Background: Standard first-line treatment for advanced gastric cancer includes combination chemotherapy with a platinum agent and a fluoropyrimidine. The anti–PD-1 humanized monoclonal antibody pembrolizumab (pembro) has shown promising antitumor activity as monotherapy in patients (pts) with advanced gastric cancer. We report preliminary safety data for pts with advanced gastric cancer treated with pembro + cisplatin and 5-FU in the multicohort, phase 2 KEYNOTE-059 study (NCT02335411). Methods: Eligible pts were aged ≥ 18 y and had HER2^– relapsed or metastatic gastric or gastroesophageal junction adenocarcinoma, ECOG PS 0-1, and no prior therapy for metastatic disease. Pts received pembro 200 mg + 5-FU 800 mg/m² (or capecitabine 1000 mg/m² in Japan) + cisplatin 80 mg/m² Q3W for 6 cycles followed by pembro + 5-FU for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Primary end point was safety and tolerability of the combination. Results: Of the 17 pts enrolled (10 from Asia, 7 from outside Asia), 70.6% were men, and median age was 58.0 y. Three pts (17.6%) had a prior gastrectomy—2 total, 1 partial. As of the Aug 12, 2015, data cutoff date, median follow-up duration was 3.6 mo (range 2.6-5.4), and pts received a median of 5 treatment cycles (range 3-7). Only 1 pt (5.9%) discontinued treatment (due to progressive disease). There were no treatment-related deaths or discontinuations. Twelve pts (70.6%) experienced treatment-related adverse events (AEs) of any grade, most commonly neutropenia/decreased neutrophils (n = 7, 41.2%), stomatitis (n = 6, 35.3%), and decreased appetite (n = 5, 29.4%). Eight pts (47.1%) experienced ≥ 1 grade 3-4 treatment-related AE; only neutropenia/decreased neutrophils (n = 4 [23.5%] grade 3, n = 3 [17.6%] grade 4) occurred in > 1 pt. AEs of interest based on immune etiology, regardless of attribution by investigator, were grade 2 infusion-related reaction and grade 2 pruritus (n = 1 [5.9%] each). Conclusions: Preliminary data from KEYNOTE-059 suggest the combination of pembro, cisplatin, and 5-FU has a manageable safety profile as first-line therapy in pts with advanced gastric cancer. Clinical trial information: NCT02335411