Background: Standard first-line treatment for advanced gastric cancer includes combination chemotherapy with a platinum agent and a fluoropyrimidine. Pembrolizumab (pembro) has shown promising antitumor activity as monotherapy in patients with advanced gastric cancer. We report preliminary safety data for patients with advanced gastric cancer treated with pembro + cisplatin + 5-FU in the multicohort, phase 2 KEYNOTE-059 study (NCT02335411). Methods: Eligible patients were aged ≥ 18 y and had HER2^– advanced gastric or gastroesophageal junction adenocarcinoma, ECOG PS 0-1, and no prior systemic therapy for metastatic disease. Patients 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 (or capecitabine) for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Results: Of the 18 patients treated, 67% were men, and median age was 58 y. As of the Oct 9, 2015 data cutoff date, median follow-up duration was 5.5 mo (range, 4.0-7.3). There were no treatment-related deaths and only 1 patient (6%) discontinued treatment because of an AE (stomatitis), which was considered by the investigator to be unrelated to pembro or chemotherapy. 17 patients (94%) experienced treatment-related AEs of any grade, most commonly stomatitis (n = 7, 39%), decreased appetite (n = 6, 33%), nausea (n = 5, 28%), and neutropenia/decreased neutrophils (n = 11, 61%) without neutropenic fever and unrelated to pembro. 12 patients (67%) experienced grade 3-4 treatment-related AEs; none were attributed to pembro. AEs attributed to pembro occurred in 7 patients (39%); the most common were diarrhea, dysgeusia, hyperthyroidism, and nausea (n = 2 each); all were grade 1/2. 8 patients (44%) experienced AEs of special interest, regardless of attribution by investigator, including hyperthyroidism, hypothyroidism, infusion-related reaction, pruritus, and vasculitis; all were grade 1/2. Conclusions: These data suggest the combination of pembro, cisplatin, and 5-FU has a manageable safety profile as first-line therapy in patients with advanced gastric cancer. Clinical trial information: NCT02335411