4045 Background: At the protocol-specified interim analysis of the KEYNOTE-859 study (NCT03675737), first-line pembro + chemo significantly improved OS (HR, 0.78; 95% CI, 0.70-0.87; P<0.0001), PFS (HR, 0.76; 95% CI, 0.67-0.85; P<0.0001), and ORR (51.3% vs 42.0%; P=0.00009) vs placebo (pbo) + chemo in patients (pts) with HER2-negative G/GEJ cancer. We report results after an additional 11 months of follow-up. Methods: Pts with previously untreated locally advanced or metastatic HER2-negative G/GEJ cancer, measurable disease per RECIST v1.1, ECOG PS 0 or 1, and known PD-L1 combined positive score (CPS) were eligible. Pts were randomly assigned 1:1 to receive pembro 200 mg or pbo IV Q3W for ≤35 cycles + investigator’s choice of chemo (5-FU + cisplatin [FP] vs capecitabine + oxaliplatin [CAPOX]). The primary end point was OS. Secondary end points included PFS, ORR, and DOR, all per RECIST v1.1 by BICR, and safety. The data cutoff was August 22, 2023. Results: The intention-to-treat (ITT) population comprised 1579 pts (pembro + chemo, n=790; pbo + chemo, n=789). Median follow-up from randomization to data cutoff was 41.6 mo (range, 33.6-48.9). In the ITT population, median OS was 12.9 mo (95% CI, 11.9-14.0) for pembro + chemo vs 11.5 mo (95% CI, 10.6-12.1) for pbo + chemo (HR, 0.79; 95% CI, 0.71-0.88), median PFS was 6.9 mo (95% CI, 6.3-7.2) vs 5.6 mo (95% CI, 5.5-5.7; HR, 0.76 [95% CI, 0.68-0.85]), ORR was 51.0% vs 42.0%, and median DOR was 8.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥1 (pembro + chemo, n=618; pbo + chemo, n=617), median OS was 13.0 mo (95% CI, 11.6-14.2) vs 11.4 mo (95% CI, 10.5-12.0; HR, 0.75 [95% CI, 0.66-0.85]), median PFS was 6.9 mo (95% CI, 6.0-7.2) vs 5.6 mo (95% CI, 5.4-5.7; HR, 0.73 [95% CI, 0.64-0.83]), ORR was 51.8% vs 42.6%, and median DOR was 8.3 mo (range, 1.2+ to 52.6+) vs 5.6 mo (range, 1.3+ to 44.3+). In pts with PD-L1 CPS ≥10 (pembro + chemo, n=280; pbo + chemo, n=273), median OS was 15.8 mo (95% CI, 14.0-19.3) vs 11.8 mo (95% CI, 10.3-12.7; HR, 0.64 [95% CI, 0.53-0.78]), median PFS was 7.8 mo (95% CI, 6.8-8.5) vs 5.6 mo (95% CI, 5.4-6.7; HR, 0.63 [95% CI, 0.51-0.77]), ORR was 60.0% vs 43.2%, and median DOR was 10.0 mo (range, 1.2+ to 52.6+) vs 5.7 mo (range, 1.4+ to 41.0+). Among all treated pts, treatment-related AEs were reported in 751 (95.7%; grade 3-5, 466 [59.4%]) for pembro + chemo and 736 (93.5%; grade 3-5, 404 [51.3%]) for pbo + chemo. Conclusions: With a median follow-up of 41.6 months, use of pembro + chemo continued to show improved OS, PFS, and ORR vs pbo + chemo, regardless of PD-L1 expression. These results continue to support pembro + chemo as a first-line treatment option for pts with locally advanced or metastatic HER2-negative G/GEJ adenocarcinoma. Clinical trial information: NCT03675737 .