Supplementary Material for: A Phase 1b Study of Lenvatinib plus Nivolumab in Patients with Unresectable Hepatocellular Carcinoma

Introduction: Despite recent advances in treatment for unresectable hepatocellular carcinoma (uHCC), median overall survival (OS) in the first-line setting across immune-based combination therapies has plateaued at 16–24 months. Evaluation of potentially more potent therapies is warranted. We report results of the first prospective phase 1b study of lenvatinib (multi-kinase inhibitor) + nivolumab (anti-PD-1 antibody) for treating advanced uHCC. Methods: This open-label study was conducted in Japan among adults (≥20 years) with histologically/cytologically confirmed HCC. Patients received monotherapy-approved doses of either 8 mg (body weight <60 kg) or 12 mg (body weight ≥60 kg) oral lenvatinib once daily + 240 mg intravenous nivolumab every 2 weeks (days 1 and 15) in 4-week cycles. Part 1 planned to enroll 6 patients to evaluate the tolerability of lenvatinib+nivolumab. Part 2 evaluated safety and preliminary anti-tumor activity. Primary endpoints were dose-limiting toxicities (DLTs; part 1 only) and safety. Secondary endpoints were objective response rate (ORR) and pharmacokinetics of lenvatinib and nivolumab. Additional exploratory endpoints (including OS and progression-free survival; part 2 only) were assessed. Results: No DLT was observed among patients (n = 6) in part 1. Treatment-related adverse events (TRAEs) were observed in all patients (n = 30) in part 1 and 2. The most common TRAEs were palmar-plantar erythrodysesthesia syndrome (60%), dysphonia (53.3%), and decreased appetite (50.0%). Distributions of lenvatinib AUC(0-t) were similar to those observed for lenvatinib in HCC previously and were within the distributions of AUC(0-τ) observed with lenvatinib monotherapy in the REFLECT trial. ORR by mRECIST per investigator review was 66.7% in part 1 and 79.2% in part 2. In part 2, median progression-free survival was 9.07 months by mRECIST per investigator review, and median OS was 26.94 months. Conclusion: Lenvatinib+nivolumab was well-tolerated and had encouraging anti-tumor activity in patients with advanced uHCC in this phase 1b study.