June 2014, Vol 3, No 4
FGFR Inhibitor Shows Promising Anticancer Activity
Inhibition of fibroblast growth factor receptors (FGFRs) 1, 2, 3, and 4 is showing promise in the treatment of cancers driven by FGFR alterations, especially bladder cancer and lung cancer, according to phase 1 studies presented at the 2014 American Association for Cancer Research annual meeting.
A phase 1 study, singled out for attention at an official press conference, showed that the investigational pan-FGFR inhibitor BGJ398 had activity against different types of solid tumors, including bladder cancer. The most notable side effect of this drug is hyperphosphatemia, an on-target effect that is manageable by dose interruptions, schedule adjustments, and phosphate-lowering medications.
“The primary purpose of this first-in-human clinical trial of BGJ398 was to look at tolerability. However, we restricted enrollment only to patients with FGFR genetic alterations in their tumors, because we believed that these patients would have the greatest chance of benefiting from the drug,” said Lecia V. Sequist, MD, MPH, associate professor of medicine, Harvard Medical School, and assistant physician, Massachusetts General Hospital, Boston.
Sequist said that she and her colleagues were especially encouraged by the activity seen in bladder cancer, “for which there are few treatment options.”
“This study clearly demonstrates the value of a personalized approach to cancer therapy with a targeted agent by showing that patients with FGFR genetic abnormalities can respond to an FGFR inhibitor,” Sequist said.
The study enrolled 107 patients with lung cancer, breast cancer, cholangiocarcinoma, or urothelial cell bladder cancer. Of those patients, 43 were treated in the dose-escalation phase of the trial. Three groups were treated in the expansion phase: squamous cell lung cancer treated daily, and 2 other groups with various cancers (one group was treated continuously daily, and the other group was treated for 3 weeks on and 1 week off).
The 125-mg daily dose was identified as the maximum tolerated dose. The 3-weeks-on/1-week-off schedule demonstrated an improved safety profile and is the schedule that will go forward for phase 2 testing.
Tumor shrinkage was observed in patients treated at doses of ?100 mg daily in the dose-escalation phase, as well as among patients in all 3 expansion arms. Tumor shrinkage was observed in various cancer types, most notably in 5 of 6 patients with bladder cancer who had an FGFR3 mutation. Anticancer activity was also observed in patients with squamous cell lung cancer, squamous cell head and neck cancer, breast cancer, and cholangiocarcinoma. Sequist said that the lung cancer data will be presented at the 2014 American Society of Clinical Oncology meeting.
Lessons learned from this phase 1 study and others include the need for proactive management to reduce hyperphosphatemia. A number of phase 2 studies are ongoing or are planned, and correlative studies of specific FGFR genetic alterations will be included.
Another abstract presented at the meeting focused on a similar drug under development – a pan-FGFR inhibitor called JNJ-42756493. The study had a similar design, similar responses, and similar adverse events – mainly hyperphosphatemia. The 9-mg daily dose was identified as the maximum tolerated dose going forward in phase 2 trials.
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