Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
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DOI：
10.1016/51470-2045(19)30301-0
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发表时间：
2020-03-01
期刊：
影响因子：
51.1
通讯作者：
Rodriguez-Abreu, Delvys
中科院分区：
文献类型：
--
作者：
Garassino, Marina C.;Gadgeel, Shirish;Rodriguez-Abreu, Delvys
背景 在 KEYNOTE-189 研究中，与安慰剂加培美曲塞铂相比，派姆单抗加培美曲塞铂可带来更好的总生存期和无进展生存期，并且确认完全或部分缓解的患者比例更高。我们的目的是评估 KEYNOTE-189 患者中预先指定的探索性患者报告结果 (PRO)。 方法 在 16 个国家的 126 个癌症中心进行的多中心、双盲、随机、安慰剂对照 3 期 KEYNOTE-189 研究中，符合条件的患者年龄为 18 岁或以上，经组织学或细胞学证实患有转移性非鳞状非小细胞肺癌，且未患有转移性非鳞状非小细胞肺癌。敏感的 EGFR 或 ALK 改变、根据实体瘤疗效评估标准（1.1 版）可测量的疾病以及东部肿瘤合作组表现状态为 0 或 1 的患者被纳入。患者被随机分配 (2:1) 接受静脉注射派姆单抗 (200 mg)，每 3 周接受一次静脉注射派姆单抗 (200 mg) 或生理盐水安慰剂，持续长达 2 年（35 个周期）；所有患者每 3 周接受 4 个周期的静脉培美曲塞（500 mg/m (2)）联合卡铂（5 mg/mL 每分钟）或顺铂（75 mg/m 2；研究者选择），共 4 个周期，随后每 3 周进行培美曲塞维持治疗。置换区组随机化（区组大小为 6）是通过交互式语音应答系统完成的，并根据 PD-L1 表达、铂类药物的选择和吸烟状况进行分层。患者、研究人员和其他研究人员不知道治疗分配。欧洲癌症研究和治疗组织生活质量问卷核心 30 (QLQ-C30) 和肺癌 13 (QLQ-LC13) 在第 15 个周期进行，此后在第 1 年每三个周期进行一次，第 23 年每四个周期进行一次。主要终点（总生存期和无进展生存期）之前已发表。主要 PRO 终点是 QLQ-C30 全球健康状况/生活质量 (GHS/QOL) 评分从基线到第 12 周（化疗期间）和第 21 周（化疗后）的变化，以及咳嗽、胸痛或呼吸困难恶化的时间。对接受至少一剂研究药物并完成至少一项 PRO 评估的所有随机分配的患者进行 PRO 分析，结果以双边名义 p 值提供。这项正在进行的研究已在 ClinicalTrials.gov 注册，编号为 NCT02578680。调查结果 2016 年 2 月 26 日至 2017 年 3 月 6 日期间，共招募了 616 名患者；截至 2017 年 11 月 8 日数据截止，中位随访时间为 10.5 个月（范围 0.220.4）。派姆单抗加培美曲塞铂治疗组 405 名患者中的 402 名患者（99%）和安慰剂加培美曲塞铂治疗组 202 名患者中的 200 名患者（99%）完成了至少一项 PRO 评估。基线时，派姆单抗加培美曲塞铂组的 402 名患者中有 359 名患者 (89%) 以及安慰剂加培美曲塞铂组的 200 名患者中有 180 名患者 (90%) 符合 QLQ-C30；第 12 周时，354 名患者中的 319 名患者（90%）和 167 名患者中的 149 名患者（89%）符合依从性；在第 21 周，326 名患者中的 249 名 (76%) 和 143 名患者中的 91 名 (64%) 分别是依从的。从基线到第12周，派姆单抗加培美曲塞铂（最小二乘平均变化：增加1.0分[95% CI -1.3至3.2]）和安慰剂加培美曲塞铂（减少-2.6分[-5.8至0.5]；组间差异：3.6分[-0.1至7.2]）均维持GHS/QOL评分； p=0.053）。从基线到第 21 周，派姆单抗加培美曲塞铂组的 GHS/QOL 评分（最小二乘平均变化：增加 1.3 分 [95% CI -1.2 至 3.6]）比安慰剂加培美曲塞铂组（减少 -4.0 分 [-7.7 至 -0.3]）更好；组间差异：5.3 分 [1.1 至 9.5]； p=0.014）。派姆单抗加培美曲塞铂组未达到咳嗽、胸痛或呼吸困难恶化的中位时间（95% CI 10.2 个月未达到），而安慰剂加培美曲塞铂组为 7.0 个月（4.8 个月未达到）（风险比 0.81 [95% CI 0.601.09]，p=0.16）。帕博利珠单抗联合标准化疗维持了 GHS/QOL，与安慰剂加化疗组相比，帕博利珠单抗加化疗组在第 21 周的 GHS/QOL 评分有所改善。这些数据进一步支持使用派姆单抗加培美曲塞铂作为转移性非鳞状非小细胞肺癌患者的一线治疗。版权所有 (C) 2020 爱思唯尔有限公司。保留所有权利。
Background Pembrolizumab plus pemetrexedplatinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexedplatinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189.Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m (2)) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m 2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 15, every three cycles thereafter during year 1, and every four cycles during years 23. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov, number NCT02578680.Findings Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10.5 months (range 0.220.4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexedplatinum group and 200 (99%) of 202 patients in the placebo plus pemetrexedplatinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexedplatinum group and 180 (90%) of 200 in the placebo plus pemetrexedplatinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexedplatinum (least-squares mean change: 1.0 point [95% CI -1.3 to 3.2] increase) and placebo plus pemetrexedplatinum (-2.6 points [-5.8 to 0.5] decrease; between-group difference: 3.6 points [-0.1 to 7.2]; p=0.053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexedplatinum (least-squares mean change: 1.3 points [95% CI -1.2 to 3.6] increase) than with placebo plus pemetrexedplatinum (-4.0 points [-7.7 to -0.3] decrease; between-group difference: 5.3 points [1.1 to 9.5]; p=0.014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10.2 months to not reached) with pembrolizumab plus pemetrexedplatinum, and was 7.0 months (4.8 months to not reached) with placebo plus pemetrexedplatinum (hazard ratio 0.81 [95% CI 0.601.09], p=0.16).Interpretation The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexedplatinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. Copyright (C) 2020 Elsevier Ltd. All rights reserved.