Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial
Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial
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DOI：
10.1016/s1470-2045(21)00604-5
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发表时间：
2022-01-01
期刊：
影响因子：
51.1
通讯作者：
Sangro, Bruno
中科院分区：
文献类型：
--
作者：
Yau, Thomas;Park, Joong-Won;Sangro, Bruno
在1-2期CheckMate 040研究中，单药nivolumab在晚期肝细胞癌患者中显示出持久的反应，可管理的安全性和有希望的生存率。我们的目的是研究nivolumab单药治疗与索拉非尼单药治疗相比，在一线治疗晚期肝细胞癌患者中的作用。方法在这项随机、开放标签、3期试验中，在亚洲、澳大拉西亚、欧洲和北美的22个国家和地区的医疗中心进行，或在手术或局部治疗后疾病进展;既往未接受过肝细胞癌全身治疗，Child-Pugh A级和东部肿瘤协作组体能状态评分为0或1，且无论病毒性肝炎状态如何，均随机分配（1：1）通过交互式语音应答系统接收纳武单抗（240 mg静脉注射，每2周一次）或索拉非尼（400 mg口服，每日两次），直至疾病进展或出现不可接受的毒性。主要终点是在意向治疗人群中评估的总生存期。在接受至少一剂研究药物的所有患者中评估安全性。这项已完成的试验注册于ClinicalTrials.gov，NCT 02576509。结果在2016年1月11日至2017年5月24日期间，743名患者被随机分配至治疗组（nivolumab，n=371;索拉非尼，n=372）。在主要分析中，nivolumab组的总生存期中位随访时间为15.2个月（IQR 5.7-28.0），索拉非尼组为13.4个月（5.7-25.9）。nivolumab组的中位总生存期为16.4个月（95%CI 13.9-18.4），索拉非尼组为14.7个月（11.9-17.2）（风险比0.85 [95%CI 0.72-1.02]; p=0.075;最短随访时间为22.8个月）;未达到方案定义的显著性水平p=0.0419。最常见的3级或更严重的治疗相关不良事件是掌跖红肿（1 [
Background Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.Methods In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.Findings Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15.2 months (IQR 5.7-28.0) for the nivolumab group and 13.4 months (5.7-25.9) in the sorafenib group. Median overall survival was 16.4 months (95% CI 13.9-18.4) with nivolumab and 14.7 months (11.9-17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72-1.02]; p=0.075; minimum follow-up 22.8 months); the protocol-defined significance level of p=0.0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [