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Clinical Trial
. 2025 Oct;30(10):2003-2011.
doi: 10.1007/s10147-025-02847-6. Epub 2025 Aug 1.

First-line pembrolizumab plus chemotherapy for participants in Japan with gastric or gastroesophageal junction adenocarcinoma: subgroup analysis of the phase 3 KEYNOTE-859 study

Hisateru Yasui  1 , Masaki Aizawa  2 , Kensei Yamaguchi  3 , Akihito Kawazoe  4 , Hiroki Hara  5 , Masahiro Tsuda  6 , Hirokazu Shoji  7 , Naotoshi Sugimoto  8 , Nobuhiro Shibata  9 , Kenji Amagai  10 , Yasuhiro Choda  11 , Shiro Iwagami  12 , Taito Esaki  13 , Shigenori Kadowaki  14 , Shinichi Shiratori  15 , Shirong Han  15 , Sonal Bordia  16 , Kohei Shitara  17
Affiliations
Clinical Trial

First-line pembrolizumab plus chemotherapy for participants in Japan with gastric or gastroesophageal junction adenocarcinoma: subgroup analysis of the phase 3 KEYNOTE-859 study

Hisateru Yasui et al. Int J Clin Oncol. 2025 Oct.

Abstract

Background: In the global phase 3 KEYNOTE-859 study (NCT03675737), first-line pembrolizumab plus chemotherapy significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus placebo plus chemotherapy in participants with advanced human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. This post hoc analysis of KEYNOTE-859 evaluated outcomes in participants enrolled in Japan.

Methods: Participants with untreated locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma were randomly assigned to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for ≤ 35 cycles plus investigator's choice of chemotherapy. The primary end point was OS. Secondary end points were ORR, DOR, and PFS per RECIST v1.1, by blinded independent central review, and safety. Data cutoff was October 3, 2022.

Results: Overall, 101 participants were enrolled in Japan (n = 48 pembrolizumab plus chemotherapy [pembrolizumab group]; n = 53 placebo plus chemotherapy [placebo group]). Median follow-up was 28.9 months (range, 22.0-42.0). Median OS was 16.8 months with pembrolizumab versus 13.3 months with placebo (hazard ratio [HR], 0.71; 95% CI, 0.44-1.13). Grade 3 or 4 treatment-related adverse events occurred in 41.7% of participants given pembrolizumab and 39.6% of participants given placebo; none were grade 5.

Conclusions: Consistent with the global KEYNOTE-859 results, OS was better with pembrolizumab plus chemotherapy, with manageable safety, for participants enrolled in Japan. Results continue to support pembrolizumab plus chemotherapy as a new first-line treatment option for patients with advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma.

Trial registration: ClinicalTrials.gov, NCT03675737.

Keywords: Adenocarcinoma; Gastric cancer; Gastroesophageal junction cancer; Japan; Pembrolizumab.

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Conflict of interest statement

Declarations. Conflict of interest: Hisateru Yasui reports honoraria from Chugai Pharma, MSD, and Yakult Honsha and research funding (to the institution) from MSD. Masaki Aizawa reports honoraria from Bristol Myers Squibb KK, MSD, Ono Pharmaceutical, Medtronic, Taiho Pharmaceutical, and Johnson & Johnson/MedTech. Kensei Yamaguchi reports honoraria from Bristol Myers Squibb KK, Eli Lilly Japan KK, Taiho Pharmaceutical Co., Ltd., and Ono. Akihito Kawazoe reports honoraria from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, and Eli Lilly and research funding from AstraZeneca (institution) and AbbVie. Hiroki Hara reports honoraria from Astellas, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Merck Biopharma, Miyarisan Pharmaceutical, MSD, Ono Pharmaceutical, Taiho, Takeda, and Yakult and research funding from ALX Oncology, Amgen, Astellas, AstraZeneca, Bayer, Chugai, Daiichi Sankyo, Janssen, Jazz Pharma, MSD, Ono Pharmaceutical and Taiho. Masahiro Tsuda reports research funding from Toray. Hirokazu Shoji reports honoraria from Ono Pharmaceutical and Bristol Myers Squibb, and research grants from Ono Pharmaceutical and Takeda Pharmaceuticals. Naotoshi Sugimoto reports grants from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Lilly Japan, Daiichi Sankyo, Sumitomo Pharma, Chugai Pharma, BeiGene, Solasia Pharma, Astellas Pharma, and Eisai. Nobuhiro Shibata reports consulting fees for advisory board membership from Kyowa Kirin Co., Ltd. and Daiichi Sankyo Co., Ltd.; honoraria from Kyowa Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Nippon Kayaku Co., Ltd., Merck Biopharma Co., Ltd., and Bristol Myers Squibb K.K.; and research funding from Daiichi Sankyo Co., Ltd., MSD K.K., AstraZeneca K.K., and Eli Lilly Japan KK. Kenji Amagai reports research funding from MSD. Taito Esaki reports research funding from MSD, Ono Pharmaceutical, Chugai, Amgen, ALX Oncology, Seagen, Taiho, Daiichi Sankyo, Pfizer, Jazz Pharmaceuticals, Asahi Kasei Pharma, Quintiles, Astellas Amgen Biopharma, Novartis, and Syneos Health. Shigenori Kadowaki reports honoraria from Ono Pharmaceutical, Taiho, MSD, Daiichi Sankyo, Merck KGaA, Bristol Myers Squibb, Eli Lilly, Chugai, Bayer, Eisai, and Novartis and research funding from Ono Pharmaceutical, Taiho, MSD, Nobel, Janssen, Bayer, Eli Lilly, Chugai, Daiichi Sankyo, AbbVie, and AstraZeneca. Shinichi Shiratori is an employee of MSD KK, Tokyo, Japan, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. Shirong Han is an employee of MSD KK, Tokyo, Japan, and may hold stock in Merck & Co., Inc., Rahway, NJ, USA. Sonal Bordia is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. Kohei Shitara reports receiving personal fees for consulting and advisory roles from Bristol Myers Squibb, Takeda, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Merck, Astellas, Guardant Health Japan, Janssen, AstraZeneca, Zymeworks Biopharmaceuticals, ALX Oncology Inc., Bayer, GlaxoSmithKline KK, HEALIOS KK, Moderna, Inc., and Arcus Biosciences, Inc.; honoraria from Bristol Myers Squibb, Ono Pharmaceutical, Janssen, Eli Lilly, Astellas, and AstraZeneca; and research funding from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck, Amgen, Eisai, PRA Health Sciences, Syneos Health, AstraZeneca, PPD-SNBL KK, and Toray Industries, Inc. Industries, Inc. Yasuhiro Choda and Shiro Iwagami declare no conflicts of interest. Meeting presentation: The data were described, in part, at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO-GI) annual meeting held virtually January 18–20, 2024.

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