Immunotherapy Response in Microsatellite Instability–High Gastroesophageal Adenocarcinoma

Importance: Comprehensive clinical data stratified by microsatellite instability (MSI) status in gastroesophageal adenocarcinoma (GEA) are limited. Objective: To characterize treatment pathways and clinical outcomes following immune checkpoint inhibitor (ICI) therapy in patients with deficient mismatch repair (dMMR) or MSI-high (MSI-H) GEA. Design, Setting, and Participants: This retrospective cohort study was conducted from June 2020 to August 2025 at a single tertiary cancer center in Texas. Of 3316 patients diagnosed with GEA, 1638 who underwent MSI testing were included. Exposures: ICI-based therapy with nivolumab plus ipilimumab or with pembrolizumab. Main Outcomes and Measures: Incidence of dMMR, overall survival, best objective response, clinical or pathological complete response (cCR/pCR), and clinicopathological factors associated with ICI response. Results: Among the 1638 patients included, the mean (SD) age was 62.5 (12.8) years, and 1204 (73.5%) were male. There were 83 individuals (5.1%) with dMMR tumors. The 3-year overall survival rate for patients with dMMR was 84.7% with and 68.5% without curative-intent surgery vs 72.3% with and 32.3% without curative-intent surgery for patients with proficient mismatch repair. Among the 83 patients with dMMR, 34 had metastatic and 49 had locoregional disease; 30 and 25 patients in each group received ICI-based therapy, respectively, with 16 of 26 evaluable patients (61.5%) achieving best objective response and 12 of 23 (52.2%) achieving pCR/cCR, respectively (both considered ICI responsive). Among the 25 locoregional cases treated with ICI, 10 proceeded to surgery, with all achieving residual tumor (R0) resection and 3 (30%) demonstrating pCR. Of the remaining patients, 9 achieved cCR and were transitioned to active surveillance. For patients who achieved cCR or pCR, response was reached after 2 to 4 cycles of nivolumab plus ipilimumab or 6 to 12 cycles of pembrolizumab, and none experienced recurrence or death (median [IQR] follow-up after achieving cCR or pCR, 26.0 [16.3-40.0] months). Individuals who were ICI responsive and nonresponsive did not significantly differ in human epidermal growth factor receptor 2 (ERBB2; formerly HER2 or HER2/neu) status, combined positive score, or claudin-18, isoform 2 (CLDN18.2), expression, whereas Lynch syndrome was more common in responders. Conclusions and Relevance: In this single-center cohort of dMMR GEA, ICI-based therapy demonstrated high response rates in both metastatic and locoregional settings. The durable responses in locoregional disease suggest the potential to consider nonoperative management in selected individuals. Further research is needed to improve prediction of ICI response and refine treatment strategies.