Regorafenib, a multikinase inhibitor, has been approved as a treatment for locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in people who have been treated with imatinib and sunitinib, the other two treatments approved for GIST, the Food and Drug Administration announced on Feb. 26.
Regorafenib was first approved in September as a treatment for metastatic colorectal cancer, and "provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement. The recommended dose is 160 mg orally once a day for the first 21 days of each 28-day cycle, according to the prescribing information for regorafenib, which is marketed as Stivarga by Bayer HealthCare Pharmaceuticals.
Approval was based on the interim results of the phase III GRID (GIST – Regorafenib In Progressive Disease) study, comparing placebo plus best supportive care (BSC) to regorafenib plus BSC in 199 patients with locally advanced, unresectable, or metastatic GIST, previously treated with imatinib and sunitinib, according to the FDA statement, as well as the statement issued by the manufacturer. The median progression-free survival (the primary endpoint) was 4.8 months among those on regorafenib, compared with 0.8 months among those on placebo, a statistically significant difference (Lancet 381;9863:295-302). At the time of the planned interim analysis, there was no statistically significant difference in overall survival.
The most common adverse events associated with treatment, reported by at least 30% of those treated, included hand-foot syndrome, diarrhea, mucositis, dysphonia, asthenia/fatigue, hypertension, reduced appetite and food intake, and rash. Serious adverse events, affecting less than 1% of patients, included hepatotoxicity, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and intestinal perforations. The regorafenib label includes a boxed warning about the risk of hepatotoxicity associated with treatment, noting that severe and sometimes fatal hepatotoxicity has been reported in clinical trials, and that hepatic function should be monitored before and during treatment.
Regorafenib inhibits multiple kinases that are involved in normal cellular functions, as well as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment, according to the manufacturer.
Regorafenib was the focus of the FDA’s priority review program, which evaluates the drug in 6 months instead of the usual 12 months, and is designated for products "that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products," according to the FDA statement.
The FDA cites a National Cancer Institute estimate that 3,300-6,000 new cases of GIST are diagnosed every year in the United States, affecting mostly older adults. The previously approved colorectal cancer indication is for people who have metastatic colorectal cancer, who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
Imatinib (Gleevec) and sunitinib (Sutent) are both orally administered kinase inhibitors.