帕博利珠单抗辅助治疗用于肾细胞癌的总生存期。

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

机构信息

From Dana-Farber Cancer Institute and Harvard Medical School (T.K.C.) and Beth Israel Deaconess Medical Center (D.F.M.) - all in Boston; Poznan University of Medical Sciences, Poznan (P.T.), and Provincial Hospital in Torun, Torun (P.S.) - both in Poland; Samsung Medical Center, Sungkyunkwan University School of Medicine (S.H.P.), and Asan Medical Center, University of Ulsan College of Medicine (J.-L.L.) - both in Seoul, South Korea; Beatson West of Scotland Cancer Centre and the University of Glasgow, Glasgow (B.V.), Edinburgh Cancer Centre and the University of Edinburgh, Edinburgh (S.N.S.), and Imperial College Healthcare NHS Trust (N.S.), Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute (T.P.), and Queen Mary University of London (T.P.), London - all in the United Kingdom; Fiona Stanley Hospital, Perth, WA (T.F.), and Maquarie University, Sydney (H.G.) - both in Australia; Fakultní Nemocnice Ostrava, Ostrava (J.H.), and Palacký University and University Hospital Olomouc, Olomouc (B.M.) - all in the Czech Republic; Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.C.); Abramson Cancer Center, Penn Medicine, Philadelphia (N.B.H.); Fundación Arturo López Pérez, Santiago, Chile (M.M.); University Hospital Bordeaux-Hôpital Saint-André, Bordeaux (M.G.-G.), Hôpital Européen Georges Pompidou, Université Paris Cité, Paris (S.O.), and Centre Hospitalier Universitaire de Montpellier, Montpellier (D.T.) - all in France; the University of Texas Southwestern Medical Center, Dallas (T.Z., H.H.), and Texas Oncology-Houston, Houston (G.D.); Rocky Mountain Cancer Centers, Aurora, CO (J.M.B.); Omsk Clinical Oncology Dispensary, Omsk, Russia (E.K.); the University of Michigan, Ann Arbor (A.A.); the University of Toyama, Toyama, Japan (H.K.); Instituto de Cancer e Transplante de Curitiba, Curitiba, Brazil (A.S.); the London Regional Cancer Program, London Health Sciences Centre, Western University, London, ON, Canada (E.W.); and Merck, Rahway, NJ (J.C., A.E., J.E.B., R.F.P.).

出版信息

N Engl J Med. 2024 Apr 18;390(15):1359-1371. doi: 10.1056/NEJMoa2312695.

DOI:10.1056/NEJMoa2312695

PMID:38631003

Abstract

BACKGROUND

Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain.

METHODS

In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point.

RESULTS

A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy.

CONCLUSIONS

Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

摘要

背景

帕博利珠单抗辅助治疗肾细胞癌术后的适应证是基于 KEYNOTE-564 试验中疾病无进展生存的显著改善。该试验的第三次预设中期分析结果是否也将有利于帕博利珠单抗治疗肾癌患者的总生存时间尚不确定。

方法

在这项 3 期、双盲、安慰剂对照试验中，我们按 1:1 的比例随机分配（分层因素为手术切除后有高复发风险的）透明细胞肾细胞癌患者，接受派姆单抗（剂量为 200mg）或安慰剂，每 3 周给药 17 个周期（约 1 年），直至疾病复发、出现不可接受的毒性作用或撤回同意。先前已显示研究者评估的疾病无进展生存有显著改善（主要终点）。总生存是关键次要终点。安全性是次要终点。

结果

共有 496 名患者被分配接受派姆单抗治疗，498 名患者接受安慰剂治疗。截至 2023 年 9 月 15 日，中位随访时间为 57.2 个月。无疾病进展生存获益与之前的分析一致（复发或死亡的风险比为 0.72；95%置信区间 [CI]，0.59 至 0.87）。与安慰剂相比，派姆单抗治疗观察到总生存的显著改善（死亡风险比为 0.62；95%CI，0.44 至 0.87；P=0.005）。派姆单抗组 48 个月的总生存率为 91.2%，安慰剂组为 86.0%；在各关键亚组中，获益一致。派姆单抗治疗相关的任何原因的严重不良事件发生率更高（20.7%，安慰剂组为 11.5%），与派姆单抗或安慰剂相关的 3 级或 4 级不良事件发生率更高（18.6%，安慰剂组为 1.2%）。没有死亡归因于派姆单抗治疗。