Immune checkpoint inhibitor (ICI) therapy targeting anti-programmed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is the backbone of numerous combination regimens aimed at improving the objective response and survival of patients with hepatocellular carcinoma (HCC). Clinical trials of immuno-oncology regimens in other cancer types have shed light on issues of study design, including how to choose candidate regimens based on early-phase trial results, statistical considerations in trials with multiple primary endpoints, and the importance of predictive biomarkers. In this review, the updated data from early-phase trials of combination immunotherapy for HCC are summarised. Since the most extensively tested combination regimens for advanced HCC comprise anti-PD-1/anti-PD-L1 agents plus antiangiogenic agents, the relative benefit and antitumor mechanism of antiangiogenic multikinase inhibitors versus specific VEGF/VEGFR inhibitors are discussed. Other critical issues in the development of combination immunotherapy, including optimal management of immune-related adverse events and the value of ICI therapy in combination with locoregional treatment for HCC, are also explored.

中文翻译：

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免疫检查点抑制剂联合治疗肝细胞癌的挑战

靶向抗程序性细胞死亡-1（anti-PD-1）或其配体（抗 PD-L1）的免疫检查点抑制剂 (ICI) 疗法是众多联合方案的支柱，旨在改善患有肝细胞癌（HCC）。其他癌症类型的免疫肿瘤学方案的临床试验揭示了研究设计的问题，包括如何根据早期试验结果选择候选方案、具有多个主要终点的试验的统计考虑以及预测性生物标志物的重要性。本综述总结了 HCC 联合免疫治疗早期试验的最新数据。由于最广泛测试的晚期 HCC 联合方案包括抗 PD-1/抗 PD-L1 药物加抗血管生成药物，讨论了抗血管生成多激酶抑制剂与特异性 VEGF/VEGFR 抑制剂的相对益处和抗肿瘤机制。还探讨了联合免疫疗法开发中的其他关键问题，包括免疫相关不良事件的最佳管理以及 ICI 疗法与局部区域治疗联合治疗 HCC 的价值。