Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial
Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial
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DOI：
10.1016/s1470-2045(20)30494-0
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发表时间：
2020-11-01
期刊：
影响因子：
51.1
通讯作者：
Weber, Jeffrey
中科院分区：
文献类型：
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作者：
Ascierto, Paolo A.;Del Vecchio, Michele;Weber, Jeffrey
背景此前，CheckMate 238（一项在切除的IIIB-C期或IV期黑色素瘤患者中进行的双盲、III期辅助试验）的结果显示，与ipilimumab相比，nivolumab可显著改善无复发生存期和无远处转移生存期。本报告提供了最新的4年疗效，初始总生存率，和迟发性safety results.Methods这个多中心，双盲，随机，对照，3期试验在130个学术中心，社区医院，癌症中心在25个国家。年龄≥ 15岁、切除IIIB-C或IV期黑色素瘤且东部肿瘤协作组体能状态为0或1的患者通过交互式语音应答系统随机分配（1：1）接受nivolumab或ipilimumab治疗，并根据疾病分期和肿瘤细胞的基线PD-L1状态进行分层。患者每2周一次接受静脉内nivolumab 3 mg/kg或每3周一次静脉内ipilimumab 10 mg/kg，共4剂，然后每12周一次，直至治疗1年、疾病复发、不可接受的毒性或撤回知情同意。主要终点是研究者评估的无复发生存期，总生存期是关键的次要终点。在意向治疗人群（所有随机分配的患者）中进行疗效分析。所有接受至少一剂研究治疗的患者均纳入安全性分析。本报告中列出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2020年1月30日。该研究注册于ClinicalTrials.gov，NCT 02388906。结果2015年3月30日至11月30日，906例患者被分配至nivolumab（n=453）或ipilimumab（n=453）。中位随访时间为51.1个月（IQR 41.6-52.7）与纳武利尤单抗和50.9个月（36.2-52.3）; 4年无复发生存率为51.7% nivolumab组为41.2%（95%CI 46.8-56.3），ipilimumab组为41.2%（36.4-45.9）（风险比[HR] 0.71 [95%CI 0.60-0.86]; p=0.0003）。与211在观察到的302例预期死亡中（纳武单抗组453例患者中有100例[22%]，伊匹单抗组453例患者中有111例125%1）（原计划88%的电力需要的73%），纳武单抗组的4年总生存率为77.9%（95%CI 73.7-81.5），伊匹单抗组为76.6%（72.2-80.3）（HR 0.87 [95%CI 0.66-1-14]; p=0.31）。452例患者中有3例（1%）和453例患者中有7例（2%）报告了迟发性3-4级治疗相关不良事件。最常见的晚期治疗相关的3级或4级不良事件是纳武单抗组的腹泻、糖尿病酮症酸中毒和肺炎（各1例患者），以及伊匹单抗组的结肠炎（2例患者）。伊匹单抗组之前报告的两例治疗相关死亡归因于研究药物毒性（1例患者骨髓发育不全，1例患者结肠炎）;没有报告进一步的治疗相关死亡。解释在至少4年的随访中，纳武利尤单抗在切除的IIIB-C或IV期黑色素瘤中表现出与伊匹单抗相比的持续无复发生存益处，表明纳武利尤单抗具有长期治疗益处。由于死亡人数少于预期，两组的总生存率相似。纳武单抗仍然是切除的高风险黑色素瘤患者的有效辅助治疗，其安全性比易普利姆玛更耐受。版权所有（C）2020 Elsevier Lid。All rights reserved.
Background Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.Methods This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30,2020. This study is registered with ClinicalTrials.gov , NCT02388906.Findings Between March 30 and Nov 30,2015,906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51.1 months (IQR 41.6-52.7) with nivolumab and 50.9 months (36.2-52.3) with ipilimumab; 4-year recurrence-free survival was 51.7% (95% CI 46.8-56.3) in the nivolumab group and 41.2% (36.4-45.9) in the ipilimumab group (hazard ratio [HR] 0.71 [95% CI 0.60-0.86]; p=0.0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 125%1 of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77.9% (95% CI 73.7-81.5) with nivolumab and 76.6% (72.2-80.3) with ipilimumab (HR 0.87 [95% CI 0.66-1-14]; p=0.31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneurnonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.Interpretation At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Copyright (C) 2020 Elsevier Lid. All rights reserved.