Background: Combination therapy with the anti-HER2 antibody trastuzumab plus fluoropyrimidine and platinum is the current standard of care for patients with HER2+ mG/GEJc. We hypothesize that combination anti–PD-1 and anti-HER2 therapy will result in T-cell activation, augment antibody-dependent, cell-mediated cytotoxicity, and potentiate antitumor immune response in HER2+ patients. A phase 2 study in HER2+ mG/GEJc demonstrated the safety and preliminary efficacy of trastuzumab/pembrolizumab/chemotherapy; the objective response rate was 87%, and the disease control rate was 100% (Janjigian YY, ASCO GI 2019). KEYNOTE-811 (ClinicalTrials.gov, NCT03615326), a global, multicenter, randomized, placebo-controlled, phase 3 study, is underway. Methods: Key eligibility criteria are age ≥18 years; previously untreated unresectable or metastatic HER2+ (centrally confirmed IHC 3+ or IHC 2+/ISH > 2.0) G/GEJ cancer; life expectancy > 6 months with RECIST v1.1 measurable disease; and adequate organ function and performance status (ECOG PS of 0 or 1). Patients will be randomly assigned 1:1 to receive chemotherapy with pembrolizumab 200 mg intravenously (IV) or placebo with trastuzumab 6 mg/kg (after 8 mg/kg load) every 3 weeks (Q3W) up to 2 years or until intolerable toxicity or disease progression. Investigator-choice chemotherapy will include day 1 cisplatin 80 mg/m² IV and 5-fluorouracil 800 mg/m²/day IV (days 1-5) or oxaliplatin 130 mg/m² IV and capecitabine 1000 mg/m² BID days 1-14 (Q3W). Primary end points are progression-free survival and overall survival. Secondary end points are objective response rate, duration of response, and safety and tolerability. Adverse events are graded per CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Patients will be followed up for survival. Planned enrollment is approximately 692 patients. Clinical trial information: NCT03615326