单药免疫检查点抑制剂(ICIs)已经在晚期肝细胞癌(HCC)患者中进行了测试，其显示出15-20%的客观反应率，大多数没有显著的总生存(OS)益处。此外，约30%的HCC表现出对ICIs的内在抗性。在缺乏预测性生物标志物以确定哪些患者最可能从免疫疗法中受益的情况下，研究转向探索与更广泛患者人群潜在活性的组合方法。包括HCC患者队列的筐试验和早期研究测试了ICIs与抗血管生成抑制剂的联合以及两种不同ICIs的联合。实现的有希望的结果为随后的3期试验提供了理由，这些试验测试了抗PD-1/PD-L1与贝伐单抗、酪氨酸激酶抑制剂(TKIs)或抗CTLA-4的联合。IMbrave150试验的积极结果导致了阿特伯单抗-贝伐单抗的颠覆性批准，这是第一个在前线设置中展示改善生存的方案，自索拉非尼获批以来。更近期，HIMALAYA试验证明了Durvalumab-Tremelimumab（STRIDE方案）优于索拉非尼，建立了新的一线选择。相比之下，ICIs和TKIs的组合取得了不一致的结果，只有一项3期试验显示出了总生存(OS)的益处。对于晚期HCC患者的快速演变的治疗景观，未来的研究留下了重要的未满足需求。这些包括治疗选择和顺序、标志物的识别、局部区域治疗的组合以及新的免疫疗法药物的开发。本文综述了先进HCC中免疫组合疗法的科学依据和可用的临床数据。版权所有2023年欧洲肝脏研究协会。由Elsevier B.V出版。保留所有权利。

Single-agent immune checkpoint inhibitors (ICIs) have been tested in patients with advanced hepatocellular carcinoma (HCC) showing an objective response rate of 15-20%, mostly without a significant overall survival (OS) benefit. Furthermore, approximately 30% of HCC shows intrinsic resistance to ICIs. In the absence of predictive biomarkers to identify patients likely to benefit most from immunotherapy, research has moved to exploring combinations with potential activity in broader patient populations. Basket trials, including cohorts of patients with HCC, and early phase studies tested the combination of ICIs with antiangiogenic agents as well as the combination of two different ICIs. The achieved promising results provided the rationale for the following phase 3 trials, which tested the combination of anti-PD-1/PD-L1 with bevacizumab, or tyrosine kinase inhibitors (TKIs), or anti-CTLA-4. Positive results from the IMbrave150 trial led to the practice-changing approval of atezolizumab-bevacizumab, the first regimen to demonstrate improved survival in the front-line setting, since the approval of sorafenib. More recently, the HIMALAYA trial demonstrated the superiority of durvalumab-tremelimumab (STRIDE regimen) over sorafenib, establishing a new first-line option. In contrast, inconsistent results have been achieved with combinations of ICIs and TKIs, with only one phase 3 trial showing an OS benefit. The rapidly evolving therapeutic landscape for patients with advanced HCC has left significant unmet needs to be addressed in future research. These include choice and sequencing of treatments, identification of biomarkers, combinations with locoregional therapies, and development of new immunotherapy agents. This review summarizes the scientific rationale and available clinical data for combination immunotherapy in advanced HCC.Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.