Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, CIBEREHD, Madrid, Spain.
J Hepatol. 2021 Sep;75(3):600-609. doi: 10.1016/j.jhep.2021.04.047. Epub 2021 May 26.
BACKGROUND & AIMS: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. METHODS: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. CONCLUSIONS: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. LAY SUMMARY: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. CLINICAL TRIAL NUMBER: NCT01658878.
背景与目的：患有晚期肝细胞癌（aHCC）和 Child-Pugh B 级肝功能的患者通常被排除在临床试验之外。在之前的研究中，接受索拉非尼治疗的这些患者的总生存期约为 3-5 个月；因此，需要新的治疗方法。纳武单抗，单独或与伊匹单抗联合使用，在美国有条件批准用于治疗先前接受过索拉非尼治疗的 aHCC 患者。我们描述了纳武单抗单药治疗 Child-Pugh B 级患者的结果。
方法：这是一项 I/II 期、开放标签、非对照、多中心试验（27 个中心），纳入了 Child-Pugh B（B7-B8）级 aHCC 患者。患者每 2 周接受静脉注射纳武单抗 240mg，直至出现不可接受的毒性或疾病进展。主要终点是研究者评估的客观缓解率（ORR）（使用实体瘤反应评估标准 1.1 版）和缓解持续时间。使用国家癌症研究所不良事件通用术语标准 4.0 评估安全性。
结果：25 名索拉非尼初治患者和 24 名索拉非尼治疗患者于 2016 年 11 月至 2017 年 10 月开始治疗（中位随访时间 16.3 个月）。研究者评估的 ORR 为 12%（95%CI，5-25%），有 6 名患者有缓解；疾病控制率为 55%（95%CI，40-69%）。中位缓解时间为 2.7 个月（四分位间距，1.4-4.2），中位缓解持续时间为 9.9 个月（95%CI，9.7-9.9）。25 名患者（51%）报告了与治疗相关的不良事件（TRAEs），其中 2 名患者（4%）因 TRAE 而停药。最常见的 3/4 级 TRAE 为氨基转移酶升高（n=2）、淀粉酶升高（n=2）和天门冬氨酸氨基转移酶升高（n=2）。纳武单抗的安全性与 Child-Pugh A 级 aHCC 患者的安全性相当。
结论：纳武单抗在 Child-Pugh B 级 aHCC 患者中具有临床活性和良好的安全性，且毒性可管理，表明其可能适合 Child-Pugh B 级 aHCC 患者。
患者教育：对于患有晚期肝细胞癌的患者，几乎所有的系统治疗都需要非常好的肝功能，即 Child-Pugh A 级。这项研究的结果表明，纳武单抗在 Child-Pugh B 级肝功能轻度至中度受损或肝功能失代偿的肝细胞癌患者中具有临床活性和可接受的安全性，这些患者可能排除了其他治疗方法。需要进一步的研究来评估纳武单抗在这一患者人群中的安全性和疗效。
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