4029 Background: Clinical trials of first-line (1L) immunotherapy (IO) in gastroesophageal cancer (GEC) demonstrate greater benefit in patients with microsatellite instability–high or mismatch repair–deficient (MSI-H/dMMR) tumors compared with the overall trial population. However, the benefit is not universal, and outcomes remain suboptimal for a subset of patients. Real-world (RW) evidence describing outcomes with 1L IO in MSI-H/dMMR GEC is limited. This study characterized treatment patterns and outcomes among RW MSI-H/dMMR GEC patients treated with 1L IO to better define residual unmet need. Methods: Using the Flatiron Health electronic health record-derived deidentified database, adults (≥18 years) diagnosed with locally advanced unresectable, metastatic, or recurrent gastric (GC), gastroesophageal junction (GEJ), or esophageal cancer (EC) between 17 Apr 2021 and 31 Dec 2024 were identified. Patients were required to have documented MSI-H or dMMR status and no trastuzumab exposure. Data were available through 08 Sep 2025. Time to next treatment or death served as a RW proxy for progression. Results: Among 3,047 eligible patients, MSI-H/dMMR prevalence varied by disease site and stage, ranging from 5.8% in metastatic GC to 17.6% in locally advanced GC; from 2.4% to 10.4% in GEJ disease; and from 3.4% to 4.4% in EC. A total of 199 MSI-H/dMMR GEC patients were identified (median age 75 years IQR 66–82; 36% female; 37% metastatic at diagnosis; 95% adenocarcinoma). Of the 155 MSI-H/dMMR patients who received 1L therapy, 32% received IO alone, 31% IO plus chemotherapy, and 37% chemotherapy alone. Among patients treated with 1L IO ± chemotherapy, 37% initiated 2L therapy or died within 6 months, increasing to 47% and 54% by 9 and 12 months, respectively. Baseline characteristics were largely similar between patients with and without progression within the first 12 months (Table). Conclusions: In this real-world cohort of MSI-H/dMMR GEC patients, a substantial proportion experienced early treatment failure despite 1L IO. More than one-third initiated second line therapy or died within 6 months, and over half progressed or died within 1 year. These findings underscore heterogeneity in benefit from 1L IO and highlight an ongoing need for improved risk stratification and alternative precision-based treatment approaches. Characteristics of MSI-H/dMMR GEC patients by progression status at 12 months post start of 1L IO therapy. ProgressorsN=35 Non-progressors**N=30 Age, Median IQR 72 66, 83 73 64, 80 Female, % 34.3 40.0 Location, % GC 62.9 63.3 GEJ 8.6 13.3 EC 28.6 23.3 Status*, % Metastatic 48.6 46.7 Non-metastatic 45.8 50.0 ECOG at 1L*, % 0/1 25.7 26.7 2+ 57.1 50.0 *Some patients are missing disease status and/or ECOG. **Patients included in non-progressors were required to have activity in the data at least 12 months after 1L IO initiation.
Rhodes et al. (Wed,) studied this question.