Background: Despite advances in therapy, outcomes of patients with gastric cancer in the US remain poor. Recent data demonstrated that 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. We initiated a clinical trial to evaluate the benefit of PD-1 checkpoint immunotherapy in this subset of patients with resectable gastric cancer. Methods: Interim analysis performed on this phase 2 multi-institutional clinical trial (NCT03257163) is presented. Patients with clinically staged T2-T4, N0-N3, M0 gastric adenocarcinoma are evaluated for loss of mismatch repair proteins, expression of EBV or PDL1 expression with CPS > 1%. Consented patients receive 2 cycles of neoadjuvant pembolizumab followed by surgical resection. Following surgery, patients receive adjuvant chemoradiation (45 Gy) with 5 cycles of capecitabine and concurrent pembrolizumab, followed by up to 1 year of pembrolizumab. The primary endpoint is disease-free survival. Results: Of the 15 patients currently enrolled (planned enrollment = 40), 6 patients were MSI-H, 2 EBV (+), and 7 had PDL1 expression with CPS > 1%. Two patients did not undergo surgical resection as 1 patient was found to have peritoneal disease at time of exploration and second was deemed too frail to proceed with surgery. In the 13 patients who underwent surgical resection, all are alive without evidence of recurrent disease (follow up 1 month – 22 months). After 2 cycles of pembrolizumab, 2 patients with MSI-H tumors had pathologic complete response. Clinical T stage was downstaged in 5 patients and clinical N stage was downstaged in 2 patients. PD-1 checkpoint immunotherapy was well tolerated with minimal need for dose reduction and limited toxicity. Conclusions: Early results from our phase 2 clinical trial show immunotherapy to be well tolerated with limited toxicity. Following 2 cycles of pembrolizumab, 2 patients with MSI-H had complete pathologic response and above a third of our patients were downstaged. No recurrences have been observed in the short-term follow-up of surgically resected patients. Clinical trial information: NCT03257163