Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m² of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490.