Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial
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DOI：
10.1016/s0140-6736(18)31257-1
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发表时间：
2018-07-14
期刊：
影响因子：
168.9
通讯作者：
Fuchs, Charles S.
中科院分区：
文献类型：
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作者：
Shitara, Kohei;Ozguroglu, Mustafa;Fuchs, Charles S.
背景：晚期胃或胃-食道交界部癌症患者在化疗过程中预后较差。我们比较了Pembrolizumab和紫杉醇在晚期胃或胃食道交界部癌症患者中的作用，这些患者使用铂和氟嘧啶进行一线化疗。方法这项随机、开放标签的3期研究在30个国家的148个医疗中心进行。符合条件的患者按1：1随机分组，每层4人，采用交互式语音应答和集成网络应答系统，接受培溴利珠单抗200 mg每3周一次，最长持续2年，或接受标准剂量紫杉醇。主要终点是程序性细胞死亡配体1(PD-L1)联合阳性评分(CPS)为1或更高的患者的总体生存期和无进展生存期。对所有患者进行安全性评估，而不考虑CPS。总体生存的显著阈值为p=0.0135(单侧)。这项试验在ClinicalTrials.gov注册，编号NCT02370498。在2015年6月4日至2016年7月26日期间，共有592名患者入选。在PD-L1 CPS为1或更高的395名患者中，196名患者被分配接受培溴利珠单抗治疗，199名患者被分配接受紫杉醇治疗。截至2017年10月26日，在CPS为1或更高的人群中，已有326名患者死亡(培溴利珠单抗组196名患者中的151名[77%]，紫杉醇组199名患者中的175名[88%])。培溴利珠单抗和紫杉醇的中位总生存期分别为9.1个月(95%CI 6.2~10.7)和8.3个月(7.6~9.0)(风险比[HR]0.82，95%CI 0.66~1.03；单侧p=0.0421)。培溴利珠单抗和紫杉醇的中位无进展生存期分别为1.5个月(95%CI 1.4~2.0)和4.1个月(3.1~4.2)(HR 1.27，95%CI 1.03~1.57)。在总体人群中，接受培溴利珠单抗治疗的294名患者中有42名(14%)发生了与3-5级治疗相关的不良事件，在接受紫杉醇治疗的276名患者中有96名(35%)发生了与3-5级治疗相关的不良事件。与作为PD-L1 CPS为1或更高的晚期胃癌或胃食道交界处癌症的二线治疗方法相比，解释的培溴利珠单抗并未显著提高总体生存率。培溴利珠单抗的安全性比紫杉醇好。培溴利珠单抗治疗胃癌和胃食道癌的其他试验正在进行中。版权所有(C)2018爱思唯尔有限公司。保留所有权利。
Background Patients with advanced gastric or gastro-oesophageal junction cancer that progresses on chemotherapy have poor outcomes. We compared pembrolizumab with paclitaxel in patients with advanced gastric or gastrooesophageal junction cancer that progressed on first-line chemotherapy with a platinum and fluoropyrimidine.Methods This randomised, open-label, phase 3 study was done at 148 medical centres in 30 countries. Eligible patients were randomised (1: 1) in blocks of four per stratum with an interactive voice-response and integrated web-response system to receive either pembrolizumab 200 mg every 3 weeks for up to 2 years or standard-dose paclitaxel. Primary endpoints were overall survival and progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or higher. Safety was assessed in all patients, irrespective of CPS. The significance threshold for overall survival was p=0.0135 (one-sided). This trial is registered at ClinicalTrials.gov, number NCT02370498.Findings Between June 4, 2015, and July 26, 2016, 592 patients were enrolled. Of the 395 patients who had a PD-L1 CPS of 1 or higher, 196 patients were assigned to receive pembrolizumab and 199 patients were assigned to receive paclitaxel. As of Oct 26, 2017, 326 patients in the population with CPS of 1 or higher had died (151 [77%] of 196 patients in the pembrolizumab group and 175 [88%] of 199 patients in the paclitaxel group). Median overall survival was 9.1 months (95% CI 6.2-10.7) with pembrolizumab and 8.3 months (7.6-9.0) with paclitaxel (hazard ratio [HR] 0.82, 95% CI 0.66-1.03; one-sided p=0.0421). Median progression-free survival was 1.5 months (95% CI 1.4-2.0) with pembrolizumab and 4.1 months (3.1-4.2) with paclitaxel (HR 1.27, 95% CI 1.03-1.57). In the total population, grade 3-5 treatment-related adverse events occurred in 42 (14%) of the 294 patients treated with pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel.Interpretation Pembrolizumab did not significantly improve overall survival compared with paclitaxel as second-line therapy for advanced gastric or gastro-oesophageal junction cancer with PD-L1 CPS of 1 or higher. Pembrolizumab had a better safety profile than paclitaxel. Additional trials of pembrolizumab in gastric and gastro-oesophageal cancer are ongoing. Copyright (c) 2018 Elsevier Ltd. All rights reserved.