Background: First-line (1L) treatment of GEJC and EAC is similar to that for gastric adenocarcinomas, based on evidence from 2 large phase 3 gastric and esophageal cancer trials. The phase 3 KEYNOTE-590 trial (NCT03189719) showed 1L pembro + chemo significantly improved OS and PFS in pts with esophageal cancer. The phase 3 KEYNOTE-859 trial (NCT03675737) showed 1L pembro + chemo significantly improved OS, PFS, and ORR in pts with HER2-negative gastric cancer or GEJC. This post hoc, exploratory analysis was conducted to examine the efficacy of 1L pembro + chemo in the GEJC and EAC subgroups of KEYNOTE-590 and the GEJ subgroup of KEYNOTE-859. Methods: Pts with untreated advanced EAC or Siewert type 1 adenocarcinoma of the GEJ (KEYNOTE-590) or HER2-negative GEJ adenocarcinoma (KEYNOTE-859), measurable disease per RECIST v1.1, and ECOG PS 0 or 1 were evaluated. In both studies, pts were randomly assigned 1:1 to receive pembro 200 mg IV or pbo every 3 wk (Q3W) for ≤35 cycles, each with chemo (5-fluorouracil + cisplatin [FP] in KEYNOTE-590; FP or capecitabine + oxaliplatin in KEYNOTE-859). Efficacy end points for this analysis were OS and PFS (per RECIST v1.1 by blinded independent central review) by tumor subtype. Database cutoff was July 2, 2020, for KEYNOTE-590 and July 1, 2022, for KEYNOTE-859. Results: Overall, 201 pts from KEYNOTE-590 (n=99 pembro + chemo; n=102 pbo + chemo) with GEJC or EAC and 334 pts from KEYNOTE-859 (n=149 pembro + chemo; n=185 pbo + chemo) with GEJC were included. In KEYNOTE-590, 91 pts had GEJC only (n=41 pembro + chemo; n=50 pbo + chemo) and 169 (n=82 pembro + chemo; n=87 pbo + chemo) had GEJC + EAC + CPS ≥1. In KEYNOTE-859, 287 pts (n=123 pembro + chemo; n=164 pbo + chemo) had GEJC + CPS ≥1. Demographic and baseline characteristics were well balanced. Median time from randomization to database cutoff for pts with GEJC and EAC was 23.5 mo (range, 15.3-33.6) in KEYNOTE-590 and 25.8 mo (range, 12.4-43.0) in KEYNOTE-859. Efficacy outcomes by tumor type are shown in the Table. Conclusions: Consistent with results from the ITT populations of KEYNOTE-590 and KEYNOTE-859, 1L pembro + chemo provided clinically meaningful improvement in OS and PFS vs chemo in pts with untreated advanced GEJC and EAC. These data support the use of 1L pembro + chemo for pts with advanced GEJC and EAC. Clinical trial information: NCT03189719 and NCT03675737.