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Pembrolizumab可提高复发或转移性头颈部鳞癌患者的生存率
作者:小柯机器人 发布时间:2019/11/1 16:03:54

Pembrolizumab单独或联合化疗与西妥昔单抗联合化疗治疗复发或转移性头颈部鳞状细胞癌的疗效观察,这一成果由美国耶鲁大学医学院Barbara Burtness团队取得。2019年10月31日,《柳叶刀》在线发表了这项成果。

2015年4月20日至2017年1月17日,研究组在37个国家的200个地点进行了一项随机、临床3期研究(KEYNOTE-048),招募了882名未经治疗的局部不可治愈的复发或转移性HNSCC患者。根据参与者的PD-L1表达、p16状态和症状进行分层,按照1:1:1将其随机分为三组,其中301名接受Pembrolizumab单药治疗,281名接受Pembrolizumab+铂+5-氟尿嘧啶(Pembrolizumab化疗)治疗,300名接受西妥昔单抗+铂+5-氟尿嘧啶(西妥昔单抗化疗)治疗。有754名(85%)患者的PD-L1综合阳性评分(CPS)≥1,381名(43%)患者CPS≥20。

在二次中期分析中,对于CPS≥20和CPS≥1的患者,单独Pembrolizumab组中位总生存期分别为14.9个月和12.3个月,显著长于西妥昔单抗化疗组(10.7个月和10.3个月),但两组间所有患者的中位总生存期相差不大;Pembrolizumab化疗组中所有患者的中位总生存期为13.0个月,显著长于西妥昔单抗化疗组(10.7个月)。在最终分析中,对于CPS≥20和CPS≥1的患者,Pembrolizumab化疗组的中位总生存期分别为14.7个月和13.6个月,均显著高于西妥昔单抗化疗组(分别为11.0个月和10.4个月)。

二次中期分析中,单独Pembrolizumab组和Pembrolizumab化疗组的无进展生存率均未得到显著改善。最终分析中,单独Pembrolizumab组中有55%的患者发生3级及以上全因不良事件,Pembrolizumab化疗组为85%,西妥昔单抗化疗组为83%。单独Pembrolizumab组中有8%的患者因不良反应致死,Pembrolizumab化疗组为12%,西妥昔单抗化疗组为10%。

研究表明,Pembrolizumab+铂+5-氟尿嘧啶是治疗复发或转移性HNSCC的首选一线治疗方法,而Pembrolizumab单药则是治疗PD-L1阳性复发或转移性HNSCC的首选一线治疗方法。

附:英文原文

Title: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study

Author: Barbara Burtness, Kevin J Harrington, Richard Greil, Denis Soulières, Makoto Tahara, Gilberto de Castro, Amanda Psyrri, Neus Basté, Prakash Neupane, se Bratland, Thorsten Fuereder, Brett G M Hughes, Ricard Mesía, Nuttapong Ngamphaiboon, Tamara Rordorf, Wan Zamaniah Wan Ishak, Ruey-Long Hong, René González Mendoza, Ananya Roy, Yayan Zhang, Burak Gumuscu, Jonathan D Cheng, Fan Jin, Danny Rischin, Guillermo Lerzo, Marcelo Tatangelo, Mirta Varela, Juan Jose Zarba, Michael Boyer, Hui Gan, Bo Gao, Brett Hughes, Girish Mallesara, Danny Rischin, Anne Taylor, Martin Burian, Thorsten Fuereder, Richard Greil, Carlos Henrique Barrios, Dalvaro Oliveira de Castro Junior, Gilberto Castro, Fabio Andre Franke, Gustavo Girotto, Iane Pinto Figueiredo Lima, Ulisses Ribaldo Nicolau, Gustavo Dix Junqueira Pinto, Lucas Santos, Ana-Paula Victorino, Neil Chua, Felix Couture, Richard Gregg, Aaron Hansen, John Hilton, Joy McCarthy, Denis Soulieres, Rodrigo Ascui, Pablo Gonzalez, Luis Villanueva, Marco Torregroza, Angela Zambrano, Petra Holeckova, Zdenek Kral, Bohuslav Melichar, Jana Prausova, Milan Vosmik, Maria Andersen, Niels Gyldenkerne, Hannes Jurgens, Kadri Putnik, Petri Reinikainen, Viktor Gruenwald, Simon Laban, Gerasimos Aravantinos, Ioannis Boukovinas, Vassilis Georgoulias, Amanda Psyrri, Dora Kwong, Yousuf Al-Farhat, Tibor Csoszi, Jozsef Erfan, Geza Horvai, Laszlo Landherr, Eva Remenar, Agnes Ruzsa, Judit Szota, Salem Billan, Iris Gluck, Orit Gutfeld, Aron Popovtzer, Marco Benasso, Simona Bui, Vittorio Ferrari, Lisa Licitra, Franco Nole, Takashi Fujii, Yasushi Fujimoto, Nobuhiro Hanai, Hiroki Hara, Koji Matsumoto, Kenji Mitsugi, Nobuya Monden, Masahiro Nakayama, Kenji Okami, Nobuhiko Oridate, Kiyoto Shiga, Yasushi Shimizu, Masashi Sugasawa, Makoto Tahara, Masanobu Takahashi, Shunji Takahashi, Kaoru Tanaka, Tsutomu Ueda, Hironori Yamaguchi, Tomoko Yamazaki, Ryuji Yasumatsu, Tomoya Yokota, Tomokazu Yoshizaki, Iveta Kudaba, Zinaida Stara, Wan Zamaniah Wan Ishak, Soon Keat Cheah, Jose Aguilar Ponce, Rene Gonzalez Mendoza

Issue&Volume: October 31, 2019

Abstract: 

Background

Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.

Methods

KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.

Findings

Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45–0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64–0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71–1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63–0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45–0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53–0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.

Interpretation

Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

DOI: 10.1016/S0140-6736(19)32591-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32591-7/fulltext

期刊信息

LANCET:《柳叶刀》,创刊于1823年。隶属于爱思唯尔出版社,最新IF:59.102
官方网址:http://www.thelancet.com/
投稿链接:http://ees.elsevier.com/thelancet