Pembrolizumab plus chemotherapy as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma: 4.5-year follow-up from the randomized phase III KEYNOTE-859 study
In brief
Pembrolizumab plus chemotherapy adds 1.4 months median survival in advanced HER2-negative gastric cancer
After 4½ years of follow-up, first-line pembrolizumab with chemotherapy extended median overall survival to 12.9 months versus 11.5 months with chemotherapy alone, a 22% reduction in death risk. Benefit was seen across all PD-L1 levels, though severe treatment-related adverse events were slightly more common, leaving the magnitude of clinical impact under discussion.
- Journal
- ESMO open (Q1)
- Published
- 16 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- S Y Rha, L S Wyrwicz, P Yañez, Y Bai, M-H Ryu, J Lee, et al.
- PMID
- 42748509
- DOI
- 10.1016/j.esmoop.2026.108536
Why clinicians should know about it
- Picked for Oncology and Radiation Oncology (top studies of the week, 20 September 2026): Phase III KEYNOTE‑859 long‑term follow‑up of pembrolizumab + chemo
- Picked for Radiation Oncology (top studies of the week, 20 September 2026): Not relevant to radiation oncology
Abstract
BACKGROUND: KEYNOTE-859 showed a favorable benefit-risk profile for pembrolizumab plus chemotherapy compared with placebo plus chemotherapy, regardless of programmed death-ligand 1 (PD-L1) status, in participants with untreated locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Outcomes after a median study follow-up of 4.5 years are reported. PATIENTS AND METHODS: Overall, 1579 participants were randomly assigned 1 : 1 to pembrolizumab 200 mg or placebo plus chemotherapy every 3 weeks for ≤35 cycles. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival, objective response rate, and duration of response, all per RECIST v1.1 by blinded independent central review, and safety. RESULTS: The median study follow-up was 54.8 months (Q1-Q3, 46.8-62.1) at data cut-off (27 September 2024). In the intention-to-treat population, the median OS was 12.9 months for pembrolizumab plus chemotherapy compared with 11.5 months for placebo plus chemotherapy [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.70-0.86]. Median OS was longer in the PD-L1 combined positive score (CPS) ≥1 (13.0 compared with 11.4 months; HR 0.74, 95% CI 0.66-0.84) and CPS ≥10 (15.8 compared with 11.8 months; HR 0.64, 95% CI 0.53-0.77) populations. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 458 participants (58.3%) receiving pembrolizumab plus chemotherapy and 388 (49.3%) receiving placebo plus chemotherapy; grade 5 treatment-related AEs occurred in 8 participants (1.0%) and 16 participants (2.0%), respectively. CONCLUSIONS: Extended follow-up confirms that first-line pembrolizumab plus chemotherapy improves efficacy and maintains a manageable safety profile compared with placebo plus chemotherapy, regardless of PD-L1 status, supporting this combination as a first-line treatment option for locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.