Background: Locally advanced esophagogastric adenocarcinoma (EGA) is commonly treated with neoadjuvant chemoradiation (CRT) prior to surgical resection. Adjuvant immunotherapy has been shown to improve outcomes for these patients. The primary objective of this trial was to investigate whether neoadjuvant pembrolizumab (P) + CRT improves pathologic complete response (pCR) compared to historical control of neoadjuvant CRT alone. Exploratory endpoints included time to local recurrence (TTLR), time to distant recurrence (TTDR), progression-free survival (PFS), and overall survival (OS). Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating neoadjuvant P + CRT followed by adjuvant P in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of P were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant P. Pathologic response was scored from 0-3 based on tumor regression grading (TRG): 0 indicating a complete response, 1 marked response (<10% residual disease), 2 partial response, and 3 poor or no response. pCR was defined as the absence of viable tumor cells at the primary tumor site and all resected lymph nodes in the surgical specimens (ypT0N0, TRG 0). Major pathologic response (MPR) was defined as TRG 0-1. Treatment-responders (R) are those with MPR, while non-responders (NR) are those with TRG 2-3 TTLR was time from enrollment to local recurrence (LR); distant recurrences (DR) were ignored and deaths were censored. TTDR was defined analogously. PFS was time from enrollment to LR, DR, or death due to any cause. OS was time from enrollment to death due to any cause. The Kaplan-Meier method was used to estimate TTLR, TTDR, PFS, and OS. Two-sided statistical tests were performed with an α of <0.05 considered significant. Results: 35 patients were enrolled from 2017-2022. 30 underwent neoadjuvant P + CRT followed by surgical resection. pCR and MPR rates were previously reported: 35.5% and 50%, respectively. Median follow-up of the whole cohort was 35.5 mo. PFS was significantly improved in R vs NR (p=0.046), and there was a trend towards improved OS (p=0.084), and TTDR (p=0.069). There was no significant difference in TTLR (p=0.128). At three years, in R vs NR, PFS was 72.7% vs 46.2%, OS was 80.0% vs 58.3%, TTLR was 100% vs 81.8%, and TTDR was 81.8% vs 53.8%. Conclusions: Patients undergoing neoadjuvant P + CRT for EGA experienced higher rates of pCR/MPR compared to historical controls treated with CRT alone. MPR correlated with improved PFS, with a trend towards improved OS, indicating the clinical significance of pathologic response. These correlations appear to be driven primarily by decreased risk of developing distant metastases. Clinical trial information: NCT03064490.