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.引言：尽管不可切除肝细胞癌（unresectable hepatocellular carcinoma, uHCC）的治疗近年来取得进展，但一线免疫联合治疗的中位总生存期（overall survival, OS）已停滞在16~24个月，因此有必要评估潜在更有效的治疗方案。本研究报告了仑伐替尼（lenvatinib，多激酶抑制剂）联合纳武利尤单抗（nivolumab，抗PD-1抗体）治疗晚期不可切除肝细胞癌的首个前瞻性1b期临床试验结果。 方法：本研究为开放标签临床试验，在日本开展，纳入经组织学/细胞学确诊的肝细胞癌成年患者（年龄≥20岁）。患者接受经单药治疗获批剂量的仑伐替尼：体质量<60kg者予8mg，体质量≥60kg者予12mg，每日1次口服；联合240mg纳武利尤单抗静脉输注，每2周一次（第1、15天），每4周为一个治疗周期。试验分为两个部分：第1部分计划纳入6例患者，以评估仑伐替尼联合纳武利尤单抗的耐受性；第2部分评估安全性与初步抗肿瘤活性。主要终点为剂量限制性毒性（dose-limiting toxicities, DLTs，仅第1部分）与安全性；次要终点为客观缓解率（objective response rate, ORR）以及仑伐替尼和纳武利尤单抗的药代动力学。额外探索性终点（包括总生存期与无进展生存期，仅第2部分）亦进行了评估。 结果：第1部分的6例患者均未观察到剂量限制性毒性。第1、2部分共30例患者均出现了治疗相关不良事件（treatment-related adverse events, TRAEs），最常见的治疗相关不良事件为掌跖感觉丧失性红斑综合征（60%）、发音困难（53.3%）及食欲下降（50.0%）。仑伐替尼的AUC(0-t)分布与既往肝细胞癌患者中仑伐替尼的暴露量分布相似，且处于REFLECT试验中单药使用仑伐替尼时观察到的AUC(0-τ)分布范围内。经研究者依据mRECIST标准评估的客观缓解率：第1部分为66.7%，第2部分为79.2%。第2部分中，经研究者依据mRECIST标准评估的中位无进展生存期为9.07个月，中位总生存期为26.94个月。 结论：本项1b期临床试验结果显示，仑伐替尼联合纳武利尤单抗耐受性良好，在晚期不可切除肝细胞癌患者中展现出令人鼓舞的抗肿瘤活性。