Background: Certain subtypes of gastric cancer are less responsive to perioperative chemotherapy. Preliminary data suggest that patients with microsatellite unstable tumors (MSI-H), EBV expressing tumors, and tumors with high PD-L1 expression may benefit from immunotherapy. This trial evaluates the benefit of PD-1 checkpoint immunotherapy in this subset of patients with operable gastric cancer. Methods: This is an interim analysis of this Phase II multicenter clinical trial (NCT03257163). Patients with clinically staged T2-T4, N0-N3, M0 gastric adenocarcinoma with MSI-H, EBV positive, or PDL1 expression with CPS>/= 1% were included. Patients receive two cycles of neoadjuvant pembrolizumab followed by gastrectomy. Postoperatively, patients receive one cycle of adjuvant capecitabine + pembrolizumab, then chemoradiation (45 Gy in 25 fractions) with capecitabine + pembrolizumab, then two cycles capecitabine + pembrolizumab, followed by 1-year total of pembrolizumab. Primary endpoint is DFS. Results: 33 patients have been enrolled (planned = 40), median age 67.5 years (range, 44 – 88 years), median follow up duration 18.1 months (range, 2.3-42.5 months). Patients were 30.3% Hispanic, 27% Asian, 24% Black, 24% White. Of the 33 patients, 12 were MSI-H, 3 EBV (+), and 27 had PDL1 expression with CPS >/= 1%. Tumors were of advanced clinical stage with 84.8% ≥ cT3 and 57.6% cN(+). All patients received two cycles of neoadjuvant pembrolizumab. Six patients did not undergo surgical resection: peritoneal disease (n=2), soft tissue metastases (n=1), locally unresectable (n=2), and frailty (n=1). Of the 27 patients who completed surgery, treatment effect was seen in 46%, down-staging in 50%, and complete pathologic response seen in 3 patients, 2 of whom has MSI-H tumors and one whose tumor was PDL1+. Two patients did not receive adjuvant therapy due to postoperative complications. A total of 20 patients have received optimal therapy as defined as postoperative RT and >/=2 cycles of adjuvant pembrolizumab. Four patients had adjuvant pembrolizumab monotherapy (after chemoradiation) stopped due to rash (n=2), pneumonia (n=1), and colitis (n=1). The estimated DFS at 24 months is 60% for the entire cohort (n=33). For the optimal therapy cohort (n=20), the DFS at 24 months is 80%. Conclusions: In this biomarker-driven cohort of operable gastric adenocarcinoma patients, results are promising for patients who receive two cycles of preoperative pembrolizumab followed by postoperative concurrent pembrolizumab with chemoradiation therapy, and chemotherapy. This study presents a novel and effective paradigm for the management of localized gastric cancer and warrants additional evaluation. Clinical trial information: NCT03257163.