1. 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
- Author
-
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, Immaculada Ales Diaz, Gustavo Alves, Sumitra Anand, Cagatay Arslan, Jamil Asselah, Eric Assenat, Francine Aubin, Li-Yuan Bai, Yuxian Bai, Susan Bates, Stephen Begbie, Irit Ben-Aharon, Nina Beri, Marie-Luise Berres, Jean-Frederic Blanc, Ivan Borbath, Robert Bordonaro, Giovanni Brandi, Adam Burgoyne, Kritiya Butthongkomvong, Ke Cao, Marcela Carballido, Marcos Camandaroba, Stephan Lam Chang, Jen-Shi Chen, Ming-Huang Chen, Xiaoming Chen, Ashley Cheng, Tai-Jan Chiu, Hye Jin Choi, Hong Jae Chon, Joelle Collignon, Antonio Cubillo Gracian, Sarah Davis, Ricardo Saraiva de Carvalho, D.J.A. de Groot, Anne Demols, Judith De Vos, Maria Diab, Jacob Easaw, Martin Eatock, Rawad Elias, Fredericus Eskens, Alfredo Falcone, Plinio Fernandez, Richard Finn, Fabio Franke, Masayuki Furukawa, Olumide Gbolahan, Karen Geboes, Keri-Lee Geneser, Zhimin Geng, Ravit Geva, Roopinder Gillmore, Thorsten Goetze, Hongfeng Gou, Julieta Grasselli, Shanzhi Gu, Mahmut Gumus, Nadia Haj Mohammad, Chunyi Hao, Hakan Harputluoglu, Hassan Hatoum, Volker Heinemann, Wang Kwong Ho, Chiun Hsu, Ayala Hubert, Juneul Hwang, Mevlude Inanc, Soledad Iseas, Vaishnavi Jeyasingam, Paula Jimenez Fonseca, Warren Joubert, Jitlada Juengsamarn, Diego Kaen, Masahi Kanai, Stefan Kasper-Virchow, Ghazaleh Kazemi, Fergal Kelleher, Robin Kelley, Jin Won Kim, Jong Gwang Kim, Ana Beatriz Kinupe Abrahao, Heinz Klumpen, Mark Kochenderfer, Fatih Kose, Ho Ching Lam, Choong-kun Lee, Hyun Woo Lee, Margaret Lee, Myung Ah Lee, Wai Man Sarah Lee, Samuel Le Sourd, Dongliang Li, Wei Li, Houjie Liang, Tingbo Liang, Chun Sen Lim, Brian Lingerfelt, Charles Lopez, John Low, Teresa Macarulla Mercade, David Malka, Yimin Mao, Gianluca Masi, Steven McCune, Ray McDermott, Elaine McWhirter, Guillermo Mendez, Michele Milella, Tomonori Mizutani, Camila Moniz, Luisa Morales, Andres Jesús Munoz Martin, Bruno Nervi, Nuttapong Ngamphaiboon, Sang Cheul Oh, Berna Oksuzoglu, Darryl Outlaw, Mustafa Ozguroglu, Ozgur Ozyilkan, Claudio Painemeal, Yueyin Pan, Chuang Peng, Caroline Petorin, Denis Pezet, Derek Power, Shukui Qin, Aflah Roohullah, Hyewon Ryu, Pamela Salman, Rita Sasidharan, Taroh Satho, Kornelius Schulze, Martin Scott-Brown, Ruben Segovia, Thomas Seufferlin, Salvatore Siena, Isabelle Sinapi, Cristina Smolenschi, Tianqiang Song, Aumkhae Sookprasert, Nopadol Soparattanapaisarn, Naureen Starling, Stacey Stein, Salomon Stemmer, Haichuan Su, Rie Sugimoto, Thatthan Suksombooncharoen, Vincent Tam, Ai Lian Tan, Chih Kiang Tan, Suebpong Tanasanvimon, Giuseppe Tonini, Giampaolo Tortora, Akihito Tsuji, Rodrigo Uribe, Marino Venerito, Helena Verdaguer Mata, Ana Paula Victorino, James Wade, Dirk Thomas Waldschmidt, Lu Wang, Wan Zamaniah Wan Isahk, Harpeet Wasan, Rui Weschenfelder, Chun Yin Wong, Yoke Fui Wong, Suayib Yalcin, Patricio Yanez Weber, Xuezhong Yang, Hisateru Yasui, Ozan Yazici, Chia-Jui Yen, Jieer Ying, Wenchang Yu, Haitao Zhao, Helen Diller Family Comprehensive Cancer Center [San Francisco], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Kyorin University School of Medicine [Tokyo, Japan], Kyorin University [Tokyo, Japan], The University of Hong Kong (HKU), The Chinese University of Hong Kong [Hong Kong], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], University of Manchester [Manchester], Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., and Internal medicine
- Subjects
[SDV.CAN]Life Sciences [q-bio]/Cancer ,General Medicine - Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF