FGFR inhibitor works in multiple cancers.

A pan-FGFR inhibitor yielded positive safety and effi cacy results in multiple cancers, particularly invasive bladder cancer. Investigators reported fi ndings from the phase I trial on April 8 at the American Association for Cancer Research Annual Meeting 2014 in San Diego, CA. FGFRs are a family of receptor tyrosine kinases involved in cell proliferation and survival. Mutations, amplifi cations, and translocations in these receptors have been implicated in the development of numerous cancers, including urothelial bladder cancer, squamous non–small cell lung cancer (NSCLC), and breast cancer. The pan-FGFR inhibitor BGJ398 (Novartis Oncology) selectively blocks FGFR signaling. Various doses—ranging from 5 mg to 150 mg—given once or twice a day were tested in 43 patients with advanced solid tumors showing any FGFR genetic alteration. The maximum tolerated dose of BGJ398 was identifi ed as 125 mg a day. In the expansion phase of the study, 64 patients with cancers harboring FGFR genetic alterations were separated into three groups that all received 125 mg daily. The fi rst group included 18 patients with FGFR1-amplifi ed squamous NSCLC. The second group included 21 patients with other types of cancer harboring FGFR genetic alterations. The third group also included patients with various FGFR-altered cancer types, but the 25 patients in this group were treated on a 3-weeks-on, 1-week-off schedule rather than taking the drug continuously. Six patients achieved a partial response: two with FGFR3-mutated bladder cancer—one of whom saw her tumor shrink by 45% and has remained on treatment more than 8 months—and four with FGFR1-amplifi ed squamous NSCLC. Two other bladder cancer patients experienced tumor shrinkage of greater than 25%. One patient with cholangiocarcinoma with an FGFR2 gene fusion and four patients with FGFR1-amplifi ed breast cancer also experienced some tumor shrinkage. “These fi ndings suggest that certain types of cancer, specifi cally bladder cancers and squamous lung cancers that are dependent on FGFR for survival, can be treated with FGFR blockers,” said principal investigator Lecia V. Sequist, MD, an associate professor of medicine at Harvard Medical School and Massachusetts General Hospital in Boston. The most common drug-related adverse event was an abnormally high serum phosphate level, a side effect that can be managed through diet, phosphate-lowering therapy, or drug interruptions, Sequist said. Other adverse events were generally mild and included stomatitis, hair loss, decreased appetite, and fatigue. No targeted drugs are currently approved to treat bladder cancer or squamous NSCLC. “This agent could open up a new treatment realm for a signifi cant subset of these populations,” Sequist said. Indeed, FGFR3 is mutated in 15% of invasive bladder cancers, and FGFR1 is amplifi ed in about 20% of squamous NSCLC. Researchers chose the 3-weeks-on, 1-week-off treatment schedule based on its better safety profi le. Researchers are planning phase II trials of BGJ398 in cholangiocarcinoma and bladder, lung, and endometrial cancers. A phase II trial in glioblastoma is already under way. ■ NOTED