Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) provide durable benefit in high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) gastrointestinal (GI) tumors, but real-world evidence across colorectal cancer (CRC) and non-CRC primaries remains limited. MATERIALS AND METHODS: We conducted a multicenter retrospective study including 122 patients with advanced MSI-H/dMMR GI tumors treated with ICIs in eight Spanish university hospitals. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), response, and safety. RESULTS: Median age at ICI initiation was 70.4 years; 79.5% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1. CRC accounted for 54.9% of cases, gastroesophageal adenocarcinoma (GEA) for 34.4%, and other GI tumors for 10.7%. At a median follow-up of 33 months, median PFS was 46.0 months [95% confidence interval (CI) 30.6-61.4 months] and median OS was 53.2 months (95% CI 42.6-63.7 months), with 36-month rates of 57.1% for PFS and 62.8% for OS. The objective response rate (ORR) was 77.7% and the disease control rate (DCR) was 91.1%, with comparable efficacy across CRC, GEA, and other GI tumor subgroups. In multivariable analysis, ECOG PS was the only independent prognostic factor for both OS and PFS. Treatment was generally well tolerated; 47.5% of patients experienced adverse events, grade ≥3 in 10.7%, with no treatment-related deaths. CONCLUSIONS: In this multicenter European real-world cohort, ICIs demonstrated clinically meaningful and durable benefit in advanced MSI-H/dMMR GI tumors, confirming pivotal trial results in routine practice. ECOG PS emerged as the main independent prognostic factor, underscoring its central role in patient selection.