Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial
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DOI：
10.1016/s0140-6736(18)32409-7
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发表时间：
2019-05-04
期刊：
影响因子：
168.9
通讯作者：
Lopes, Gilberto
中科院分区：
文献类型：
--
作者：
Mok, Tony S. K.;Wu, Yi-Long;Lopes, Gilberto
Pembrolizumab单药治疗可改善程序性死亡配体1（PD-L1）肿瘤比例评分（TPS）≥ 50%的未经治疗的转移性非小细胞肺癌患者的总体和无进展生存期。我们调查了PD-L1 TPS为1%或更高的患者接受pembrolizumab单药治疗后的总生存率。方法这项随机、开放标签、3期研究在32个国家的213个医疗中心进行。符合条件的患者为既往未经治疗的局部晚期或转移性非小细胞肺癌成人（≥ 18岁），无致敏EGFR突变或ALK易位，东部肿瘤协作组（ECOG）体能状态评分为0或1，预期寿命≥ 3个月，PD-L1 TPS ≥ 1%。随机化由计算机生成，通过交互式语音应答和集成网络应答系统访问，并按入组地区（东亚vs世界其他地区）、ECOG体能状态评分（0 vs 1）、组织学（鳞状vs非鳞状）和PD-L1 TPS（>= 50% vs 1-49%）分层。入组的患者以1：1的比例随机分配，每层4人，接受帕博利珠单抗200 mg，每3周一次，最多35个周期，或研究者选择的铂类化疗4至6个周期。主要终点是意向治疗人群中TPS ≥ 50%、≥ 20%和≥ 1%（单侧显著性阈值，分别为p=0.0122、p=0.0120和p=0.0124）患者的总生存期，如果既往结果显著，则按顺序进行评估。本研究已在ClinicalTrials注册。结果从2014年12月19日至2017年3月6日，1274例PD-L1 TPS ≥ 1%的患者（902例男性，372例女性，中位年龄63岁[IQR 57-69]）被分配至派姆单抗（n=637）或化疗（n = 637），并纳入意向治疗人群。599例（47%）TPS ≥ 50%，818例（64%）TPS ≥ 20%。截至2018年2月26日，中位随访时间为12.8个月。在所有三个TPS人群中，帕博利珠单抗组的总生存期显著长于化疗组（>= 50%风险比0.69，95% CI 0.56-0.85，p=0.0003; >= 20% 0.77，0.64-0.92，p=0.0020，和>= 1% 0.81，0.71-0.93，p=0.0018）。TPS人群的中位生存期为20. 0个月（95% CI 15. 0）。pembrolizumab组与化疗组分别为12.2个月（10.4-14.2）、17.7个月（15.3-22.1）与13.0个月（11.6-15.3）和16.7个月（13.7）与12.1个月（11.3-13.3）。帕博利珠单抗组636例治疗患者中有113例（18%）发生3级或更严重的治疗相关不良事件，化疗组615例患者中有252例（41%）发生3级或更严重的治疗相关不良事件，分别导致13例（2%）和14例（2%）患者死亡，效益-风险特征表明，帕博利珠单抗单药治疗可以扩展为第一种治疗，线治疗局部晚期或转移性非小细胞肺癌患者，无致敏EGFR或ALK改变，PD-L1 TPS低。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (>= 18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (>= 50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0.0122, p=0.0120, and p=0.0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials. gov, number NCT02220894.Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12.8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (>= 50% hazard ratio 0.69, 95% CI 0.56-0.85, p=0.0003; >= 20% 0.77, 0.64-0.92, p=0.0020, and >= 1% 0.81, 0.71-0.93, p=0.0018). The median surival values by TPS population were 20.0 months (95% CI 15. 4-24.9) for pembrolizumab versus 12.2 months (10.4-14.2) for chemotherapy, 17.7 months (15.3-22.1) versus 13.0 months (11.6-15.3), and 16.7 months (13.7) versus 12.1 months (11.3-13.3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Copyright (C) 2019 Elsevier Ltd. All rights reserved.