Background: Trastuzumab (tras) plus chemotherapy (chemo) is standard-of-care (SOC) 1L therapy for HER2+ metastatic G/GEJ cancer. In two phase 2 studies, tras, chemo, and pembrolizumab (pembro) in combination showed promising efficacy and manageable safety. The ongoing global, randomized, double-blind, placebo-controlled phase 3 KEYNOTE-811 study is assessing whether adding pembro to SOC improves efficacy vs SOC alone for HER2+ metastatic G/GEJ cancer (NCT03615326). Methods: Eligible patients (pts) with previously untreated, unresectable or metastatic HER2+ G/GEJ cancer and ECOG PS 0 or 1 are randomized 1:1 to pembro 200 mg IV Q3W or placebo IV Q3W. All pts receive tras and investigator’s choice of 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX). Treatment is given up to 2 y or until intolerable toxicity or PD. Dual primary end points are PFS per RECIST v1.1 by blinded, independent central review (BICR) and OS. Secondary end points are ORR and DOR per RECIST v1.1 by BICR and safety. Planned enrollment in the global cohort is 692 pts; accrual is almost complete. The protocol-specified first interim analysis (IA1) was to occur when the first 260 pts enrolled had ≥8.5 mo of follow-up and tested whether pembro + SOC significantly improved ORR; the superiority boundary was P = 0.002. The ORR difference was calculated using the Miettinen and Nurminen method stratified by the randomization stratification factors of geographic region, PD-L1 status, and chemo choice. Efficacy is presented for the first 264 pts enrolled. Safety is presented for all treated pts enrolled as of Jun 17, 2020. Results: Among the first 264 pts enrolled, 133 were randomized to pembro + SOC, 131 to placebo + SOC; 0.8% had MSI-H tumors, CAPOX was chosen for 87.1%, and median study follow-up was 12.0 mo (range, 8.5-19.4). Confirmed ORR (95% CI) was 74.4% (66.2-81.6) for pembro + SOC vs 51.9% (43.0-60.7) for placebo + SOC (difference, 22.7 percentage points [95% CI, 11.2-33.7], P = 0.00006); CR rate was 11.3% vs 3.1% and DCR (95% CI) was 96.2% (91.4-98.8) vs 89.3 (82.7-94.0). Median (range) DOR was 10.6 mo (1.1+ to 16.5+) for pembro + SOC vs 9.5 mo (1.4+ to 15.4+) for placebo + SOC; KM estimates of DOR ≥6 mo and ≥9 mo were 70.3% vs 61.4% and 58.4% vs 51.1%. As of data cutoff, 433/434 enrolled pts were treated (217/217 pembro + SOC, 216/217 placebo + SOC). AEs were grade 3-5 in 57.1% of pts with pembro + SOC vs 57.4% with placebo + SOC, led to death in 3.2% vs 4.6%, and led to discontinuation of any drug in 24.4% vs 25.9%. Conclusions: Adding pembro to tras and chemo resulted in a substantial, statistically significant increase in ORR versus trastuzumab and chemo alone as 1L therapy for HER2+ metastatic G/GEJ cancer; responses were durable and safety was manageable. These initial data support pembro plus tras and chemo as a potential new treatment option for this population. Clinical trial information: NCT03615326