Supplementary Material for: A phase 1b study of botensilimab and balstilimab in treatment-refractory hepatocellular carcinoma

Introduction: Botensilimab (BOT) is an Fc-enhanced multifunctional anti–CTLA-4 antibody with differentiated mechanisms of action, designed to extend therapy to cold/poorly immunogenic solid tumors. Patients with hepatocellular carcinoma (HCC) who progress on or after first-line immunotherapy have limited treatment options. Here, we report findings from a phase 1b study of BOT plus balstilimab (BAL; anti–PD-1 antibody) in previously treated patients with HCC.
Methods: This is an open-label, nonrandomized, phase 1b, multicenter study of BOT±BAL in patients with advanced solid tumors. The study began with dose escalation (3+3 design) then dose expansion with multiple disease-specific cohorts. An expanded cohort of 19 patients with HCC who progressed on or after prior immunotherapy (primarily atezolizumab/bevacizumab) are included in this analysis. Patients with HCC received BOT intravenously at 1 or 2 mg/kg once every 6 weeks for up to 2 years plus BAL intravenously 3 mg/kg once every 2 weeks, for up to 2 years. Endpoints included safety, objective response rate (ORR), disease control rate, duration of response (DOR), and progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint.
Results: Among 18 efficacy-evaluable patients (with ≥1 post-baseline 6-week imaging scan), ORR was 17% (3/18; 95% CI, 4–41), and 18-week clinical benefit rate (a complete or partial response or stable disease) 50% (9/18; 95% CI, 26–74). Median PFS was 4.4 months (95% CI, 1.4–6.9), and median OS 12.3 months (95% CI, 8.4–21.4). Thirteen patients (68%) experienced any-grade immune-mediated treatment-related adverse events (TRAEs), with 37% (7/19) grade 3. The most common immune-mediated TRAEs included diarrhea/colitis (37% [7/19]; 16% grade 3 [3/19]), hepatitis (21% [4/19]; 16% grade 3 [3/19]), and dermatologic events (21% [4/19]; 5% grade 3 [1/19]). There were no treatment-related deaths or new safety signals outside of the class.
Conclusions: The BOT/BAL combination demonstrated durable responses and manageable safety in treatment-refractory patients with HCC previously treated with immunotherapy, supporting further investigation in randomized studies. Despite the small sample size and high percentage of patients with ALBI grade 2 liver disease, these results provide early evidence of antitumor activity in a difficult-to-treat disease setting.
Trial Registration Clinicaltrials.gov Identifier: NCT03860272

引言：博替利单抗（Botensilimab, BOT）是一款Fc增强型多功能抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）抗体，具有独特的作用机制，旨在将治疗范围拓展至冷肿瘤/低免疫原性实体瘤。对于一线免疫治疗期间或之后进展的肝细胞癌（hepatocellular carcinoma, HCC）患者，当前治疗选择十分有限。本研究报道了BOT联合巴替利单抗（balstilimab, BAL；抗PD-1抗体）在既往接受过治疗的HCC患者中的1b期临床试验结果。
方法：本研究为一项开放标签、非随机、多中心1b期临床试验，评估BOT单药或联合BAL治疗晚期实体瘤患者的疗效。研究首先采用剂量爬坡（3+3设计），随后针对多个特定瘤种队列开展剂量扩展。本次分析纳入了19例既往接受免疫治疗（主要为阿替利珠单抗/贝伐珠单抗）后进展的HCC患者扩展队列。HCC患者的给药方案为：静脉输注BOT 1或2 mg/kg，每6周1次，最长给药时长为2年；同时静脉输注BAL 3 mg/kg，每2周1次，最长给药时长为2年。研究终点包括安全性、客观缓解率（objective response rate, ORR）、疾病控制率、缓解持续时间（duration of response, DOR）、无进展生存期（progression-free survival, PFS）；总生存期（overall survival, OS）为探索性终点。
结果：在18例可评估疗效的患者（至少完成1次基线后6周影像学扫描）中，客观缓解率为17%（3/18；95%置信区间[CI], 4–41），18周临床获益率（完全缓解或部分缓解或疾病稳定）为50%（9/18；95%置信区间[CI], 26–74）。中位无进展生存期为4.4个月（95%置信区间[CI], 1.4–6.9），中位总生存期为12.3个月（95%置信区间[CI], 8.4–21.4）。13例患者（68%）发生了任意级别的免疫介导的治疗相关不良事件（TRAEs），其中37%（7/19）为3级不良反应。最常见的免疫介导的TRAEs包括腹泻/结肠炎（37% [7/19]；16%为3级 [3/19]）、肝炎（21% [4/19]；16%为3级 [3/19]）以及皮肤不良反应（21% [4/19]；5%为3级 [1/19]）。未发生治疗相关死亡，也未观察到该类药物之外的新安全信号。
结论：BOT与BAL联合方案在既往接受过免疫治疗的难治性HCC患者中展现出持久的抗肿瘤应答与可控的安全性，支持开展随机对照临床试验进行进一步研究。尽管本研究样本量较小，且ALBI分级为2级肝病的患者占比较高，但上述结果仍为这一难治性瘤种提供了早期抗肿瘤活性证据。
临床试验注册：Clinicaltrials.gov 标识符：NCT03860272