A multicenter dose-defining/expansion phase 1b study of first-line regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma

Background and Aims: Combinations including an immune checkpoint inhibitor are preferred first-line treatments for advanced hepatocellular carcinoma (HCC). We investigated the safety of regorafenib plus pembrolizumab as first-line systemic therapy for advanced HCC. Approach and Results: This was a dose-defining/expansion phase 1b study in adults with advanced HCC without prior systemic treatment. Patients received regorafenib 80 or 120 mg/day for 3 weeks plus pembrolizumab 200 mg every 3 weeks in 4-week cycles (rego-80/pembro or rego-120/pembro): rego-80/pembro in the dose-defining phase; rego-80/pembro or rego-120/pembro in two dose-expansion cohorts. The primary objective was to assess safety; antitumor activity was a secondary objective. The MTD of regorafenib was 120 mg/day plus pembrolizumab; 4/19 patients receiving rego-120/pembro experienced DLTs (grade 3 increased aspartate aminotransferase [AST] with grade 1/2 increased bilirubin [n=2], and grade 3 rash [n=2]). The most common treatment-emergent adverse events (TEAEs) in the overall safety cohort (n=57) were diarrhea (53%) and fatigue (51%). The most common grade ≥3 TEAEs were increased AST (18%) and hypertension (16%). Dose modifications due to study drug-related adverse events were less frequent with rego-80/pembro than with rego-120/pembro. The objective response rate (ORR) in 54 response-evaluable patients was 31% and the disease control rate (DCR) was 89%. Exploratory analyses suggested an association between lower angiogenesis and transforming growth factor-β signalling before treatment and response. Conclusion: Treatment with rego/pembro is feasible in patients with advanced HCC with a manageable safety profile. ORR and DCR are promising and consistent with other immunotherapy combinations in this setting.