Regorafenib (Stivarga®) is a multi-kinase inhibitor: In the European Union, regorafenib is licensed by the EMA since 2012 for pretreated patients with mCRC and has –in July 2017– received a positive CHMP-opinion as monotherapy for the treatment of adult patients with hepatocellular carcinoma (HCC) who have previously been treated with sorafenib. The positive CHMP-opinion is based on a single pivotal, randomised, double-blind, phase III trial sponsored by the MAH (Bayer) comparing regorafenib (160 mg oral once daily in a 3/1 schedule) plus BSC (best supportive care) with placebo plus BSC in patients with HCC already treated with sorafenib (the RESORCE trial).

Overall, 573 patients were randomised in the RESORCE trial: 379 in the regorafenib plus BSC group and 194 in the placebo plus BSC group. The population included in this trial was notably restricted to those who tolerated sorafenib treatment and with a Child-Pugh score of A and a preserved general state. Demographic and baseline disease characteristics were balanced across both treatment arms. This study met its primary endpoint: OS median OS time was 10.6 months in the regorafenib group and 7.8 months in the placebo group, corresponding to an absolute gain of 2.8 months in favour of regorafenib with a hazard ratio (HR) of 0.627 (95% confidence interval [CI] 0.500, 0.785), p=0.000020. The addition of regorafenib to BSC also induced an improvement in median progression free survival (PFS) from 1.5 months to 3.1 months: HR=0.455 (95% CI 0.371, 0.558), p<0.000001; absolute gain = 1.6 months. Data from the RESORCE trial suggested the absence of a clinically relevant difference between the two groups in terms of health-related quality of life (HRQoL) as measured by the following scales: EuroQoL five dimensions questionnaire (EQ-5D) and Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire (FACT-hep).

More Grade ≥ 3 drug-related adverse events (AEs) were seen in the regorafenib group (51.9%) than in the placebo group (17.6%); similarly, drug-related serious adverse event (SAE) rates were higher in the regorafenib group (10.4%) than in the placebo group (2.6%). Drug-related AEs leading to the permanent discontinuation of study drug were also higher in the regorafenib group (10.4%) than in the placebo group (3.6%). The most frequent drug-related Grade 3 AEs in the regorafenib group were: hypertension (12.8%), hand-foot skin reaction (HFSR, 12.3%), blood bilirubin increased (5.1%), a spartate transaminase (AST) increased (4.5%) and hypophosphataemia (4.3%).