VP1-2023: Pembrolizumab (pembro) plus chemotherapy (chemo) as first-line therapy for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Phase III KEYNOTE-859 study

PD-1 inhibitors in combination with chemo have shown efficacy in G/GEJ cancer. We present results of the double-blind, placebo-controlled KEYNOTE-859 study of pembro + fluoropyrimidine- and platinum-containing chemo for advanced HER2-negative G/GEJ cancer (NCT03675737). Patients (pts) with HER2-negative, locally advanced or metastatic G/GEJ adenocarcinoma of known PD-L1 combined positive score (CPS) were randomized 1:1 to pembro 200 mg or placebo IV Q3W for ≤35 cycles; all pts received investigator’s choice of 5-FU + cisplatin (FP) or capecitabine + oxaliplatin (CAPOX). Randomization was stratified by region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 CPS (<1 vs ≥1), and chemo choice (FP vs CAPOX). The primary end point was OS; secondary end points were PFS, ORR, and DOR per RECIST v1.1 by blinded independent central review and safety. Efficacy was assessed in the ITT population, safety in the as-treated population. Data are from the interim analysis (03 Oct 2022 data cutoff). 1579 pts were randomized to pembro + chemo (n = 790) or placebo + chemo (n = 789). Median study follow-up was 31.0 mo (range 15.3-46.3). Baseline characteristics were balanced between arms. Median OS was 12.9 mo with pembro + chemo vs 11.5 mo with placebo + chemo (HR 0.78, 95% CI 0.70-0.87; P < 0.0001). Median PFS was 6.9 mo vs 5.6 mo (HR 0.76, 95% CI 0.67-0.85; P < 0.0001). Results were generally consistent across subgroups, including those by PD-L1 CPS. ORR was 51.3% vs 42.0% (P = 0.00009). Median DOR was 8.0 mo vs 5.7 mo. Grade 3-5 treatment-related AEs occurred in 59.4% of 785 pts treated with pembro + chemo and 51.1% of 787 treated with placebo + chemo; 1.0% and 2.0%, respectively, died of treatment-related AEs. Pembro + fluoropyrimidine- and platinum-containing chemo provided statistically significant, clinically meaningful improvements in OS, PFS, and ORR in pts with locally advanced or metastatic, HER2-negative G/GEJ adenocarcinoma of any PD-L1 expression level. No new safety signals were seen. These data support pembro + chemo as a new treatment option for this population.