The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (hcc) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (fda) and the European Medicines Agency. In phase ii studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval by the fda of nivolumab and pembrolizumab for second-line treatment. However, phase iii trials of nivolumab in the first line and pembrolizumab in the second line as single agents failed to reach statistical significance, although clinical benefit for a subset of patients with long durations of response could be demonstrated. Despite that setback, immunotherapy for hcc is a promising therapeutic approach, and the combination of immunotherapy with other treatment modalities such as monoclonal antibodies, tyrosine kinase inhibitors, or local therapies has the potential to increase the overall response rate and survival. Recently, the results of a phase iii trial of combination atezolizumab-bevacizumab compared with sorafenib showed a highly significant survival benefit and median overall survival that was not reached in the immunotherapy arm, making the combination the preferred standard of care in first-line therapy. Despite the impressive results and generally good toxicity profile of immunotherapy, patients who respond to therapy constitute only a subset of the overall population, and response rates are still limited. This review focuses on the currently reported results and ongoing clinical trials of checkpoint inhibitor-based immunotherapy in hcc.

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免疫疗法在肝细胞癌治疗中的作用：当前标准和未来方向

大约十年来，多激酶抑制剂索拉非尼是唯一被批准用于晚期肝细胞癌 (hcc) 的全身疗法。近年来，由于多项三期临床试验的积极结果，获批药物的数量显着增加。乐伐替尼作为一线治疗药物，以及二线治疗药物瑞戈非尼、卡博替尼和雷莫芦单抗现已获得美国食品和药物管理局 (FDA) 和欧洲药品管理局的批准。在 II 期研究中，纳武单抗免疫疗法和派姆单抗单一疗法在未接受治疗和接受过治疗的患者的总体生存率方面取得了令人印象深刻的结果，导致 FDA 加速批准纳武单抗和派姆单抗用于二线治疗。然而，一线药物纳武单抗和二线药物帕博利珠单抗作为单一药物的 III 期试验未能达到统计学显着性，尽管可以证明对部分具有长反应持续时间的患者的临床益处。尽管存在这些挫折，肝癌的免疫疗法仍然是一种有前途的治疗方法，并且免疫疗法与单克隆抗体、酪氨酸激酶抑制剂或局部疗法等其他治疗方式的结合有可能提高总体缓解率和生存率。最近，阿特朱单抗-贝伐单抗组合与索拉非尼相比的 3 期试验结果显示，免疫治疗组未达到高度显着的生存获益和中位总生存期，使该组合成为一线治疗的首选护理标准。尽管免疫疗法取得了令人印象深刻的结果并且总体上具有良好的毒性特征，但对治疗有反应的患者仅占总人群的一小部分，并且反应率仍然有限。本综述重点关注目前报道的基于检查点抑制剂的肝癌免疫疗法的结果和正在进行的临床试验。