BackgroundPatients with microsatellite-high (MSI-H) metastatic colorectal cancers (CRC) may experience long-lasting benefit from immune checkpoint inhibitors (ICI) upon stopping therapy. However, optimal timing and patient selection criteria for early treatment withdrawal remain undefined. In this single-center retrospective study, we characterized the clinical response and associated survival outcomes of patients who received elective early versus late treatment discontinuation. MethodsWe retrospectively analyzed patients with MSI-H metastatic CRC treated with ICI therapy from May 2015 to April 2024. Early ICI discontinuation was defined as treatment withdrawal before two years, and late ICI discontinuation as after two years. Response was assessed using Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan Meier method. Efficacy outcomes between early and late ICI discontinuation groups were compared using a log-rank test. ResultsOf 36 patients with MSI-H metastatic CRC, 12 underwent elective early ICI discontinuation and 9 experienced late ICI discontinuation. After a median follow-up of 32 months post-treatment, 91.7% (11/12) in the early discontinuation group remain off therapy without progression. PFS and OS outcomes between the early and late discontinuation groups were similarly favorable (p=0.88 and p=0.85, respectively), despite a 12-month difference in median duration of ICI therapy (13.3 and 25.6 months, respectively). The most common reason for elective early treatment discontinuation was clinical remission (n=10), defined as a complete response, or a partial response with negative PET and/or ctDNA testing. ConclusionsEarly ICI discontinuation guided by response criteria resulted in low rates of recurrence. Survival outcomes between early and late ICI discontinuation groups were comparable, suggesting that treatment duration can be individualized based on clinical response without compromising favorable long-term prognosis. Micro abstractImmune checkpoint inhibitors offer the potential for long-term benefit in microsatellite instability-high metastatic colorectal cancers. In this retrospective analysis, patients who electively discontinued immunotherapy early due to an objective response or clinical remission—determined by CT, PET and/or circulating tumor DNA—rarely experienced disease progression. Using response as a criterion for early treatment withdrawal may allow for individualized therapy without compromising long-term clinical benefit.