Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial
复制标题
晚期黑色素瘤中尼伐单抗加伊匹单抗或单用尼伐单抗与单用伊匹单抗的比较（CheckMate 067）： 多中心、随机、3 期试验的 4 年结果
DOI：
10.1016/s1470-2045(18)30700-9
复制
发表时间：
2018-11-01
期刊：
影响因子：
51.1
通讯作者：
Wolchok, Jedd D.
中科院分区：
文献类型：
--
作者：
Hodi, Frank Stephen;Chiarion-Sileni, Vanna;Wolchok, Jedd D.
背景 先前报道的 3 期 CheckMate 067 试验结果显示，与单独使用伊匹单抗相比，纳武单抗加伊匹单抗或单用纳武单抗治疗晚期黑色素瘤患者的客观反应、无进展生存期和总生存期显着改善。本报告的目的是提供本研究的 4 年更新疗效和安全性数据。 方法 在这项 3 期试验中，符合条件的患者年龄为 18 岁或以上，患有先前未经治疗、不可切除的 III 期或 IV 期黑色素瘤，已知 BRAFV(600) 突变状态，东部肿瘤合作组表现状态为 0 或 1。患者被随机分配为 1:1:1 接受静脉注射纳武单抗 1 mg/kg 加伊匹单抗治疗每 3 周 3 mg/kg，共四剂，随后每 2 周 3 mg/kg 纳武单抗，或每 2 周 3 mg/kg 纳武单抗加安慰剂，或每 3 周 3 mg/kg 伊匹木单抗，四剂加安慰剂。随机化是通过交互式语音应答系统完成的，该系统具有排列的块计划（块大小为 6），并按 PD-L1 状态、BRAF 突变状态和转移阶段进行分层。患者、研究人员、研究中心工作人员和研究资助者对所施用的研究药物不知情。共同主要终点是无进展生存期和总生存期。对意向治疗人群进行疗效分析，同时对接受至少一剂研究药物的所有患者进行安全性评估。本报告中提供的结果反映了正在进行的研究的 4 年更新，数据库锁定日期为 2018 年 5 月 10 日。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01844505。结果 2013 年 7 月 3 日至 2014 年 3 月 31 日期间，入组了 945 名患者，并随机分配至纳武单抗加易普利姆玛 (n=314)、纳武单抗(n=316) 或伊匹单抗 (n=315)。纳武单抗加伊匹单抗组的中位随访时间为 46.9 个月（IQR 10.9-51.8），纳武单抗组为 36.0 个月（10.5-51.4），伊匹单抗组为 18.6 个月（7.6-49.5）。自最终患者入组和随机分组之日起至少 48 个月的随访中，纳武单抗加伊匹单抗组未达到中位总生存期（95% CI 38.2 - 未达到），纳武单抗组为 36.9 个月（28.3 - 未达到），伊匹单抗组为 19.9 个月（16.9-24.6）。联合用药与易普利姆玛的死亡风险比为 0.54（95% CI 0.44-0.67；p
Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV(600) mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46.9 months (IQR 10.9-51.8) in the nivolumab plus ipilimumab group, 36.0 months (10.5-51.4) in the nivolumab group, and 18.6 months (7.6-49.5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38.2-not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3-not reached) in the nivolumab group, and 19.9 months (16.9-24.6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0.54 (95% CI 0.44-0.67; p