Real-world evidence of lower-dose intensity of immune checkpoint inhibitors in MSI-H/dMMR gastrointestinal cancers from a resource-constrained setting.

Background: Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) gastrointestinal (GI) malignancies. However, in fragile settings, especially in low- and middle-income countries (LMIC) and areas of conflict, access remains severely limited by prohibitive costs and supply chain disruptions. Starting in late 2019, Lebanon's economic crisis led to health system collapse, currency devaluation, medication shortages, and ongoing conflict, which necessitated adaptive treatment strategies. Early pharmacodynamic studies suggest lower ICI doses may achieve comparable efficacy; however, real-world evidence from conflict-affected settings where dose reductions occur by necessity rather than design remains absent. This study examines ICI dosing outcomes during Lebanon's acute crisis period. Methods: We conducted a retrospective analysis of adult patients with metastatic MSI-H/dMMR GI cancers treated with ICIs at the American University of Beirut Medical Center between 2018 and 2024, encompassing Lebanon's economic collapse and acute health system fragility. Dose-intensity was calculated as the percentage of actual dose received compared to the recommended dose. Patients were stratified into <75% and ≥75% dose-intensity groups based on actual doses delivered under resource constraints. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and immune-related adverse events (irAEs). Exploratory endpoint was overall survival (OS). Results: Twenty-nine patients were included, 19/29 patients (65.5%) had colorectal cancer. 18/29 patients (62%) received ≥75% of the recommended dose-intensity, while eleven (38%) received <75%. ORR was 63.6% and 66.7% respectively (p = 0.362), while CBR was 90.9% and 72.2% respectively. No statistically significant difference in PFS or OS was observed. All irAEs (n=4; 14%) occurred in patients receiving ≥75% dose-intensity and included grade 3 diarrhea, grade 3 interstitial nephritis and erythroderma and grade 2 polyarthritis. Conclusions: In LMIC with a conflict-affected health system and experiencing medication shortages and economic collapse, lower dose-intensity ICIs may be feasible for MSI-H/dMMR GI malignancies, offering a pragmatic approach to maintain treatment continuity when standard dosing is inaccessible. These findings are exploratory, highlighting the need for larger prospective studies and the importance of integrating health system context, resilience, and adaptation into oncology research in fragile settings.