The results of a phase-3 clinical trial led by a Stanford researcher showed that two targeted treatments can extend the lifespan and delay the need for chemotherapy in women with a common type of metastatic breast cancer.
September 29, 2019 - By Krista Conger
Women with a common type of advanced metastatic breast cancer live about nine months longer when hormone therapy is paired with a second drug than do those who receive hormone therapy alone, according to an international, multicenter phase-3 clinical trial led by a researcher at the Stanford University School of Medicine.
The second drug belongs to a class of molecules known as CDK4/6 inhibitors that work to block the division of cancer cells.
Breast cancers are classified according to the presence of specific proteins within or on the surface of tumor cells, and these categories are used to guide treatment decisions. Cancers that express high levels of the estrogen receptor often rely on estrogen to grow and are known as hormone-receptor-positive cancers. The protein HER2, which stands for human epidermal growth factor receptor 2, also is often expressed on cancer cells. When it’s not, the cancer is known as HER2-negative.
The randomized, double-blind trial enrolled nearly 700 women with hormone-receptor-positive, HER2-negative breast cancers at 142 centers in 19 countries. Prior to enrollment, the women had seen their cancers progress while on endocrine therapy, which is the standard first-line treatment for this type of breast cancer.
About 40,000 women in the United States die of metastatic breast cancer each year, most of them from hormone-receptor-positive, HER2-negative breast cancer, said George Sledge, MD, professor of medicine and the chief of the division of oncology at Stanford.
“Data from this trial pretty clearly shows that if you take this drug combination, you live longer,” said Sledge, who is the principal investigator of the trial, called MONARCH 2. “It also delays the point at which we need to start these women on chemotherapy. So not only do you live longer, you have a better quality of life.”
Sledge is a medical oncologist specializing in breast cancer treatment who sees patients at the Stanford Women’s Cancer Center.
In 2017, a preliminary analysis of data from the trial indicated that the drug combination significantly increased the progression-free survival — or the length of time from enrollment in a clinical trial until the disease worsens or the participant dies — compared with hormone therapy alone.
Today, the trial is about 77% complete, and the new data definitively indicate that the drug combination also extends the overall survival rate of the women. The study was funded by Eli Lilly and Co., which developed and markets abemaciclib, the drug tested in the trial.
Sledge is the lead author of the study, which will be published online Sept. 29 in JAMA Oncology to coincide with a presentation of the findings at the 2019 meeting of the European Society of Medical Oncology in Barcelona, Spain. Antonio Llombart-Cussac, MD, PhD, chairman of the medical oncology service at the University Hospital Arnau de Vilanova in Valencia, Spain, is the senior author.
Endocrine therapy, or hormone therapy, is a common first-line treatment for hormone-receptor-positive, HER2-negative breast cancer because it is relatively effective and nontoxic. This approach either blocks the ability of the body to make estrogen or treats the cancer with drugs that block the binding of estrogen to the cancer cells.
However, these cancers can become resistant to endocrine therapy over time. Recently, physicians have started combining endocrine therapy with a new class of drugs known as CDK4/6 inhibitors in an effort to improve treatment outcomes. These drugs target proteins in cancer cells that are necessary to drive the division of the cells and the growth of the tumors. But until now, the combination had not been proven to enhance the survival of women with advanced metastatic cancers.
The MONARCH 2 trial was launched in 2014 to test the efficacy of a CDK4/6 inhibitor called abemaciclib in combination with an endocrine therapy called fulvestrant for hormone-receptor-positive, HER2-negative advanced breast cancer. The women enrolled in the trial had experienced disease progression while being treated with an endocrine therapy other than fulvestrant.
Women were randomly assigned in a 2 to 1 ratio to receive either abemaciclib and fulvestrant (446 women), or fulvestrant plus a placebo (223 women). Neither the women nor their physicians knew to which group they had been assigned. They were monitored until their disease progressed or the women died or withdrew from the trial.
After three years, the study investigators saw that treatment with abemaciclib plus fulvestrant extended the length of time between study enrollment and disease progression by about seven months as compared with women who received fulvestrant plus the placebo.
Longer median survival time
After five years, 338 of the 669 women had died. Of those, 211 had received the drug combination, and 127 of those in the control arm. Women receiving both fulvestrant and abemaciclib had a median survival time of 46.7 months, compared with 37.3 months for those who had received fulvestrant plus placebo — an increase of 9.4 months. Furthermore, women who received both drugs were able to delay starting chemotherapy for about 28 months longer on average than those in the control group.
“Doctors don’t render their patients immortal,” Sledge said. “We still haven’t cured metastatic breast cancer. But this is a drug that increases survival and reduces the need for chemotherapy. Women can live longer and have a relatively good quality of life and more time with their families, their children and their loved ones.”
Researchers from Kyoto University in Japan, the Universitaire Ziekenhuizen Leuven in Belgium, the Yonsei Cancer Center in South Korea, the Saitama Cancer Center in Japan, the Centre Paul Strauss in France, the Arkhangelsk Regional Clinical Oncology Dispensary in Russia, the Adelaide Cancer Centre in Australia, the Osaka National Hospital in Japan, the University of Vermont Cancer Center, Kaiser Permanente, the Eberhard Karls University in Germany, the Instituto Oncologico Veneto in Italy, the Royal Marsden NSH Foundation Trust in the UK, the Hospital Arnau Vilanova in Spain and Eli Lilly and Co. also contributed to the study.
The study was funded by Eli Lilly and Co.
Stanford’s Department of Medicine also supported the work.
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