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FGFR-targeted therapy demonstrated activity in solid tumors
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Patients with solid tumors with fibroblast growth receptor genetic alterations demonstrated tumor shrinkage with the novel agent BGJ398, according to study results presented at the American Association for Cancer Research Annual Meeting.
The benefit was particularly apparent among patients with FGFR3-mutated urothelial cancer.
“An emerging concept in cancer treatment is to try to treat cancers with a genetically defined alteration with an inhibitor of the receptor tyrosine kinase that drives the cancer growth,” Lecia V. Sequist, MD, MPH, associate professor of medicine at Harvard Medical School and Massachusetts General Hospital, said during a press conference. “This clinical study enrolled patients with many different tumor types. There are many types of tumors that have alterations of FGFR. Importantly, in contrast to other, more promiscuous multitargeted kinase inhibitors that happen to inhibit FGFR as one of their targets, BGJ398 has really no significant inhibition of the VEGF family of receptors.”
Sequist and colleagues enrolled 107 patients with solid tumors expressing FGFR genetic alterations. The cohort included patients with squamous cell lung carcinoma, breast cancer, cholangiocarcinoma and urothelial cell cancer.
Forty-three patients were included in the dose escalation phase. Researchers observed anticancer activity in patients who received at least 100-mg doses of BGJ398 (Novartis). Investigators determined the maximum tolerated dose was 125 mg.
The expansion phase consisted of three cohorts. One included 18 patients with FGFR1-amplified squamous cell lung carcinoma assigned daily BGJ398. The other two cohorts included patients with other FGFR-altered tumors; 21 patients received BGJ398 daily for 4 weeks, and 25 patients received the drug daily for 3 weeks.
Investigators reported anticancer activity in all three arms, and patients with various types of cancer demonstrated benefit.
Four of five patients with FGFR3-mutated urothelial cancer demonstrated tumor shrinkage, including two patients who achieved partial responses. The overall response rate for patients with FGFR3-mutated urothelial cancer was 40%, and the disease control rate was 100%.
One patient with FGFR1-amplified squamous cell lung carcinoma achieved a partial response. Further data from patients with lung cancer will be presented at the ASCO Annual Meeting, Sequist said.
Eighty-two patients discontinued the study; of these patients, 56 discontinued due to disease progression, 12 did so due to consent withdrawal and 10 stopped because of adverse events.
The most common adverse events associated with treatment were hyperphosphatemia (78%), stomatitis (37%), alopecia (32%), decreased appetite (32%) and fatigue (22%). Grade 3 or grade 4 stomatitis occurred in 7% of the patients.
Most dose reductions or interruptions were due to hyperphosphatemia, which was manageable when researchers altered the dose schedule from 125 mg continuously, to 125 mg daily for 3 weeks followed by 1 week off, Sequist said.
“Clinical activity was observed in multiple tumor types and patients with FGFR3-mutated bladder cancer might be especially sensitive to BGJ398. This may be a driver mutation situation,” Sequist said. “These different alterations in FGFR in different tumor types may have different degrees of importance. For example, a lot of patients who progressed had breast cancer, and the FGFR amplification seen in breast cancer may not be as much of a driver event in these patients, or there may be another genetic factor that is modulating, since there were some breast cancer patients who had tumor shrinkage. Further investigation into the specific subtypes is ongoing in order to really understand this complexity.”
For more information:
Sequist LV. Abstract #CT325. Presented at: AACR Annual Meeting 2014; San Diego; April 5-9.
Disclosure: The study was funded by Novartis. Sequist reports unpaid consultant roles with AstraZeneca, Boehringer Ingelheim, Clovis, Merrimack and Taiho.
Perspective
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Louis M. Weiner, MD
This provides us with additional, powerful evidence of the importance of targeting specific mutations in cancers in order to get maximum probability of objective response. It really exemplifies the potential power of targeted therapies. This is a trial that exemplifies the evolution of our field. Here we are doing a phase 1, early-stage clinical trial where every patient had a molecularly defined abnormality that was required for them to go on the treatment. This would not have been possible even a few years ago. To think this was such a broad screening effort that involved so many different cancers, it really is a demonstration of how our field has evolved and changed in only a few short years.
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