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

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.