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Cited by 690Gastric Cancer Management and OutcomesCancer Immunotherapy and BiomarkersIntraperitoneal and Appendiceal Malignancies

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

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Rha, Sun Young, Oh, Do-Youn, Yañez, Patricio, Bai, Yuxian, Ryu, Min-Hee, Lee, Jeeyun, Rivera, Fernando, Alves, Gustavo Vasconcelos +218 more·2023·The Lancet Oncology
DOI 10.1016/s1470-2045(23)00515-6
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Abstract

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.

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  • In KEYNOTE-859 phase III trial, adding pembrolizumab to platinum/chemotherapy significantly improved OS with manageable toxicity in locally advanced or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma.

    “Additionally, in the KEYNOTE-859 phase III trial assessing patients with locally advanced or metastatic HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, adding pembrolizumab to platinum/chemotherapy treatment significantly improved OS with a manageable toxicity profile compared to the placebo/chemotherapy group [111].”

    From Advances in platinum-based cancer therapy: overcoming platinum resistance through rational combinatorial strategies (2025) · cites this paper as [111]

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  1. Xu, 2021, Sintilimab plus chemotherapy (chemo) versus chemo as first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ORIENT-16): first results of a randomized, double-blind, phase III study, Ann Oncol, 32, S1283
  2. Liang, 2017, Longitudinal data analysis of continuous and discrete responses for pre-post designs, Indian J Stat, 62, 134

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Rha, S. Y., Oh, D.-Y., Yañez, P., Bai, Y., Ryu, M.-H., Lee, J., Rivera, F., Alves, G. V., Garrido, M., Shiu, K.-K., Fernández, M. G., Li, J., Lowery, M. A., Çil, T., Cruz, F. M., Qin, S., Luo, S., Pan, H., Wainberg, Z. A., Yin, L., Bordia, S., Bhagia, P., Wyrwicz, L. S., Mendez, G., O'Connor, J. M., Yanzi Castilla, A., Cundom, J., Kaen, D., Wong, R., Ng, W., Aghmesheh, M., Peressoni, M., Andrade, C., Franke, F., Alves, G., Cruz, F. J., Vianna, K., Monteiro, M. M., Raphael, M., Berry, S., Jang, R., Tan, A., Asselah, J., Yanez Weber, P., Mahave, M., Sanchez, C., Salman, P., Bai, Y., Li, J., Zhang, X., Liu, T., Lin, X., Qin, S., Yang, J., Luo, S., Li, W., Ying, J., Chen, X., Zeng, S., Qu, Y., Yang, L., Zhao, L., Chen, P., Pan, H., Li, E., Ye, F., Lu, J., Liang, X., Zhao, Q., Yin, X., Li, J., Ling, Y., Lv, G., Li, S., Guerrero, A., Rubiano, J., Gonzalez Fernandez, M., Manneh Kopp, R., Guzman Ramirez, A., Corrales, L., Gonzalez Herrera, I., Melichar, B., Buchler, T., Svoboda, T., Obermannova, R., Vrana, D., Cvek, J., Pfeiffer, P., Baeksgaard, L., Yilmaz, M., Boige, V., Lopez-Trabada, D., Borg, C., Pannier, D., Hiret, S., Di Fiore, F., Metges, J.-P., Arnold, D., Martens, U., Lordick, F., Stein, A., Castro, H., Lopez, K., Ramirez, J., Aguilar, M., Chivalan, M., Chan, W., Cheng, A., Yeo, W., Arkosy, P., Csoszi, T., Hitre, E., Horvath, Z., Lowery, M., McDermott, R., Morris, P., Hubert, A., Brenner, B., Ben-Aharon, I., Shacham-Shmueli, E., Man, S., Pelles Avraham, S., Brenner, R., Mishaeli, M., Di Bartolomeo, M., Fazio, N., Lonardi, S., Garufi, C., Satoh, T., Hara, H., Iwagami, S., Yasui, H., Tsuda, M., Shimoyama, T., Shoji, H., Sugimoto, N., Shibata, N., Yamaguchi, K., Amagai, K., Choda, Y., Esaki, T., Yabusaki, H., Oshima, T., Tsuji, A., Kawakami, H., Kawazoe, A., Ishido, K., Kadowaki, S., Martinez Rodriguez, J., Herrera Martinez, M., Huitzil Melendez, F., Ramirez Godinez, F., Balancan, P., Damianovich, D., Castro Oliden, V., Grados, J., Torres, C., Wyrwicz, L., Wysocki, P., Hajac, L., Zolnierek, J., Karaszewska, B., Rha, S. Y., Lee, J., Ryu, M.-H., Oh, D.-Y., Orlova, R., Tjulandin, S., Fadeeva, N., Makarycheva, Y., Nosov, D., Smagina, M., Chan, S., Jacobs, C., Kraus, P., Landers, G., Robertson, B., Ruff, P., Schoeman, E., Maurel, J.-M., Diez Garcia, M., Jimenez Fonseca, P., Gallego Plazas, J., Rivera Herrero, F., Miranda Poma, J., Layos Romero, L., Fritsch, R., Bastian, S., Winterhalder, R., Dosso, S. D., Kossler, T., Yeh, K.-H., Yen, C.-J., Chen, Y.-Y., Lin, J., Bilici, M., Ozguroglu, M., Cil, T., Oksuzoglu, B., Harputluoglu, H., Karaoglu, A., Hacibekiroglu, I., Erdogan, B., Yalcin, S., Adamchuk, H., Bondarenko, I., Kolesnik, O., Ostapenko, Y., Kryzhanivska, A., Leshchenko, L., Ilin, I., Shparyk, Y., Trukhin, D., Voitko, N., Roy, R., Young, A.-M., Medley, L., Shiu, K.-K., Celano, P., Overton, L., Raj, M., Dunne, R., Wainberg, Z., Dayyani, F., Larson, T., & Kochenderfer, M.
Affiliations
  • Marqués de Valdecilla University Hospital (ES)
  • Hospital Nossa Senhora da Conceição (BR)
  • Adana Hospital (TR)
  • Instituto Brasileiro de Controle do Câncer (BR)
  • University of California, Los Angeles (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • The Maria Sklodowska-Curie National Research Institute of Oncology (PL)
  • Sir Run Run Shaw Hospital (CN)
  • Zhengzhou University (CN)
  • Tongji University (CN)
  • Yonsei University (KR)
ORCID
Venue
The Lancet Oncology
Publisher
Elsevier BV
Published
2023-11
Volume
24
Issue
11
Pages
1181-1195
ISSN
1470-2045 (ISSN-L)
DOI
10.1016/s1470-2045(23)00515-6
OpenAlex
W4387849849
Cited by
690
References
22
Citations by year
2026: 219 · 2025: 302 · 2024: 160 · 2023: 8 · 2021: 1
FWCI
126.94
Type
journal article
Language
en
Update notices
erratum (2024-12-01)
Open access
Licence
Locations
  • The Lancet Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
  • Omeka S (Universidad de La Frontera) (submittedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
Keywords
pembrolizumab, HER2-negative gastric cancer, PD-1 inhibitors, PD-L1 expression, 5-fluorouracil, cisplatin, capecitabine, oxaliplatin, overall survival, immune checkpoint inhibitors, first-line therapy, metastatic gastric cancer, treatment safety, immune-related adverse events, PD-L1 combined positive score
MeSH terms
Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Double-Blind Method, Esophageal Neoplasms, Female, Humans, Male, Stomach Neoplasms, B7-H1 Antigen, Antibodies, Monoclonal, Humanized

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