Pembrolizumab 对比安慰剂作为完全切除的 IB-IIIA 期非小细胞肺癌的辅助治疗

30 September 2022

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial

（Lancet Oncol IF：54.433）

O'Brien M, Paz-Ares L, Marreaud S, Dafni U, Oselin K, Havel L, Esteban E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee JS, Nakagawa K, Yang J, Samkari A, Keller SM, Mauer M, Jha N, Stahel R, Besse B, Peters S; EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol. 2022 Sep 9:S1470-2045(22)00518-6. doi: 10.1016/S1470-2045(22)00518-6. Epub ahead of print. PMID: 36108662.

Background 背景

Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC.

Pembrolizumab 是晚期非小细胞肺癌 (NSCLC) 的标准治疗方案。我们评估了pembrolizumab作为完全切除的 IB-IIIA 期 NSCLC 的辅助治疗。

Methods 方法

 In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting.

在这项随机、三盲、三期试验（PEARLS/KEYNOTE-091）中，从29个国家的196个医疗中心招募了患者。符合条件的患者年龄在18岁或以上，根据美国癌症联合委员会的分期系统（第七版），任何组织学或PD-L1表达水平的完全切除、病理证实的IB期（肿瘤直径≥4厘米）、II期或IIIA期NSCLC，以及东部合作肿瘤组的表现状态为0或1；根据国家和地方指南，对于IB期疾病应考虑辅助化疗，对于II期和IIIA期疾病则强烈建议辅助化疗。使用中央交互式语音应答系统，符合条件的参与者被随机分配（1:1），使用最小化技术并根据疾病阶段、先前的辅助化疗、PD-L1表达和地理区域进行分层，分配到pembrolizumab 200毫克或安慰剂，两者均每3周静脉注射一次，最多18个周期。参与者、调查人员和分析人员对治疗分配都是保密的。双重主要终点是总体人群和PD-L1肿瘤比例评分（TPS）为50%或以上的人群的无病生存率。疗效是在意向治疗（ITT）人群中评估的（即所有被随机分配到治疗组的参与者）。安全性是在所有随机分配到治疗的参与者中评估的，他们至少接受了一剂量的研究治疗。在此，我们报告第二次中期分析的结果，预先指定在PD-L1 TPS达到或超过50%的人群中发生约118例无病生存事件时进行。该研究已在ClinicalTrials.gov注册，编号为NCT02504372，目前正在进行中，但没有招募。

Findings 结果

 Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo.

2016年1月20日至2020年5月6日期间，1955名筛选的参与者中有1177人（60%）被随机分配到pembrolizumab（n=590，包括n=168，PD-L1 TPS≥50%）或安慰剂（n=587；包括n=165，PD-L1 TPS≥50%）并纳入ITT人群。截至数据截止日（2021年9月20日），本中期分析的中位随访时间为35-6个月（IQR 27-1-45-5）。在总体人群中，pembrolizumab组的中位无病生存期为53-6个月（95%CI为39-2至未达到），而安慰剂组为42-0个月（31-3至未达到）（HR 0-76[95%CI 0-63-0-91]，P=0-0014）。在PD-L1 TPS达到或超过50%的人群中，pembrolizumab组（95% CI 44-3至未达到）或安慰剂组（95% CI 35-8至未达到；HR 0-82 [95% CI 0-57-1-18]；p=0-14）均未达到中位无病生存。在580名接受pembrolizumab的参与者中，有198人（34%）发生了3级或更严重的不良事件，在581名接受安慰剂的参与者中，有150人（26%）发生了不良事件。任何一个治疗组中至少有10名参与者发生了3级或更严重的事件，其中接受pembrolizumab的有高血压（35[6%]）和肺炎（12[2%]），接受安慰剂的有高血压（32[6%]）。pembrolizumab组有142人（24%）发生严重不良事件，安慰剂组有90人（15%）；超过1%的参与者发生的严重不良事件是pembrolizumab的肺实质性炎症（13[2%]）、肺炎（12[2%]）和腹泻（7[1%]）以及安慰剂的肺实质性炎症（9[2%]）。有4名（1%）接受pembrolizumab治疗的参与者因治疗相关的不良事件而死亡（1人因心源性休克和心肌炎，1人因脓毒性休克和心肌炎，1人因肺炎，1人因突然死亡），没有接受安慰剂治疗的参与者死亡。 

Interpretation 解释

Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression.

与安慰剂相比，Pembrolizumab显着提高了无病生存期，并且与完全切除的 PD-L1 未选择的 IB-IIIA 期 NSCLC 的新安全信号无关。Pembrolizumab 可能是完全切除后 IB-IIIA 期 NSCLC 的一种新治疗选择，并且在推荐时辅助化疗，无论 PD-L1 表达如何。

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