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Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial

2023; Elsevier BV; Volume: 401; Issue: 10391 Linguagem: Inglês

10.1016/s0140-6736(23)00727-4

1474-547X

Robin Kate Kelley, Makoto Ueno, Changhoon Yoo, Richard S. Finn, Junji Furuse, Zhenggang Ren, Thomas Yau, Heinz‐Josef Klümpen, Stephen L. Chan, Masato Ozaka, Chris Verslype, Mohamed Bouattour, Joon Oh Park, Olga Barajas, Uwe Pelzer, Juan W. Valle, Li Yu, Usha Malhotra, Abby B. Siegel, Julien Edeline, Arndt Vogel, Mehmet Akce, Inmaculada Alés Díaz, Gustavo R. Alves, Sumitra Anand, Çağatay Arslan, Jamil Asselah, Éric Assenat, F. Aubin, Li‐Yuan Bai, Yuxian Bai, Olga Barajas, Susan E. Bates, Stephen Begbie, Irit Ben‐Aharon, Nina Beri, Marie‐Luise Berres, Jean‐Frédéric Blanc, Ivan Borbath, Robert Bordonaro, Mohamed Bouattour, Giovanni Brandi, Adam M. Burgoyne, Kritiya Butthongkomvong, Marcos Pedro Guedes Camandaroba, Ke Cao, Marcela Carballido, Stephen L. Chan, Jen‐Shi Chen, Ming‐Huang Chen, Xiaohong Chen, Ashley Cheng, Tai‐Jan Chiu, Hye Jin Choi, Hong Jae Chon, Joëlle Collignon, Antonio Cubillo Gracián, S. Lindsey Davis, Ricardo Saraiva de Carvalho, D.J.A. de Groot, Anne Demols, Judith De Vos, Maria Diab, Jacob C. Easaw, Martin Eatock, Julien Edeline, Rawad Elias, Fredericus Eskens, Alfredo Falcone, Plinio Fernández, Richard S. Finn, Fábio Franke, Masayuki Furukawa, Junji Furuse, Olumide B. Gbolahan, Karen Geboes, Keri-Lee Geneser, Zhimin Geng, Ravit Geva, Roopinder Gillmore, Thorsten Oliver Goetze, Hongfeng Gou, Julieta Grasselli, Shanzhi Gu, Mahmut Gümüş, Nadia Haj Mohammad, Chunyi Hao, Hakan Harputluoğlu, Hassan Hatoum, Volker Heinemann, Wang Kwong Ho, Chiun Hsu, Ayala Hubert, Jun‐Eul Hwang, Mevlüde İnanç, Soledad Iseas, Vaishnavi Jeyasingam, Paula Jiménez Fonseca, Warren Joubert, Jitlada Juengsamarn, Diego Kaen, Masashi Kanai, Stefan Kasper‐Virchow, Ghazaleh Kazemi, Fergal C. Kelleher, Robin Kate Kelley, Jin Won Kim, Jong Gwang Kim, Ana Beatriz Kinupe Abrahão, Heinz‐Josef Klümpen, Mark D. Kochenderfer, Fatih Köse, Ho Ching Lam, Choong‐kun Lee, Hyun Woo Lee, Margaret Lee, Myung Ah Lee, Wai Man Sarah Lee, Samuel Le Sourd, Dongliang Li, Wěi Li, Houjie Liang, Tingbo Liang, Chun Sen Lim, Brian M. Lingerfelt, Charles D. Lopez, J.N. Low, T. Macarulla Mercadé, David Malka, Yimin Mao, Gianluca Masi, Steven McCune, Ray McDermott, Elaine McWhirter, Guillermo Méndez, Michèle Milella, Nobumasa Mizuno, Tomonori Mizutani, Camila Motta Venchiarutti Moniz, Luisa Morales, Andrés J. Muñoz Martín, Bruno Nervi, Nuttapong Ngamphaiboon, Sang Cheul Oh, Berna Öksüzoğlu, Darryl Outlaw, Masato Ozaka, Mustafa Özgüroğlu, Özgür Özyılkan, Claudio Painemal, Yueyin Pan, Joon Oh Park, Uwe Pelzer, Chuang Peng, Caroline Pétorin, Denis Pezet, Derek G. Power, Shukui Qin, Zhenggang Ren, Aflah Roohullah, Hyewon Ryu, Pamela Salman, Mitsuhito Sasaki, Rita Sasidharan, Taroh Satoh, Kornelius Schulze, Martin Scott-Brown, Ruben Segovia, Thomas Seufferlein, Salvatore Siena, Isabelle Sinapi, Cristina Smolenschi, Tianqiang Song, Aumkhae Sookprasert, Nopadol Soparattanapaisarn, Naureen Starling, Stacey Stein, Salomon M. Stemmer, Haichuan Su, Rie Sugimoto, Thatthan Suksombooncharoen, Vincent C. Tam, Ai Lian Tan, Chih Kiang Tan, Suebpong Tanasanvimon, Giuseppe Tonini, Giampaolo Tortora, Akihito Tsuji, Makoto Ueno, Rodrigo Uribe-Pacheco, Marino Venerito, Helena Verdaguer Mata, Chris Verslype, Ana Paula Victorino, Arndt Vogel, James C. Wade, Dirk Waldschmidt, Lu Wang, Wan Zamaniah Wan Isahk, H.S. Wasan, Rui Weschenfelder, Chun Yin Wong, Yoke Fui Wong, Şuayib Yalçın, Patricio Yanez Weber, Xuezhong Yang, Hisateru Yasui, Thomas Yau, Ozan Yazıcı, Chia‐Jui Yen, Jieer Ying, Changhoon Yoo, Wenchang Yu, Haitao Zhao,

Pancreatic and Hepatic Oncology Research

Background Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.