Pembrolizumab or placebo plus chemotherapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: An updated analysis of KEYNOTE-859 for patients enrolled in Asia.
Authors: Chia Jui Yen, Do-Youn Oh, Yuxian Bai, Min-Hee Ryu, Jeeyun Lee, Jin Li, Lin Yang, Hisateru Yasui, Hiroshi Yabusaki, Ka On Lam, Kensei Yamaguchi, Kun-Huei Yeh, Lina Yin, Pierre Leconte, Pooja Bhagia, Sun Young Rha
Journal: Journal of Clinical Oncology (2025)

464 Background: After a median follow-up of 41.6 months, data from the global phase 3 KEYNOTE-859 study (NCT03675737; N = 1579) continued to show that use of pembrolizumab (pembro) plus chemotherapy (chemo) improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), with manageable safety, versus placebo (pbo) plus chemo for patients (pts) with advanced HER2-negative G/GEJ adenocarcinoma. Here, we report updated results from the subgroup analysis of pts enrolled in Asia after an additional 11 months of follow-up from the first interim analysis. Methods: Eligible pts aged ≥18 years with locally advanced unresectable or metastatic HER2-negative G/GEJ adenocarcinoma, an ECOG performance status (PS) of 0 or 1, and measurable disease per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles; all pts received investigator’s choice of chemo (FP or CAPOX). The primary end point was OS. Secondary end points included PFS, ORR, and DOR per RECIST v1.1 by blinded independent central review, and safety. Efficacy end points were evaluated in all randomly assigned pts (intention to treat). Results: A total of 525 pts (263, pembro plus chemo; 262, pbo plus chemo) were enrolled in KEYNOTE-859 in Asia. The median time from randomization to database cutoff (August 22, 2023) was 39.2 months (range, 26.0-56.8). The median OS was 17.3 months (95% CI, 14.8-19.5) for pembro plus chemo versus 13.0 months (95% CI, 11.8-14.4) for pbo plus chemo (HR, 0.75; 95% CI, 0.62-0.91). The median PFS was 8.4 months (95% CI, 7.1-9.6) for pembro plus chemo versus 5.8 months (95% CI, 5.6-6.9) for pbo plus chemo (HR, 0.72; 95% CI, 0.58-0.89). The ORR was 61.2% (95% CI, 55.0-67.1; 36, complete response [CR]; 125, partial response [PR]) for pembro plus chemo and 48.5% (95% CI, 42.3-54.7; 24, CR; 103, PR;) for pbo plus chemo. The median DOR was 10.0 months (range, 1.2+ to 50.8+) for pembro plus chemo and 5.8 months (range, 1.3+ to 44.3+) for pbo plus chemo; 28.9% and 23.3% of pts, respectively, had a response lasting ≥24 months. Grade 3-5 treatment-related adverse events (AEs) occurred in 155 pts (59.2%) in the pembro plus chemo group and 119 pts (45.4%) in the pbo plus chemo group. Treatment-related AEs led to death in 1 pt (0.4%) in the pembro plus chemo group (unknown cause) and 2 pts (0.8%) in the pbo plus chemo group (cerebral hemorrhage and abnormal liver function). Immune-mediated AEs and infusion reactions occurred in 85 pts (32.4%) in the pembro plus chemo group and 35 pts (13.4%) in the pbo plus chemo group. Conclusions: The addition of pembro to chemo improved OS, PFS, and ORR in pts with advanced HER2-negative G/GEJ adenocarcinoma from Asia enrolled in KEYNOTE-859, with no new safety signals. These results further support first-line pembro plus chemo as a treatment option for this population. Clinical trial information: NCT03675737 .