Randomized phase II study comparing two doses of regorafenib in second-line treatment for advanced hepatocellular carcinoma

Background & Aims The RESORCE trial confirmed regorafenib as a second-line treatment for advanced hepatocellular carcinoma (HCC) in patients who tolerated sorafenib. However, its safety and efficacy in patients with diverse treatment histories remain unknown. The REGAIN study sought to assess regorafenib in patients not included in the RESORCE trial. Methods This single-center, randomized, open-label, dose-comparison trial included HCC patients who had previously received sorafenib 200 mg/day or 400 mg every other day (Arm A), lenvatinib (Arm B), or atezolizumab plus bevacizumab (Arm C). Patients were randomly assigned to receive regorafenib at the standard (160 mg/day) or reduced (80 mg/day) starting dose. For early safety assessment, discontinuation due to adverse events (AEs) during the first cycle among the first six patients in each dose group was defined as a measure of evaluation. The primary endpoint was time to progression (TTP), and efficacy was evaluated using mRECIST. Results Thirty-six patients were enrolled (12 per Arm). Although the study did not reach its originally planned sample size, it provided safety and exploratory efficacy data. Discontinuation in the first cycle due to AEs was observed in one patient (Arm C, standard-dose group). The efficacy outcomes were comparable between the standard- and reduced-dose groups: median TTP was 4.6 vs. 3.0 months (p = 0.810), progression-free survival was 4.6 vs. 3.4 months (p = 0.811), and overall survival was 18.1 vs. 17.7 months (p = 0.728). The objective response rate was 22.2% in both groups. Conclusions Regorafenib can be safely administered with varying treatment histories. Further investigation is warranted to validate the clinical utility of reduced starting dose, which may optimize treatment strategies for advanced HCC in real-world settings. Impact and Implications Sequencing and extending systemic therapies can improve the prognosis of advanced hepatocellular carcinoma (HCC), but comprehensive evidence on second-line and subsequent treatments remains limited. This study evaluated regorafenib in modern clinical scenarios, including patients intolerant to sorafenib and those previously treated with lenvatinib or atezolizumab plus bevacizumab. Regorafenib was safely administered at 160 mg/day and 80 mg/day, and an exploratory efficacy analysis found no significant difference between the two starting doses. These findings support the integration of regorafenib into personalized treatment strategies for advanced HCC, providing physicians specializing in liver cancer treatment with greater flexibility in selecting appropriate therapeutic sequences while also expanding treatment options for patients facing increasingly limited systemic therapy choices. Clinical trial number JRCTs031190103