Nearly three-quarters of people with a subtype of a rare form of deadly blood cancer saw their cancers become undetectable — as measured by imaging, laboratory tests and examination of biopsy specimens — after treatment with a drug called pemigatinib in a Phase 2, multicenter, international trial run by Stanford Medicine. The responses lasted months to years and enabled potentially curative stem cell transplants in 13 out of 45 trial participants.
The cancers, called myeloid/lymphoid neoplasms, or MLN, can be either chronic or acute (also referred to as blast phase) at the time of diagnosis. A subset of these diseases is characterized by rearrangements in the gene for a protein called fibroblast growth factor receptor 1, or FGFR1, which causes the protein to be abnormally active. This subset of MLN with rearrangements in the FGFR1 gene is particularly aggressive, with a one-year overall survival rate of 43%. Pemigatinib interferes with FGFR1 activity.
Although people in the chronic phase of the disease responded most dramatically to pemigatinib in the trial, nearly half of the participants in blast phase also experienced complete, but less durable, responses.
“Essentially everyone in the chronic phase of the disease responded well to pemigatinib treatment, and the response rate for people in the acute phase — about 44% — is still very impressive,” said professor of hematology Jason Gotlib, MD, the principal investigator for the trial. “Furthermore, the responses for people in the chronic phase are durable. I have one patient who has been on the drug for more than seven years and whose disease has not relapsed.”
At 12 and 24 months, respectively, estimated progression-free survival rates were 78% and 70%, and overall survival rates were 79% and 72%.
The dramatic results of the ongoing trial, which launched in 2017, caused the Food and Drug Administration to approve the use of pemigatinib in patients with previously treated myeloid/lymphoid neoplasms with rearrangements in the FGFR1 gene in 2022.
Inhibiting FGFR1 activity
Gotlib, a member of the Stanford Cancer Insitute, is the senior author of a study reporting the trial’s final outcome on Aug. 26 in NEJM Evidence. Srdan Verstovsek, MD, PhD, formerly at the University of Texas MD Anderson Cancer Center and now chief medical officer of Redwood City, California-based Kartos Therapeutics, Inc., and Jean-Jacques Kiladjian, MD, PhD, professor of clinical pharmacology at Paris Diderot University, are the lead authors of the research. The trial, called FIGHT-203, was funded by Delaware-based Incyte Corporation, which makes and markets pemigatinib under the trade name Pemazyre.
The chronic phase of MLN with a FGFR1 gene rearrangement typically progresses to an acute phase within months and has a median survival of under two years, while people with the acute phase of the disease typically live fewer than 12 months. Fortunately, cases are rare — fewer than 100 are diagnosed each year worldwide.
The only possible cure for these cancers is a hematopoietic stem cell transplant (commonly called a bone marrow transplant). But not all patients are healthy enough for a transplant, which requires intensive pretreatment to eliminate the patient’s immune system and can result in graft-versus-host disease. Furthermore, the relapse rate for people in the blast phase of the disease after transplant can exceed 50%.
The use of pemigatinib to reduce the burden of disease prior to transplant could make the procedure more successful, the researchers believe. And its use after transplant may reduce the possibility of relapse.
This is an extremely rare disease that is difficult to diagnose and for which few good treatment options have existed. But this drug treatment gave impressive results in patients…. It’s another example of targeted therapy giving patients who otherwise have little hope a chance for extended survival and an improved quality of life.”
FGFR1 belongs to a large class of proteins called tyrosine kinases. Previous attempts to use drugs that block tyrosine kinase activity to treat MLN have been unsuccessful because of their broad mechanism of action.
“Pemigatinib is more selective,” Gotlib said. “It specifically inhibits FGFR activity.”
A bridge to transplant
MLN are not the only cancers associated with FGFR gene rearrangement. Cancers of the bile duct, or cholangiocarcinomas, frequently have rearrangements in the gene encoding another FGFR family member, FGFR2. Pemigatinib, which inhibits FGFR1, FGFR2 and FGFR3, was approved by the FDA for the treatment of metastatic cholangiocarcinomas in 2020.
“The idea for the trial started when Srdan Verstovsek treated a patient with a MLN with a FGFR1 gene rearrangement with pemigatinib, thinking that maybe it would work because it had had success in treating metastatic cholangiocarcinoma,” Gotlib said. The patient responded well, and the investigators planned a clinical trial of pemigatinib.
Because the disease is so rare, it took several years to enroll the 45 participants in FIGHT-203. When the trial launched, participants were given pemigatinib as a daily oral drug either for two weeks on and one week off, or continuously. While side effects including elevated levels of phosphate in the blood and mouth sores occurred, they were managed with dose modifications and drug interruptions.
Among the 24 patients with chronic phase disease, 23 had a complete clinical response after a median of six weeks of pemigatinib treatment, and seven were subsequently able to undergo stem cell transplantation. This response lasted for at least a year in 16 of the 23 patients.
Among the 18 people in the blast phase of the disease, eight achieved a complete response. However, the duration of the responses were shorter — only two lasted six months or longer. Still, five of these patients were able to undergo transplantation.
Three previously treated patients entered the trial without clinical evidence of disease but with persistence of their FGFR1 gene rearrangement. All three showed a complete response, and one proceeded to transplantation.
“This is an extremely rare disease that is difficult to diagnose and for which few good treatment options have existed,” Gotlib said. “But this drug treatment gave impressive results in patients with both chronic and acute phases of these cancers and provided a bridge to transplant for many patients. It’s another example of targeted therapy giving patients who otherwise have little hope a chance for extended survival and an improved quality of life.”
