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Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

2023; Elsevier BV; Volume: 24; Issue: 11 Linguagem: Inglês

10.1016/s1470-2045(23)00515-6

1474-5488

Sun Young Rha, Do‐Youn Oh, Patricio Yañez, Yuxian Bai, Min‐Hee Ryu, Jeeyun Lee, Fernando Rivera, Gustavo Vasconcelos Alves, Marcelo Garrido, Kai‐Keen Shiu, M. Fernández, Jin Li, Maeve A. Lowery, Timuçin Çil, Felipe Melo Cruz, Shukui Qin, Suxia Luo, Hongming Pan, Zev A. Wainberg, Lina Yin, Sonal Bordia, Pooja Bhagia, Lucjan Wyrwicz, Guillermo Méndez, Juan Manuel O’Connor, Alvaro Yanzi Castilla, Juan Cundom, Diego Kaen, Rachel Wong, Weng Ng, Morteza Aghmesheh, Mauricio Peressoni, Carlos Eduardo Mattos da Cunha Andrade, Fábio Franke, Gustavo R. Alves, Felipe Jose Cruz, Karina Vianna, Maria Marcela Monteiro, Michael J. Raphael, Scott Berry, Raymond Woo-Jun Jang, Ann Tan, Jamil Asselah, Patricio Yanez Weber, Mauricio Mahave, César Sánchez, Pamela Salman, Yuxian Bai, Jin Li, Xiaochun Zhang, Tianshu Liu, Xiaoyan Lin, Shukui Qin, Jianwei Yang, Suxia Luo, Wěi Li, Jieer Ying, Xi Chen, Shan Zeng, Yanli Qu, Lin Yang, Lin Zhao, Ping Chen, Hongming Pan, Enxiao Li, Feng Ye, Jianwei Lu, Xinjun Liang, Qun Zhao, Xianli Yin, Junhe Li, Ling Yang, Guoqing Lv, Shouguo Li, Álvaro Guerrero, Juan Rubiano, M. Fernández, Ray Manneh Kopp, Adrian Guzman Ramirez, Luis Corrales, Ileana Gonzalez Herrera, Bohuslav Melichar, Tomáš Büchler, Tomáš Svoboda, Radka Obermannová, David Vrána, Jakub Cvek, Per Pfeiffer, Lene Bæksgaard, Mette Yilmaz, Valérie Boige, Daniel López‐Trabada, Christophe Borg, Diane Pannier, Sandrine Hiret, Frédéric Di Fiore, Jean‐Philippe Metges, Dirk Arnold, Uwe M. Martens, Florian Lordick, Alexander Stein, Hugo R. Castro, Karla Alejandra Lopez, Julio A. Ramírez, Mynor Aguilar, Marco Chivalan, Wing‐Lok Chan, Ashley Cheng, Winnie Yeo, Peter Arkosy, Tibor Csőszi, Erika Hitre, Zsolt Horváth, Maeve A. Lowery, Ray McDermott, Patrick G. Morris, Ayala Hubert, Baruch Brenner, Irit Ben‐Aharon, Einat Shacham‐Shmueli, Sofia Man, Sharon Pelles Avraham, Ronen Brenner, Moshe Mishaeli, Maria Di Bartolomeo, Nicola Fazio, Sara Lonardi, Carlo Garufi, Taroh Satoh, Hiroki Hara, Shiro Iwagami, Hisateru Yasui, Masahiro Tsuda, Tatsu Shimoyama, Hirokazu Shoji, Naotoshi Sugimoto, Nobuhiro Shibata, Kensei Yamaguchi, Kenji Amagai, Yasuhiro Choda, Taito Esaki, Hiroshi Yabusaki, Takashi Oshima, Akihito Tsuji, Hisato Kawakami, Akihito Kawazoe, Kenji Ishido, Shigenori Kadowaki, Jorge Martinez Rodriguez, Marytere Herrera Martínez, Fidel Huitzil Melendez, Francisco Ramirez Godinez, Paola Balancan, Dragan Damianovich, Victor Castro Oliden, Julio Grados, César Torres, Lucjan Wyrwicz, Piotr J. Wysocki, Łukasz Hajac, Jakub Żołnierek, Boguslawa Karaszewska, Sun Young Rha, Jeeyun Lee, Min‐Hee Ryu, Do‐Youn Oh, Р. В. Орлова, S. Tjulandin, Natalia Fadeeva, Yulia Makarycheva, Dmitry Nosov, Maria Smagina, Sze Ham Chan, Conrad Jacobs, P Kraus, Gregory Landers, Barbara Robertson, Paul Ruff, Elizabeth Schoeman, Jean-Marc Maurel, M. Díez García, Paula Jiménez Fonseca, Javier Gállego, F. Rivera Herrero, Jesús Miranda, L. Layos Romero, Ralph Fritsch, Sara Bastian, Sun Young Rha, Sara De Dosso, Thibaud Kössler, Kun‐Huei Yeh, Chia‐Jui Yen, Yen‐Yang Chen, Johnson Lin, Mehmet Bilici, Mustafa Özgüroğlu, Timuçin Çil, Berna Öksüzoğlu, Hakan Harputluoğlu, Aziz Karaoğlu, İlhan Hacıbekiroğlu, Bülent Erdoğan, Şuayib Yalçın, Hryhoriy Adamchuk, Igor Bondarenko, Oleksii Kolesnik, Yuriy Ostapenko, Anna Kryzhanivska, Lurii Leshchenko, Ievgen Ilin, Yaroslav Shparyk, Dmytro Trukhin, Олександр Войтко, Rajarshi Roy, Anna-Mary Young, Louise Medley, Kai‐Keen Shiu, Paul Celano, Lindsay Overton, Moses S. Raj, Richard F. Dunne, Zev A. Wainberg, Farshid Dayyani, Timothy Larson, Mark D. Kochenderfer,

Pancreatic and Hepatic Oncology Research

Summary Background PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Methods KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m 2 per day) administered continuously on days 1–5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m 2 ) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m 2 ) administered twice daily on days 1–14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m 2 ) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete. Findings Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0–38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9–14·0] vs 11·5 months [10·6–12·1]; hazard ratio [HR] 0·78 [95% CI 0·70–0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6–14·2] vs 11·4 months [10·5–12·0]; 0·74 [0·65–0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8–19·3] vs 11·8 months [10·3–12·7]; 0·65 [0·53–0·79]; p<0·0001). The most common grade 3–5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified. Interpretation Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Funding Merck Sharp and Dohme.