Nivolumab 对比索拉非尼治疗晚期肝细胞癌 (CheckMate 459)：一项随

StephenW

Nivolumab 对比索拉非尼治疗晚期肝细胞癌 (CheckMate 459)：一项随机、多中心、开放标签、3 期试验

    Thomas Yau, 医学博士
    Joong-Won Park, MD
    Richard S Finn 教授，医学博士
    郑安丽教授，医学博士
    菲利普·马图林教授，医学博士
    朱利安·艾德琳，医学博士
    Masatoshi Kudo 教授，医学博士
    詹姆斯 J 哈丁，医学博士
    菲利普·梅尔教授，医学博士
    Olivier Rosmorduc 教授，医学博士
    Lucjan Wyrwicz 教授，医学博士
    医学博士 Eckart Schott 教授
    苏品秋，医学博士
    医学博士 Robin Kate Kelley 教授
    Wolfgang Sieghart，医学博士
    医学博士 Eric Assenat 教授
    Renata Zaucha 教授，医学博士
    Junji Furuse 教授，医学博士
    Ghassan K Abou-Alfa，医学博士
    Anthony B El-Khoueiry，医学博士
    医学博士 Ignacio Melero 教授
    Damir Begic，药学博士
    龚晨，博士
    Jaclyn Neely 博士
    塔米 Wisniewski，每小时英里数
    玛丽娜·柴卡，医学博士
    布鲁诺·桑格罗教授，医学博士
    显示较少

发布时间：2021年12月13日DOI：https://doi.org/10.1016/S1470-2045(21)00604-5


概括
背景
在 1-2 期 CheckMate 040 研究中，单药纳武单抗在晚期肝细胞癌患者中显示出持久的反应、可控的安全性和有希望的生存期。我们的目的是在晚期肝细胞癌患者的一线环境中研究纳武单抗单药治疗与索拉非尼单药治疗的比较。
方法
在这项在亚洲、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的随机、开放标签、3 期试验中，至少 18 岁的组织学确诊的晚期肝细胞癌患者不符合条件或患有该疾病手术或局部治疗后进展；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 分，且无论病毒性肝炎状态如何，均通过交互式语音应答系统随机分配 (1:1) 以接收nivolumab（每 2 周静脉注射 240 mg）或索拉非尼（400 mg，每天口服两次），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。这项已完成的试验已在 ClinicalTrials.gov 注册，NCT02576509。
发现
2016 年 1 月 11 日至 2017 年 5 月 24 日期间，743 名患者被随机分配接受治疗（纳武单抗，n=371；索拉非尼，n=372）。在主要分析中，nivolumab 组的中位总生存期随访时间为 15·2 个月（IQR 5·7–28·0），索拉非尼组为 13·4 个月（5·7-25·9） .纳武单抗的中位总生存期为 16·4 个月（95% CI 13·9-18·4），索拉非尼为 14·7 个月（11·9-17·2）（风险比 0·85 [95% CI 0· 72–1·02]；p=0·075；最少随访 22·8 个月）；未达到协议定义的 p=0·0419 显着性水平。最常见的 3 级或更严重的治疗相关不良事件是掌跖红斑感觉障碍（纳武单抗组 367 例患者中的 1 [<1%] 与索拉非尼组患者中的 52 例 [14%]）、天冬氨酸转氨酶升高（22 [6%] vs 13 [4%]），以及高血压（0 vs 26 [7%]）。接受纳武单抗的 43 名 (12%) 患者和接受索拉非尼的 39 名 (11%) 患者报告了严重的治疗相关不良事件。纳武单抗组 4 例死亡和索拉非尼组 1 例死亡被评估为治疗相关。
解释
与索拉非尼相比，一线纳武单抗治疗并未显着改善总生存期，但在晚期肝细胞癌患者中观察到临床活性和良好的安全性。因此，对于酪氨酸激酶抑制剂和抗血管生成药物有禁忌或有很大风险的患者，nivolumab 可能被认为是一种治疗选择。
资金
百时美施贵宝与小野制药合作。

StephenW

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

    Thomas Yau, MD
    Joong-Won Park, MD
    Prof Richard S Finn, MD
    Prof Ann-Lii Cheng, MD
    Prof Philippe Mathurin, MD
    Julien Edeline, MD
    Prof Masatoshi Kudo, MD
    James J Harding, MD
    Prof Philippe Merle, MD
    Prof Olivier Rosmorduc, MD
    Prof Lucjan Wyrwicz, MD
    Prof Eckart Schott, MD
    Su Pin Choo, MD
    Prof Robin Kate Kelley, MD
    Wolfgang Sieghart, MD
    Prof Eric Assenat, MD
    Prof Renata Zaucha, MD
    Prof Junji Furuse, MD
    Ghassan K Abou-Alfa, MD
    Anthony B El-Khoueiry, MD
    Prof Ignacio Melero, MD
    Damir Begic, PharmD
    Gong Chen, PhD
    Jaclyn Neely, PhD
    Tami Wisniewski, MPH
    Marina Tschaika, MD
    Prof Bruno Sangro, MD
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Publishedecember 13, 2021DOI:https://doi.org/10.1016/S1470-2045(21)00604-5


Summary
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 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.
Interpretation
First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.
Funding
Bristol Myers Squibb in collaboration with Ono Pharmaceutical.