On September 27, 2012, the U. S. Food and Drug Administration approved regorafenib (Stivarga tablets, Bayer HealthCare Pharmaceuticals, Inc.), for the treatment of patients with metastatic colorectal cancer (mCRC) 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.

Regorafenib, and its active metabolites, inhibit multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes, including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl pathways.
The approval was based on the results of an international, randomized (2:1), double-blind, placebo-controlled trial (Study 14387) enrolling 760 patients with previously treated mCRC.  All patients had received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with bevacizumab.  All but one patient with KRAS wild-type tumors received panitumumab or cetuximab.  Patients in the regorafenib arm received 160 mg regorafenib orally once daily for the first 21 days of each 28-day cycle plus best supportive care.  Those in the control group received matching placebo with best supportive care.
A statistically significant prolongation in overall survival was observed in patients randomized to receive regorafenib [hazard ratio (HR) 0.77 (95% CI: 0.64, 0.94); p=0.0102].  The median survival time was 6.4 months (95% CI: 5.8, 7.3) in the regorafenib arm and 5.0 months (95% CI: 4.4, 5.8) in the placebo arm. 
The trial also demonstrated a statistically significant improvement in progression-free survival [HR 0.49 (95% CI: 0.42, 0.58); p<0.0001]. The median progression-free survival was 2.0 months (95% CI: 1.9, 2.3) in the regorafenib arm and 1.7 months (95% CI: 1.7, 1.8) in the placebo arm. No difference in overall response rate was observed. Five patients (1%) in the regorafenib arm and one patient (0.4%) in the placebo arm experienced partial responses.
The safety population in Study 14387 comprised 500 patients who received regorafenib and 253 patients who received placebo. The most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib are asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension and dysphonia.
The most serious adverse drug reactions in patients receiving regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation. Regorafenib is approved with a boxed warning describing the risk of hepatotoxicity.
The recommended dose and schedule for regorafenib is 160 mg (four 40 mg tablets) orally once daily for the first 21 days of each 28-day cycle.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Page Last Updated: 05/04/2016
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