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Metastatic colorectal cancer: Regorafenib approved by FDA

Bayer HealthCare has announced that the Food and Drug Administration ( FDA ) approved Stivarga ( Regorafenib ) tablets for the treatment of patients with metastatic colorectal cancer ( mCRC ) who have been previously treated with currently available therapies ( including fluoropyrimidine-, Oxaliplatin- and Irinotecan-based chemotherapy, an anti-VEGF therapy, and if KRAS wild type, an anti-EGFR therapy ).
The approval of Stivarga is based on results from the pivotal Phase III study ( CORRECT ) that has demonstrated a statistically significant improvement in overall survival and progression-free survival compared to placebo in patients with mCRC whose disease had progressed after approved standard therapies.
Stivarga is an oral multi-kinase inhibitor that inhibits various kinases within the mechanisms involved in tumor growth and progression ( angiogenesis, oncogenesis and the tumor microenvironment ).

CORRECT ( Colorectal cancer treated with regorafenib or placebo after failure of standard therapy ) was an international, multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled 760 patients with mCRC whose disease had progressed during or within three months following last administration of approved standard therapies. Patients were randomized to receive Regorafenib plus best supportive care ( BSC ) or placebo plus BSC, respectively. Treatment cycles consisted of 160 mg of Regorafenib ( or matching placebo ) once daily for three weeks on / one week off plus BSC.

In the CORRECT trial, Regorafenib plus ( BSC ) significantly improved overall survival ( hazard ratio, HR=0.77, 2-sided p-value=0.0102 ) and progression-free survival ( HR=0.49, 2-sided p-value less than 0.0001 ) compared to placebo plus BSC.
Median overall survival was 6.4 months with Regorafenib versus 5.0 months with placebo; median progression-free survival was 2.0 months with Regorafenib versus 1.7 months with placebo.
The data also showed a survival benefit ( overall survival and progression-free survival ) in the Regorafenib arm across nearly all subgroups analyzed.
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.
History of KRAS evaluation was reported for 729 ( 96% ) patients; 430 ( 59% ) of these patients were reported to have KRAS mutation.
The most frequently observed adverse drug reactions ( greater than or equal to 30%) in patients receiving Regorafenib were asthenia/fatigue, decreased appetite and food intake, hand-foot-skin reaction / palmar-plantar erythrodysesthesia, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia. The most serious adverse drug reactions in patients receiving Regorafenib were hepatotoxicity, hemorrhage and gastrointestinal perforation.

Colorectal cancer is the fourth most common cancer worldwide, with over one million cases occurring every year. The mortality rate from colorectal cancer is approximately half of its global incidence. The five-year survival estimate for colorectal cancer on average is 55%, but is highly variable dependent on the stage of the disease ( from 74% for patients with stage I disease to only 6% for stage IV patients). In metastatic colorectal cancer, KRAS status is an important biomarker and can be a predictor of treatment response. Approximately 40% of colorectal cancers are characterized by mutations in the KRAS gene. Some of the colorectal cancer therapies currently available have demonstrated efficacy only in patients without KRAS mutations.

Regorafenib is an oral multi-kinase inhibitor that inhibits various kinases. Regorafenib inhibits several angiogenic VEGF receptor tyrosine kinases that play a role in tumor neoangiogenesis . It also inhibits various oncogenic and tumor microenvironment kinases including VEGFR 1-3, KIT, RET, PDGFR, and FGFR, which individually and collectively impact upon tumor growth, formation of a stromal microenvironment and disease progression.

Source: Bayer Healthcare, 2012