Regorafenib (Stivarga®) is a multi-kinase inhibitor indicated in heavily pretreated patients with mCRC. In the European Union, regorafenib was licensed by the EMA in August 2012 and the FDA granted marketing authorisation in the United States in September 2012.
The approval was based on the results of the CORRECT trial, an international, multicentre, placebo-controlled phase III study. The trial aimed to assess the efficacy and safety of regorafenib in patients with mCRC, who had disease progression after approved standard therapies. A total of 760 patients received either regorafenib plus best supportive care (n= 505) or placebo plus best supportive care (n= 255). Analyses showed a gain of 1.4 months on overall survival in patients of the regorafenib group compared to patients of the placebo group (HR=0.77, 95% CI 0.64-0.94; p=0.0052). The objective response rate was 1.0% in patients receiving regorafenib compared to 0.4% in patients receiving placebo, suggesting that delay of tumour progression is the primary effect of regorafenib.
Treatment-related adverse events occurred in 93% of patients in regorafenib group and 61% of patients in placebo group. The most frequent adverse events of any grade within the regorafenib group were fatigue and hand-foot skin reaction, within the placebo group fatigue and anorexia were most frequent. Adverse events of grade 3 and 4 were reported in 54% (regorafenib group) and 14% (placebo group) of patients. Furthermore, the CORRECT trial evaluated health-related quality-of-life and health utility values measured by the EORTC's (European Organisation for Research and Treatment of Cancer) general health status and quality-of-life questionnaire QLQ-C30, the EQ-5D (Euro-Qol five dimension) index questionnaire, and the EQ-5D visual analogue scale. The results in both treatment groups -both at baseline and at the end of the treatment- were similar, showing that regorafenib did not improve patients' quality-of-life.
The positive effect of regorafenib on overall survival stands in contrast to the high risk for adverse events and the potentially high costs of this therapy and, moreover, there is no improvement of patients' quality-of-life. For the use of regorafenib in these lines of therapy, detailed criteria for selecting eligible patients need to be determined.