加拿大蒙特利尔总医院Jonathan D Spicer团队，研究了围手术期新辅助化疗中添加派姆单抗第二次中期分析的患者总体生存率等预后。2024年9月28日出版的《柳叶刀》杂志发表了这项成果。

在KEYNOTE-671试验的第一次中期分析中，在围手术期新辅助化疗中添加派姆单抗显著提高了早期非小细胞肺癌（NSCLC）参与者的无事件生存率。研究组报告了第二次中期分析的总体生存率和与健康相关的生活质量结局。

KEYNOTE-671是一项在189个医疗中心进行的全球3期试验。符合条件的II期、IIIA期或IIIB期（N2）非小细胞肺癌患者（年龄≥18岁）被随机分配（1:1）接受四个周期的新辅助派姆单抗（每3周静脉注射200mg）加顺铂化疗，然后进行手术和13个周期的辅助派姆单抗治疗（每3周静脉注射200mg），或接受四个周期的新辅助安慰剂治疗（每3周静脉注射一次）加顺铂放疗，然后进行外科手术和13周的辅助安慰剂治疗。随机化使用交互式反应技术系统集中进行，并按疾病阶段、PD-L1表达、组织学和地理区域分为四个区块进行分层。参与者、研究人员和赞助商人员对治疗任务双盲；当地药剂师揭盲以支持治疗准备。双重主要终点是意向治疗人群中评估的总生存期和无事件生存期。

2018年5月11日至2021年12月15日，797名参与者被随机分配到派姆单抗组（n=397）或安慰剂组（n=400）。第二次中期分析的中位研究随访时间为36.6个月（IQR 27.6–47.8）。派姆单抗组的36个月总生存率估计为71%（95%CI 66-76），安慰剂组为64%（58-69）（风险比0.72[95%CI 0.56-0.93]；单侧p=0.0052；阈值，单侧p=0.0044）。派姆单抗组的中位无事件生存期为47.2个月（95%置信区间32.9至未达到），安慰剂组为18.3个月（14.8-22.1）（风险比0.59[95%置信区间0.48-0.72]）。在接受治疗的人群中，派姆单抗组396名参与者中有179名（45%）发生了3-5级治疗相关不良事件，安慰剂组399名参与者中也有151名（38%）发生。与治疗相关的不良事件导致派姆单抗组有4名（1%）参与者死亡，安慰剂组有3名（1%）参与者死亡。

研究结果表明，与单独使用新辅助化疗相比，新辅助派姆单抗联合化疗之后再加辅助派姆单抗具有显著总体生存益处，加上可控的安全性，该研究支持在可切除的早期NSCLC患者中使用围手术期派姆单抗。

附：英文原文

Title: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Jonathan D Spicer, Marina C Garassino, Heather Wakelee, Moishe Liberman, Terufumi Kato, Masahiro Tsuboi, Se-Hoon Lee, Ke-Neng Chen, Christophe Dooms, Margarita Majem, Ekkehard Eigendorff, Gastón L Martinengo, Olivier Bylicki, Delvys Rodríguez-Abreu, Jamie E Chaft, Silvia Novello, Jing Yang, Ashwini Arunachalam, Steven M Keller, Ayman Samkari, Shugeng Gao, Sergey Afanasyev, Samreen Ahmed, Todd Alekshun, Gustavo Alves, Ian Anderson, Luiz Henrique Araujo, Alexander Arkhipov, Arvind Arora, Jie Bai, Paul Begin, Aleksandr Belonogov, Henri Berard, Radu Berceanu-Ion, Reyes Bernabe Caro, Igor Bondarenko, Reiner Bonnet, Joaquim Bosch Barrera, Carlos Brocca, Maciej Bryl, Alessandra Bulotta, Olivier Bylicki, Antonio Calles Blanco, Enric Carcereny, Leticia Carvalho, Cristina Cebotaru, Jamie Chaft, Veena Charu, Fabio Chaves, Jun Chen, Ke-Neng Chen, Haiquan Chen, Qixun Chen, Kevin Chen, Chi-Lu Chiang, Chao-Hua Chiu, Saulius Cicenas, Elena Ciubotaru, Tudor Ciuleanu, Ioana Ciurescu, Patrick Cobb, Corlia Coetzee, Dearbhaile Collins, Diego Cortinovis, Kimberly Costas, Dan Costin, Eduardo Henrique Cronemberger, Raymund Cuevo, Sinead Cuffe, Pedro Rafael Martins De Marchi, Tadeu de Paiva Junior, Angelo Delmonte, Ingel Demedts, Koenraad Deschepper, Josiane Dias, Christophe Dooms, Boris Duchemann, Carolina Dutra, Herbert Duvivier, Ekkehard Eigendorff, Vinicius Ernani, Martin Faehling, Luiza Faria, Alexander Fedenko, Hiran Fernando, Roberto Ferrara, Vittorio Ferrari, Gene Finley, Peter Fix, Marcos Flores, Samuel Fourie, Fabio Franke, Klaus-Peter Frohling, Muhammad Furqan, Cristian Gal, Robert Galamaga, Doina Ganea, Apar Kishor Ganti, Shugeng Gao, Marina Garassino, Ryan Gentzler, Luca Gianni, Marina Gilli, Nicolas Girard, Bojidar Goranov, Vanesa Gregorc, Alastair Greystoke, Salvatore Grisanti, Christian Grohe, Michael Guarino, Jose Luiz Guimaraes, Florian Guisier, Balazs Halmos, Zane Taysir Hammoud, Ji-Youn Han, Alinta Hegmane, Fook Yew Heng, Hidehito Horinouchi, Yoshitsugu Horio, Jian Hu, Hsu-Ching Huang, Rina Hui, Norihiko Ikeda, Salvatore Intagliata, Ingrid Iordan, Conrad Jacobs, Kirti Jain, Sushil Jain

Issue&Volume: 2024/09/28

Abstract:

Background

At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis.

Methods

KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment.

Findings

Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6–47·8). 36-month overall survival estimates were 71% (95% CI 66–76) in the pembrolizumab group and 64% (58–69) in the placebo group (hazard ratio 0·72 [95% CI 0·56–0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8–22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48–0·72]). In the as-treated population, grade 3–5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group.

Interpretation

The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC.

DOI: 10.1016/S0140-6736(24)01756-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01756-2/abstract