靶向联合免疫治疗在不可切除肝细胞癌的临床研究进展

Advances in Targeted Therapy Combined with Immunotherapy for Unresectable Hepatocellular Carcinoma

原发性肝癌是国内发病率及死亡率都位居前列的恶性肿瘤,约70%的肝癌患者确诊时已经是中晚期,失去根治性手术机会。晚期肝癌的治疗一直是困扰临床医生的一大难题,2008年国内批准索拉非尼作为晚期肝癌一线治疗的靶向药物,开启靶向治疗时代,然而疗效不尽人意,患者的中位生存期仅延长了近3个月,客观缓解率仅为2%。近年来,随着免疫检查点抑制剂的快速发展,晚期肝癌治疗迎来免疫新纪元。2019年美国临床肿瘤协会上公布了IMbrave150研究,探索阿替利珠单抗联合贝伐珠单抗对比索拉非尼在晚期肝癌一线治疗的疗效,发现中位生存期延长近6个月,且亚组分析发现中国人群中位生存期达到24个月,延长近13个月。2020年阿替利珠单抗联合贝伐珠单抗被国内外各大指南列为一线推荐。IMbrave150研究拉开了靶向联合免疫治疗的序幕,同时也推动国内外多项临床研究,开启靶向联合免疫治疗在不可切除肝细胞癌探索的新征程。本文旨在探讨靶向联合免疫治疗在不可切除肝细胞癌中的应用范围、不良反应、发展趋势及挑战。

Primary hepatocellular carcinoma is a malignant tumor with high morbidity and mortality in China. Approximately 70% of hepatocellular carcinoma patients are already in middle or advanced stage at the time of diagnosis, thus have lost the opportunity of radical surgery. The treatment of advanced hepatocellular carcinoma has always been a major problem that plagues clinicians. In 2008, sorafenib was approved as a targeted drug for the first-line treatment of advanced hepatocellular carcinoma in China, opening the era of targeted therapy. The survival, however, was only extended by nearly 3 months, and the overall response rate was only 2%. With the rapid development of immune checkpoint inhibitors in recent years, the treatment of advanced hepatocellular carcinoma has entered a new era of immunotherapy. IMbrave150 published by American Society of Clinical Oncology in 2019 explored the efficacy of atezolizumab combined with bevacizumab versus sorafenib in the first-line treatment of advanced liver cancer, reporting a prolonged median survival of 6 months. The median survival time of the Chinese population reached 24 months, which was extended by nearly 13 months. In 2020, atezolizumab combined with bevacizumab was recommended as the first-line treatment scheme by major guidelines at home and abroad. IMbrave150 initiated the treatment strategy with targeted therapy and immunotherapy, and promoted it for unresectable hepatocellular carcinoma in worldwide clinical studies. The purpose of this article is to discuss the scope, adverse reactions, trends and challenges of targeted therapy combined immunotherapy in unresectable hepatocellular carcinoma.