Agents that block angiogenesis, in particular bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor, the key ligand in angiogenesis, have become an important option for many patients with non-small cell lung cancer (NSCLC). Activity was first demonstrated in Eastern Cooperative Oncology Group E4599, a large phase 3 trial that randomized patients with newly diagnosed, nonsquamous NSCLC to receive carboplatin/paclitaxel with or without bevacizumab at 15 mg/kg every 3 weeks. The study demonstrated significant improvements in response rate, progression-free survival, and overall survival with the addition of bevacizumab. Median overall survival improved from 10.3 to 12.3 months (p = 0.003). Significant toxic effects, including fatal hemoptysis, however, resulted in 15 treatment-related deaths in the bevacizumab arm. The beneficial results were recently confirmed in the European Avastin in Lung Cancer B017704 (AVAiL) trial. In AVAiL, patients with newly diagnosed nonsquamous NSCLC were randomized to receive cisplatin/gemcitabine with or without bevacizumab at doses of either 7.5 or 15 mg/kg every 3 weeks. Both doses resulted in statistically significant improvements in response rate and progression-free survival, but overall survival results have yet to be presented. Based on these encouraging results, the drug is now being studied in earlier-stage disease as neoadjuvant or adjuvant therapy and in locally advanced NSCLC. Exploration of the safety and efficacy of the drug in combination with other chemotherapeutics and targeted agents, and in previously excluded patient populations such as those with brain metastases, is also ongoing.

  View details for PubMedID 18520292

• A phase I study of XL647, an EGFR, HER2, VEGFR2 inhibitor, administered orally daily to patients (pts) with advanced solid malignancies (ASM) Wakelee, H. A., Fehling, J. M., Molina, J. R., Lensing, J. L., Funke, R. P., Miles, D., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457400823

• Activity and tolerance of XL647 in NSCLC patients with acquired resistance to EGFR-TKIs: Preliminary results of a phase II trial Miller, V. A., Wakelee, H. A., Lara, P. N., Cho, J., Chowhan, N. M., Costa, D., Vrindavanam, N., Yanagihara, R., Pennell, N., Lynch, T. J. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for DOI 10.1200/jco.2008.26.15_suppl.8028

  View details for Web of Science ID 000208457402801

• Complications of ablative therapies in lung cancer CLINICAL LUNG CANCER Padda, S., Kothary, N., Donington, J., Cannon, W., Loo, B. W., Kee, S., Wakelee, H. 2008; 9 (2): 122-126

  Abstract

  Two cases of complications secondary to the use of microwave ablation (MWA) in non-small-cell lung cancer (NSCLC) are discussed herein. The first case involves a 62-year-old man with stage IB NSCLC who declined surgery and pursued MWA. Within 7 months, he had residual disease at the MWA treatment site, and surgery was performed. The patient was found to have pleural and chest wall involvement, making complete resection impossible. The second case involves an 86-year-old woman with a second local recurrence of NSCLC and previous treatment including surgery and chemoradiation therapy. She was initially a surgical candidate but declined surgery and pursued MWA. Within 6 months, she had residual disease at the MWA treatment site. A second MWA was performed, and she developed a large cavitary abscess at the MWA site and had subsequent clinical decline. Less invasive ablation therapies and stereotactic radiosurgery are being developed for patients with inoperable lung cancer. Because these modalities have recently been developed, trials that clearly show efficacy and survival benefit are yet to be completed. Ablation procedures can result in complications, including residual disease and cavitary lesions susceptible to infection. These cases highlight the caution that should still be observed when recommending lung ablation strategies and the importance of selecting appropriate patients.

  View details for PubMedID 18501100

• Diagnosis in oncology - Lung cancer presenting with amegakaryocytic thrombocytopenia JOURNAL OF CLINICAL ONCOLOGY Witteles, W. H., Schrier, S. L., Wakelee, H. A. 2008; 26 (7): 1171-1174

  View details for DOI 10.1200/JCO.2007.14.8106

  View details for Web of Science ID 000254178100025

• Cooperative group portfolio in locally advanced non-small-cell lung cancer: Are we making progress? CLINICAL LUNG CANCER Langer, C. J., Wakelee, H., Schiller, J., Choy, H., Shepherd, F., Vokes, E. E., Adjei, A. A., Baas, P., Saijo, N., Gandara, D. R. 2008; 9 (2): 85-91

  Abstract

  Combined-modality therapy has emerged as the standard of care for fit patients with unresectable, locally advanced non-small-cell lung cancer (NSCLC). Concurrent chemotherapy/radiation has demonstrated therapeutic superiority compared with sequential or asynchronous chemotherapy and radiation in this setting. The role of consolidation or maintenance therapy with targeted agents or conventional cytotoxic agents remains unclear. We explore the portfolio of clinical trials being conducted in locally advanced NSCLC by North American cooperative oncology groups as well as ongoing trials in Europe and Japan. These efforts focus on radiation dose escalation using image-guided radiation therapy as well as newer cytotoxic agents (eg, pemetrexed) and targeted therapies (eg, cetuximab, bevacizumab, and etc) thus far unexplored in this setting.

  View details for Web of Science ID 000255039000004

  View details for PubMedID 18501094

• Lung cancer presenting with amegakaryocytic thrombocytopenia. Journal of clinical oncology Witteles, W. H., Schrier, S. L., Wakelee, H. A. 2008; 26 (7): 1171-1174

  View details for DOI 10.1200/JCO.2007.14.8106

  View details for PubMedID 18309955

• Cooperative group research efforts in lung cancer: Focus on early-stage non-small-cell lung cancer CLINICAL LUNG CANCER Wakelee, H., Langer, C., Vokes, E., Schiller, J., Baas, P., Saijo, N., Adjei, A., Shepherd, F., Choy, H., Gandara, D. R. 2008; 9 (1): 9-15

  Abstract

  Many of the most significant advances in the treatment of lung cancer have come from trials run within the cooperative group system. The leaders of the lung cancer section of each group interact throughout the year, but an annual lung cancer congress in Hawaii provides a forum for extensive discussions of ongoing and planned trials. This article is the first in a series that will focus on the key points of this discussion held at the 8th Annual Lung Cancer Congress in June 2007. Early-stage non-small-cell lung cancer trials are highlighted in this manuscript. Current work in adjuvant therapy is focused on exploring the use of bevacizumab in addition to chemotherapy for resected disease in a large Intergroup study and the use of more "personalized" chemotherapy based on specific genomic or protein expression profiles of individual tumors in smaller exploratory studies. The question of postoperative radiation therapy is being addressed within the cooperative groups. Alternative approaches to surgery, such as lesser resections in smaller tumors and accelerated radiation including stereotactic radiosurgery, are also under investigation within this framework. Ongoing trials within the cooperative groups continue to drive steady improvement in the treatment of lung cancer and offer great promise for the future.

  View details for Web of Science ID 000252840000002

  View details for PubMedID 18282352

• Tumor size is a critical determinant of local control in single fraction stereotactic radiotherapy of pulmonary tumors 50th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology (ASTRO) Loo, B. W., Shen, J., Quinlan-Davidson, S., Filion, E., Dieterich, S., Maxim, P. G., Wakelee, H. A., Whyte, R. I., Le, Q. ELSEVIER SCIENCE INC. 2008: S467?S468

  View details for Web of Science ID 000258805301520

• Review of erlotinib in the treatment of advanced non-small cell lung cancer. Biologics : targets & therapy Ganjoo, K. N., Wakelee, H. 2007; 1 (4): 335-346

  Abstract

  Epidermal growth factor receptor (EGFR) is a transmembrane receptor with a cytoplasmic tyrosine kinase (TK) domain present on many solid tumors including non-small cell lung cancer (NSCLC). Once stimulated by ligand, the downstream pathway is activated leading to cell growth, survival, and carcinogenesis. There are several methods of EGFR inhibition including monoclonal antibodies directed against the external region and small molecule inhibitors of TK domain. Erlotinib and gefitinib are orally available small molecule EGFR TK inhibitors, with proven efficacy in NSCLC. The most common side effects are skin toxicity and diarrhea. Erlotinib has been shown to improve survival compared to placebo in second or third-line therapy for NSCLC. However, erlotinib in combination with chemotherapy failed to show a survival advantage in two first-line studies which could be due to the timing of chemotherapy administration. In general, patients with adenocarcinoma histology, female gender, Asian ethnicity, and never smokers have a better response when treated with erlotinib. This could be related to the presence of EGFR mutations, lack of KRAS mutations, or overexpression of EGFR as measured by fluorescent in-situ hybridization (FISH) analysis. Future studies should concentrate on further development of predictors of clinical benefit with erlotinib, overcoming resistance to erlotinib that develops in initial responders, as well as more effective sequencing of erlotinib with chemotherapy and combinations of the drug with other "targeted" therapeutic agents.

  View details for PubMedID 19707304

  View details for PubMedCentralID PMC2721286

• A phase 1b study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI. Sikic, B. I., Wakelee, H. A., Von Mehren, M., Lewis, N. L., Plummer, E., Calvert, A., Fox, N., Kumm, E. A., Jones, S. F., Burris, H. A. AMER ASSOC CANCER RESEARCH. 2007: 3454S?3455S

  View details for Web of Science ID 000251969000373

• A phase I dose-escalation and pharmacokinetic (PK) study of XL647, a novel spectrum selective kinase inhibitor, administered orally daily to patients with advanced solid malignancies (ASM) Molina, J., Wakelee, H. A., Fehling, J. M., Lensingi, J. L., Calcagni, J., Funke, R. F., Miles, D., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2007: 3508S?3509S

  View details for Web of Science ID 000251969000535

• Metabolic tumor burden predicts for disease progression and death in lung cancer 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Lee, P., Weerasuriya, D. K., Lavori, P. W., Quon, A., Hara, W., Maxim, P. G., Le, Q., Wakelee, H. A., Donington, J. S., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: 328?33

  Abstract

  In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging.We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV).The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS.In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  View details for DOI 10.1016/j.ijrobp.2007.04.036

  View details for PubMedID 17869659

• Adjuvant chemotherapy of stage I non-small cell lung cancer in North America Workshop on Development of an International Cooperative Clinical Trail Comparing Stereotactic Radiation Therapy with Surgery for Stage I NSCLC Gandara, D. R., Wakelee, H., Calhoun, R., Jablons, D. LIPPINCOTT WILLIAMS & WILKINS. 2007: S125?S127

  Abstract

  The utility of adjuvant chemotherapy after surgical resection for early-stage non-small cell lung cancer (NSCLC) is now well established. Although a number of randomized clinical trials have demonstrated the efficacy of platinum-based chemotherapy in the overall population treated, subset analysis, excepting Japanese studies, has uniformly shown the greatest efficacy for patients with stage II and III disease and the least benefit for patient with stage I disease. We review data regarding adjuvant therapy of stage I NSCLC from clinical trials performed in North America and Europe. Pertinent trials from Japan are discussed elsewhere in this issue.

  View details for Web of Science ID 000247937100007

  View details for PubMedID 17603308

• A phase 1b study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI Sikic, B. I., Wakelee, H. A., von Mehren, M., Lewis, N., Calvert, A. H., Plummer, E. R., Fox, N. L., Howard, T., Jones, S. F., Burris, H. A. AMER SOC CLINICAL ONCOLOGY. 2007

  View details for Web of Science ID 000455043703306

• Lung cancer incidence in never smokers JOURNAL OF CLINICAL ONCOLOGY Wakelee, H. A., Chang, E. T., Gomez, S. L., Keegan, T. H., Feskanich, D., Clarke, C. A., Holmberg, L., Yong, L. C., Kolonel, L. N., Gould, M. K., West, D. W. 2007; 25 (5): 472-478

  Abstract

  Lung cancer is a leading cause of cancer death worldwide. Although smoking remains the predominant cause of lung cancer, lung cancer in never smokers is an increasingly prominent public health issue. However, data on this topic, particularly lung cancer incidence rates in never smokers, are limited.We reviewed the existing literature on lung cancer incidence and mortality rates among never smokers and present new data regarding rates in never smokers from the following large, prospective cohorts: Nurses' Health Study; Health Professionals Follow-Up Study; California Teachers Study; Multiethnic Cohort Study; Swedish Lung Cancer Register in the Uppsala/Orebro region; and First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study.Truncated age-adjusted incidence rates of lung cancer among never smokers age 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never smokers.Lung cancer in never smokers is an important public health issue, and further exploration of its incidence patterns, etiology, and biology is needed.

  View details for DOI 10.1200/JCO.2006.07.2983

  View details for PubMedID 17290054

• Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Current treatment options in oncology Cabebe, E., Wakelee, H. 2007; 8 (1): 15-27

  Abstract

  OPINION STATEMENT: Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. Bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example, the overall objective response rate of 9.5% with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients, but toxicity, notably fatigue, lead to discontinuation in 38% of patients. Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. Vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. Bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.

  View details for PubMedID 17634832

• Optimal adjuvant therapy for non-small cell lung cancer - How to handle stage I disease ONCOLOGIST Wakelee, H., Dubey, S., Gandara, D. 2007; 12 (3): 331-337

  Abstract

  The standard of care for resected stage II-IIIA non-small cell lung cancer (NSCLC) now includes adjuvant chemotherapy based on the results of three phase III studies using cisplatin-based regimens--the International Adjuvant Lung Trial, the National Cancer Institute of Canada JBR.10 trial, and the Adjuvant Navelbine International Trialist Association trial. The role of adjuvant chemotherapy for stage I disease remains controversial. A recent meta-analysis (the Lung Adjuvant Cisplatin Evaluation) showed potential harm with the addition of adjuvant cisplatin for stage IA disease and no survival benefit for this modality in stage IB disease. Updated results from the Cancer and Leukemia Group B 9633 trial, the only trial to focus exclusively on stage IB patients, no longer show a statistically significant survival benefit from adjuvant chemotherapy in this population, except for the subgroup of patients with larger tumors. It may be that trials have been underpowered to detect a small benefit for patients with stage IB disease, or there may really not be benefit to adding adjuvant therapy for this stage of disease. Additional markers, such as tumor size or the presence or absence of certain tumor proteins like ERCC1, may help to determine which patients with resected stage I NSCLC may benefit from adjuvant chemotherapy. Strategies such as inhibition of angiogenesis pathways and the epidermal growth factor receptor are under exploration.

  View details for DOI 10.1634/theoncologist.12-3-331

  View details for PubMedID 17405898

• Mid-treatment FDG-PET predicts disease progression in patients with non-small cell lung cancer Olson, M. R., Weerasuriya, D. K., Wakelee, H. A., Quon, A., Maxim, P. G., Le, Q., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: S504

  View details for DOI 10.1016/j.ijrobp.2007.07.1720

  View details for Web of Science ID 000249950201230

• Quantification of progression of non-small cell lung cancer in the interval between diagnostic and radiotherapy treatment planning PET scans Eastham, D. V., Weerasuriya, D., Wakelee, H., Quon, A., Maxim, P., Le, Q., Graves, E. E., Loo, B. W. ELSEVIER SCIENCE INC. 2007: S520?S521

  View details for DOI 10.1016/j.ijrobp.2007.07.1750

  View details for Web of Science ID 000249950201258

• A phase I dose-escalation and pharmacokinetic (PK) study of XL647, a novel spectrum selective kinase inhibitor, administered orally to patients with advanced solid malignancies (ASM) Sikic, B. I., Wakelee, H. A., Adjei, A. A., Halsey, J., Lensing, J. L., Dugay, J. D., Hanson, L. J., Reid, J. M., Piens, J. R. PERGAMON-ELSEVIER SCIENCE LTD. 2006: 106?7

  View details for Web of Science ID 000242688500338

• Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q., Loo, B. W., Ho, A., Cotrutz, C., Koong, A. C., Wakelee, H., Kee, S. T., Constantinescu, D., Whyte, R. I., Donington, J. LIPPINCOTT WILLIAMS & WILKINS. 2006: 802?9

  Abstract

  The purpose of this study was to report initial results of a phase I study using single-fraction stereotactic radiotherapy (RT) in patients with inoperable lung tumors.Eligible patients included those with inoperable T1-2N0 non-small cell lung cancer (NSCLC) or solitary lung metastases. Treatments were delivered by means of the CyberKnife. All patients underwent computed tomography-guided metallic fiducial placement in the tumor for image-guided targeting. Nine to 20 patients were treated per dose cohort starting at 15 Gy/fraction followed by dose escalation of 5 to 10 Gy to a maximal dose of 30 Gy/fraction. A minimal 3-month period was required between each dose level to monitor toxicity.Thirty-two patients (21 NSCLC and 11 metastatic tumors) were enrolled. At 25 Gy, pulmonary toxicity was noted in patients with prior pulmonary RT and treatment volumes greater than 50 cc; therefore, dose escalation to 30 Gy was applied only to unirradiated patients and treatment volume less than 50 cc. Ten patients received doses less than 20 Gy, 20 received 25 Gy, and two received 30 Gy. RT-related complications were noted for doses greater than 25 Gy and included four cases of grade 2 to 3 pneumonitis, one pleural effusion, and three possible treatment-related deaths. The 1-year freedom from local progression was 91% for dose greater than 20 Gy and 54% for dose less than 20 Gy in NSCLC (p = 0.03). NSCLC patients had significantly better freedom from relapse (p = 0.003) and borderline higher survival than those with metastatic tumors (p = 0.07).Single-fraction stereotactic RT is feasible for selected patients with lung tumors. For those with prior thoracic RT, 25 Gy may be too toxic. Higher dose was associated with improved local control. Longer follow-up is necessary to determine the treatment efficacy and toxicity.

  View details for PubMedID 17409963

• A multidisciplinary approach to management in a patient with bilateral superior sulcus non-small-cell lung carcinoma CLINICAL LUNG CANCER Roy, M. S., Le, Q., Donington, J. S., Wakelee, H. A. 2006; 8 (2): 146-148

  Abstract

  Superior sulcus tumors comprise a rare subset of non-small-cell lung carcinomas that are particularly challenging to treat because of their location and extent of nerve and vessel involvement. In this report, we present a case illustrating the uncommon situation of a patient presenting with bilateral superior sulcus tumors, and we review the latest combined therapeutic approach developed to aggressively treat the more common unilateral presentation of these tumors.

  View details for PubMedID 17026817

• Lung cancer in women: Exploring sex differences in susceptibility, biology, and therapeutic response CLINICAL LUNG CANCER Donington, J. S., Le, Q., Wakelee, H. A. 2006; 8 (1): 22-29

  Abstract

  Src tyrosine kinases regulate a large number of important mechanisms in normal and cancerous cells, are overexpressed in a broad range of tumors including lung cancer, and thus represent a potential target for cancer therapy. Preclinical experiments indicate that small-molecule inhibitors of Src block tumor growth, metastasis, and angiogenesis. Phase I data from healthy volunteers also suggest that inhibitors of Src prevent bone resorption. Several phase II trials with small-molecule inhibitors of Src are under way or have been initiated in lung cancer and in other malignancies, as discussed herein.

  View details for PubMedID 16870042

• Current status of adjuvant chemotherapy for stage IB non-small-cell lung cancer: Implications for the new intergroup trial CLINICAL LUNG CANCER Wakelee, H. A., Schiller, J. H., Gandara, D. R. 2006; 8 (1): 18-21

  Abstract

  Adjuvant chemotherapy after resection of stage II-IIIA non-small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non-small-cell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (>or= 4 cm) and will likely include only cisplatin-based regimens.

  View details for Web of Science ID 000242173500002

  View details for PubMedID 16870041

• A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM). 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H. A., Adjei, A. A., Halsey, J., Lensing, J. L., Dugay, J. D., Hanson, L. J., Reid, J. M., Piens, J. R., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2006: 131S?131S

  View details for Web of Science ID 000239009400515

• SNS-595 demonstrates clinical activity and dose-proportional pharmacokinetics (PK) in two phase I clinical studies. Hurwitz, H., Gordon, M., Advani, R., Ebbinghaus, S., Mendelson, D., Wakelee, H., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER SOC CLINICAL ONCOLOGY. 2006: 136S

  View details for Web of Science ID 000239009400534

• HGS-ETR2 - A fully human monoclonal antibody to TRAIL-R2: Results of a phase I trial in patients with advanced solid tumors. Patnaik, A., Wakelee, H., Mita, M., Fitzgerald, A., Hill, M., Fox, N., Howard, T., Ullrich, S., Tolcher, A., Sikic, B. AMER SOC CLINICAL ONCOLOGY. 2006: 123S

  View details for Web of Science ID 000239009400483

• Front line therapy with gemcitabine(G) administered immediately prior to pemetrexed (P) for patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Final report of a phase II clinical West, H. J., Belt, R. J., Wakelee, H. A., Monberg, M. J., Frye, L. A., Ye, Z., Obasaju, C. K. AMER SOC CLINICAL ONCOLOGY. 2006: 393S

  View details for Web of Science ID 000239009402441

• Sunitinib: A newly approved small-molecule inhibitor of angiogenesis DRUGS OF TODAY Cabebe, E., Wakelee, H. 2006; 42 (6): 387-398

  Abstract

  The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival. Sunitinib (SU11248, sunitinib malate; Pfizer Inc., New York, NY, USA) is a novel oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action. It targets the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), stem-cell factor receptor and Fms-like tyrosine kinase receptor 3 receptor tyrosine-kinases. In January 2006, sunitinib malate was granted approval by the U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on, or intolerance to, imatinib mesylate, as well as for the treatment of metastatic renal cell cancer. This review will discuss the development of sunitinib, particularly in acute myeloid leukemia, imatinib-resistant gastrointestinal stromal tumors and renal cell cancer. The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer, as well as its potential future development in combination therapy with other agents and in other malignancies.

  View details for DOI 10.1358/dot.2006.42.6.985633

  View details for PubMedID 16845442

• Survival differences by sex for patients with advanced non-small cell lung cancer on Eastern Cooperative Oncology Group trial 1594 11th World Conference on Lung Cancer Wakelee, H. A., Wang, W., Schiller, J. H., Langer, C. J., Sandler, A. B., Belani, C. P., Johnson, D. H. LIPPINCOTT WILLIAMS & WILKINS. 2006: 441?46

  Abstract

  Previous data suggest that women may live longer with advanced non-small cell lung cancer (NSCLC) than men. We evaluated whether sex affected survival in the Eastern Cooperative Oncology Group (ECOG) E1594 trial. E1594 randomized patients with advanced NSCLC to one of four platinum doublets and found that all four regimens had comparable efficacy.Patients in the E1594 database were divided into male and female cohorts; response and survival were calculated separately for each cohort. Known prognostic factors and differences in toxicity profiles were compared between the two cohorts.All 1157 eligible patients (431 women, 726 men) from E1594 were included in this analysis. There was no statistically significant difference in performance status, weight loss of >10%, stage, or incidence of brain metastases between women and men. Response rates were similar (19% for both; P = 0.15). The median survival time for women, however, was significantly longer at 9.2 months (95% CI, 8.1-10.4 months) versus only 7.3 months for men (95% CI, 6.8-8.0 months) (P = 0.004 log-rank test). Toxicity was generally greater in women than in men.Women in ECOG 1594 had a 1.9-month statistically significant improvement in median survival compared with men, despite similar response rates and greater toxicity and no difference in other known prognostic factors. These data strongly support the significance of sex as a separate prognostic factor in advanced NSCLC and emphasize the importance of sex as a stratification factor in future phase III NSCLC trials.

  View details for PubMedID 17409897

• Changes in the natural history of nonsmall cell lung cancer (NSCLC) - Comparison of outcomes and characteristics in patients with advanced NSCLC entered in Eastern Cooperative Oncology Group trials before and after 1990 38th Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H. A., Bernardo, P., Johnson, D. H., Schiller, J. H. JOHN WILEY & SONS INC. 2006: 2208?17

  Abstract

  Demographic factors and treatment regimens were evaluated in relation to differences in outcome between patients with advanced nonsmall cell lung cancer (NSCLC) who were diagnosed and treated on Eastern Cooperative Oncology Group Phase II and III trials from 1981 to 1990 and from 1991 to 2000.In this retrospective analysis, 6 advanced NSCLC trials were identified between 1981 and 1990, and 3 trials were identified after 1990. Patient characteristics (n = 3398 patients) and other clinical outcomes were analyzed, including progression-free survival (PFS) and overall survival (OS).Patients who entered on trials after 1990 more likely were women, received a cisplatin-containing regimen, had a performance status of 0 or 1, had Stage IIIB (vs. Stage IV) disease, had tumors with adenocarcinoma histology, had weight loss < or = 10%, and had pulmonary-only metastases (although more total metastases and brain metastases) compared with patients who were diagnosed before 1990. OS was longer post-1990 than pre-1990 (8.2 months vs. 5.8 months pre-1990), and PFS was longer post-1990 (3.5 months vs. 2.6 months pre-1990; P<.001 for both). In addition, the median interval from the date of disease progression to death increased by nearly 62% in the later decade.Improved survival in more recent NSCLC trials was explained in part by the enrollment of patients with more favorable prognostic factors. A change in the natural history of the disease was reflected by some of these changes, including increased numbers of women with the disease and changes in the patterns of metastases. Changes in eligibility criteria also accounted for some improvements in prognostic factors and improved second line therapies in the later decade. Thus, the survival improvements are likely to be multifactorial, with improved therapies also playing a major role.

  View details for DOI 10.1002/cncr.21869

  View details for PubMedID 16604529

• A phase 1 trial of weekly SNS-595 in patients (PTS) with refractory cancer Ebbinghaus, S., Gordon, M., Advani, R., Hurwitz, H., Mendelson, D., Wakelee, H., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER ASSOC CANCER RESEARCH. 2006

  View details for Web of Science ID 000454608800014

• An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers CLINICAL CANCER RESEARCH Le, Q. T., Chen, E., Salim, A., Cao, H. B., Kong, C. S., Whyte, R., Donington, J., Cannon, W., Wakelee, H., Tibshirani, R., Mitchell, J. D., Richardson, D., O'Byrne, K. J., Koong, A. C., Giaccia, A. J. 2006; 12 (5): 1507-1514

  Abstract

  To directly assess tumor oxygenation in resectable non-small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes.Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes.The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001).Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

  View details for DOI 10.1158/1078-0432.CCR-05-2049

  View details for PubMedID 16533775

• Second- and third-line treatments in non-small cell lung cancer. Current treatment options in oncology Kumar, A., Wakelee, H. 2006; 7 (1): 37-49

  Abstract

  Slow but steady progress has been made in the treatment of advanced non-small cell lung cancer. For first-line therapy, multiple chemotherapy combination therapies can extend survival and improve quality of life. And recently, for the first time ever, a noncytotoxic agent, the antivascular endothelial growth factor antibody bevacizumab, has been shown to improve survival when added to chemotherapy. Striking improvements have also been made in second-line treatment. In August 2004, only one agent was US Food and Drug Administration (FDA) approved in this setting, docetaxel, but by the beginning of 2005, two more were available, pemetrexed and erlotinib. All three of these drugs can significantly benefit patients, with 1-year survival in excess of 30%. Choosing between the three agents can be challenging, and this review focuses on the toxicity differences and predictors of response that can help guide this decision. Docetaxel and pemetrexed, both traditional intravenous cytotoxins, are excellent options for patients who have shown some response to first-line chemotherapy, but at this time, no other means exist to determine likelihood of response. When choosing between the two, pemetrexed causes significantly less neutropenia than does docetaxel, at least on the standard every-3-week regimen. With erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, there are factors that can predict for response, including little or no smoking history, and adenocarcinoma histology. Therefore, patients who fit these characteristics are good candidates for second-line erlotinib. However, the relationship between response to erlotinib and improved survival remains unclear, and several laboratory analyses that may help further, such as evaluation of EGFR gene copy number, are still under development. Although erlotinib is the only FDA-approved option currently available for third-line therapy, many patients with good performance status may benefit from third-line therapy and beyond. In addition to the approved second-line options, other single-agent chemotherapies to consider for treatment beyond second-line are gemcitabine, irinotecan, and oral topotecan. Many new drugs, including bevacizumab, ZD6474 (AstraZeneca, Wilmington, DE), sorafenib, cetuximab, paclitaxel poliglumex, epothilones, and others, alone or in combination with traditional agents, are currently undergoing investigation and hold great promise.

  View details for PubMedID 16343367

• A phase 1 dose-escalation and pharmacokinetic (PK) study of a novel spectrum-selective kinase inhibitor (SSKI), XL647, in patients with advanced solid malignancies. 17th EORTC/AACR/NCI International Conference on Molecular Targets and Cancer Therapeutics Wakelee, H., Adjei, A. A., Halsey, J., Lensing, J., Dugay, J., Hanson, L., Reid, J., Hutchison, S., Piens, J., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2005: 9029S?9029S

  View details for Web of Science ID 000234382700263

• Phase I trial of SNS-595 in patients (pts) with advanced malignancies. Advani, R., Gordon, M., Hurwitz, H., Mendelson, D., Wakelee, H., Ebbinghaus, S., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER ASSOC CANCER RESEARCH. 2005: 9056S

  View details for Web of Science ID 000234382700373

• HGS-ETR2-ST02: A phase 1 clinical trial of HGS-ETR2, a fully-human activating monoclonal antibody to TRAIL-R2, in patients with advanced solid tumors. Sarantopoulos, J., Wakelee, H., Mita, M., Fitzgerald, A., Hill, M., Fox, N. L., Howard, T., Ullrich, S., Tolcher, A. W., Sikic, B. AMER ASSOC CANCER RESEARCH. 2005: 9104S

  View details for Web of Science ID 000234382701142

• Targeting angiogenesis with vascular endothelial growth factor receptor small-molecule inhibitors: Novel agents with potential in lung cancer CLINICAL LUNG CANCER Wakelee, H. A., Schiller, J. H. 2005; 7: S31-S38

  Abstract

  The treatment of lung cancer remains a significant challenge. Although chemotherapy remains the standard approach, a plateau has been reached in its efficacy. The development of novel targeted agents, particularly those targeting the epidermal growth factor receptor, has given us another approach. Developments with antiangiogenesis agents hold promise as new approaches in lung cancer therapy. Much of the work to date has focused on the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. In this article we will focus on the tyrosine kinase inhibitors of the VEGF receptors. These compounds, including sunitinib (SU11248; Sutent), vatalanib (PTK787), ZD6474, AZD2171, GW786034, sorafenib (BAY 43-9006), CP-547,632, and AG013736, are still at an early stage of development. We present phase I data (and phase II/III data when available) of these compounds and discuss their potential development in the treatment of lung cancer.

  View details for PubMedID 16159417

• Activity of novel cytotoxic agents in lung cancer: Epothilones and topoisomerase I inhibitors CLINICAL LUNG CANCER Wakelee, H. A., Sikic, B. I. 2005; 7: S6-S12

  Abstract

  The treatment of lung cancer--small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)--is a significant challenge in oncology. The best reported median survival remains near 1 year in advanced NSCLC despite several decades of steady improvement and extensive research with traditional chemotherapy drugs and novel compounds targeted to different aspects of tumor cell growth and function (such as the epidermal growth factor receptor). Extensive-stage SCLC survival is only slightly better. Novel "targeted" therapeutic agents hold promise, but cytotoxic therapy remains the backbone of treatment. Many new cytotoxic agents are currently in development. In this review, we will focus on 2 classes of cytotoxins: epothilones and topoisomerase I inhibitors. Epothilones are microtubule stabilizers with a mechanism of action similar to that of the taxanes, with preclinical activity superior to that of the taxanes. Phase I trials have been completed for patupilone and ixabepilone, and there are encouraging phase II data with ixabepilone in NSCLC. A phase II trial of patupilone is ongoing. The camptothecins, which are topoisomerase I inhibitors, have a long history in the treatment of lung cancer, but the currently available drugs, topotecan and irinotecan, have limitations. Gimatecan and other novel camptothecins have superior preclinical activity and promising phase I/II data in NSCLC and SCLC.

  View details for PubMedID 16159420

• Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer 40th Annual Meeting of the American-Society-of-Clinical-Oncology Kuo, T., Cho, C. D., Halsey, J., Wakelee, H. A., Advani, R. H., Ford, J. M., Fisher, G. A., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2005: 5613?19

  Abstract

  To investigate the gefitinib, fluorouracil (FU), leucovorin, and oxaliplatin regimen (IFOX) in previously treated patients with metastatic colorectal cancer.Eligible patients had stage IV colorectal adenocarcinoma and had demonstrated progression or intolerance to a prior chemotherapy regimen not including oxaliplatin. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin 85 mg/m2 intravenously (IV) during 2 hours on day 1, hours 0 to 2; leucovorin 200 mg/m2 IV on days 1 and 2, hours 0 to 2; FU 400 mg/m2 IV push on days 1 and 2; and FU 600 mg/m2 IV on days 1 and 2, hours 2 to 24 (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg/d administered orally throughout the 14-day cycle.Twenty-seven patients were enrolled onto the study. The median number of prior chemotherapy regimens was two, and 74% of all patients received prior irinotecan. Nine of the 27 patients (33%) and six of the 20 patients (30%) who had prior FU and irinotecan had a partial response by Response Evaluation Criteria in Solid Tumors Group criteria. Median overall survival was 12.0 months. Median event-free survival was 5.4 months. Grade 3 to 4 toxicities included neutropenia (48%), diarrhea (48%), nausea (22%), and vomiting (15%).IFOX is an active regimen in patients with previously treated metastatic colorectal adenocarcinoma, demonstrating higher response rates than those reported with FOLFOX-4 alone in a similar patient population.

  View details for DOI 10.1200/JCO.2005.08.359

  View details for PubMedID 16110021

• Effect of bexarotene on vinorelbine and cisplatin pharmacokinetics during a Phase I study in patients with advanced non-small cell lung cancer (NSCLC) 11th World Conference on Lung Cancer Wakelee, H., Middleton, G., Dunlop, D., Kelly, C., Ramlau, R., Leighl, N., Hao, D., Zatloukal, P., Cox, K., Loewen, G. ELSEVIER IRELAND LTD. 2005: S274?S274

  View details for Web of Science ID 000231307802071

• Survival differences by gender for patients with advanced non-small cell lung cancer in Eastern Cooperative Oncology Group trial 1594 Wakelee, H., Wang, W., Schiller, J., Langer, C., Sandler, A., Belani, C., Johnson, D. ELSEVIER IRELAND LTD. 2005: S22

  View details for DOI 10.1016/S0169-5002(05)80188-6

  View details for Web of Science ID 000231307800063

• Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Wakelee, H. A., Stephenson, P., Keller, S. M., Wagner, H., Herskovic, A., Komaki, R., Marks, R. S., Perry, M. C., Livingston, R. B., Johnson, D. H. ELSEVIER IRELAND LTD. 2005: 389?97

  Abstract

  To determine the influence of adjuvant therapy on the risk of DID following resection of NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or CPORT (PORT plus four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently). The study accrued 488 patients, 242 to the PORT only arm and 246 to the CPORT arm. The overall 4 years actuarial rate of DID for the two arms combined, with a median follow-up of 82 months, was 12.9%, not significantly different from the 10.1% expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status (p=0.16). Survival distributions with regard to DID did not differ between the two treatment arms (p=0.96). DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or weight loss in the previous 6 months. The risk of DID following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or CPORT.

  View details for DOI 10.1016/j.lungcan.2004.11.007

  View details for Web of Science ID 000229645600012

  View details for PubMedID 15893008

• Phase I trial of SNS-595 in patients with advanced malignancies. Advani, R., Gordon, M., Hurwitz, H., Mendelson, D., Wakelee, H., Ebbinghaus, S., Hoch, U., Silverman, J., Havrilla, N., Adelman, D. AMER SOC CLINICAL ONCOLOGY. 2005: 159S

  View details for Web of Science ID 000230326601051

• A phase I trial of oblimersen and gemcitabine in refractory and advanced malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Fisher, G., Advani, R., Wakelee, H., Jacobs, C., Gladysheva, K., Fitzgerald, A. M., Sikic, B. AMER SOC CLINICAL ONCOLOGY. 2005: 234S?234S

  View details for Web of Science ID 000230326601349

• A phase I dose-escalation and pharmacokinetic (PK) study of a novel multiple-targeted receptor tyrosine kinase (RTK) inhibitor, XL647, in patients with advanced solid malignancies 41st Annual Meeting of the American-Society-of-Clinical-Oncology Wakelee, H., Adjei, A. A., Keer, H., Halsey, J., Hanson, L., Reid, J., Hutchison, S., Piens, J., Lacy, S., Sikic, B. I. AMER SOC CLINICAL ONCOLOGY. 2005: 227S?227S

  View details for Web of Science ID 000230326601318

• A phase I trial of irinotecan (CPT-11) with amifostine in patients with metastatic colorectal cancer INVESTIGATIONAL NEW DRUGS Wakelee, H., Fisher, G. A. 2005; 23 (3): 241-242

  View details for DOI 10.1007/s10637-005-6732-1

  View details for Web of Science ID 000228876800006

  View details for PubMedID 15868380

• Docetaxel in advanced non-small cell lung cancer EXPERT REVIEW OF ANTICANCER THERAPY Wakelee, H., Ramalingam, S., Belani, C. P. 2005; 5 (1): 13-24

  Abstract

  Based on the survival benefit demonstrated in large randomized clinical trials, docetaxel is approved for the treatment of advanced non-small cell lung cancer (NSCLC) in both the first- and second-line settings. The efficacy of docetaxel in combination with cisplatin is equivalent to some, and superior to other, platinum-based doublets for first-line management of NSCLC, and has a manageable toxicity profile. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy of patients with advanced NSCLC. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II studies. This article reviews recent studies of docetaxel as a single agent and in combination regimens with cytotoxic and more recent targeted agents in the management of advanced NSCLC.

  View details for PubMedID 15757434

• Optimizing first-line treatment options for patients with advanced NSCLC ONCOLOGIST Wakelee, H., Belani, C. P. 2005; 10: 1-10

  Abstract

  The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.

  View details for PubMedID 16368866

• Results of a phase I dose escalation study using single fraction stereotactic radiosurgery (SFSR) for lung tumors 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Le, Q. X., Ho, A., Cotrutz, C., Loo, B., Petrik, D., Wakelee, H., Kee, S. T., Whyte, R. I., Donington, J. S. ELSEVIER SCIENCE INC. 2005: S226?S226

  View details for Web of Science ID 000232083300377

• Single fraction stereotactic radiosurgery (SFSR) for lung tumors - A phase I dose escalation trial. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Le, Q. T., Ho, A., Cotrutz, C., Wakelee, H., Kee, S. T., Donington, I., Whyte, R. I. AMER SOC CLINICAL ONCOLOGY. 2004: 673S?673S

  View details for Web of Science ID 000223512402672

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. 40th Annual Meeting of the American-Society-of-Clinical-Oncology Fishe, G. A., Kuo, T., Cho, C. D., Halsey, J., Jambalos, C. N., Schwartz, E. J., Robert, R. V., Advani, R. H., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2004: 248S?248S

  View details for Web of Science ID 000223512400981

• Novel approaches for the treatment of small cell lung cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Wakelee, H., Kelly, K. 2004; 18 (2): 499-?

  View details for DOI 10.1016/j.hoc.2004.01.001

  View details for PubMedID 15094184

• A phase II study of gefitinib in combination with FOLFOX-4 (IFOX) in patients with metastatic colorectal cancer. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Cho, C. D., Fisher, G. A., Halsey, J., Jambalos, C. N., Schwartz, E. J., Rouse, R. V., Advani, R. H., Wakelee, H. A., Lum, B. L., Sikic, B. I. AMER ASSOC CANCER RESEARCH. 2003: 6103S?6103S

  View details for Web of Science ID 000187467300140

• Delta F508-CFTR channels: Kinetics, activation by forskolin, and potentiation by xanthines AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY HAWS, C. M., Nepomuceno, I. B., Krouse, M. E., Wakelee, H., Law, T., Xia, Y., Nguyen, H., Wine, J. J. 1996; 270 (5): C1544-C1555

  Abstract

  Trafficking, activation, and kinetics of delta F508-cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR were compared in stably transduced C127I mouse mammary epithelial cells. Western blots detected a small amount of fully glycosylated delta F508-CFTR Efflux of 125I was stimulated by forskolin with the same mean effective concentration (EC50; approximately 0.5 microM) for CFTR and delta F508-CFTR cells, but the maximum response was reduced more than fivefold and its latency increased approximately threefold in delta F508-CFTR cells. In delta F508-CFTR cells, 3-isobutyl-1-methylxanthine (IBMX; EC50 = 1.45 microM) and 8-cyclopentyl-1,3-dipropylxanthine (CPX; EC50 = 58 microM) increased the peak forskolin-stimulated efflux rate approximately 2.5-fold and decreased the time to peak. A sevenfold increase in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels accompanied potentiation of forskolin-induced 125I efflux by IBMX but not by CPX. Elevation of intracellular cAMP increased linear voltage-independent whole cell currents 30-fold in CFTR and 4-fold in delta F508-CFTR cells; the response rate in delta F508-CFTR cells was much slower. Single-channel currents were detected in 57 of 68 cell-attached patches from forskolin-prestimulated CFTR cells vs. 6 of 35 patches in delta F508-CFTR cells. Mean number of active channels per patch was 4.1 for CFTR [open probability (Po) = 0.34] and 0.2 for delta F508-CFTR (Po = 0.11). The lower Po of delta F508-CFTR resulted from an approximately threefold longer mean interburst interval. We estimate that forskolin-stimulated chloride conductance of delta F508-CFTR C127I cells is < 5% of CFTR cells. CPX is approximately 25-fold more potent than IBMX in potentiating delta F508-CFTR and may operate by a mechanism other than elevation of cAMP.

  View details for Web of Science ID A1996UJ81400034

  View details for PubMedID 8967457