Impact of treatment discontinuation among patients with microsatellite instability or mismatch repair-deficient metastatic colorectal cancer treated with immune checkpoint inhibitors

BACKGROUND: The optimal duration of immune checkpoint inhibitor (ICI) treatment in patients with metastatic colorectal cancer (mCRC) with microsatellite instability/mismatch repair deficiency (MSI/dMMR) remains undefined. PATIENTS AND METHODS: We retrospectively analyzed data of 84 patients with MSI/dMMR mCRC treated with ICIs at any line of therapy who discontinued treatment for any reason. RESULTS: After a median follow-up period of 48 months, 51% of patients stopped treatment due to disease progression and 49% discontinued for other reasons, including immune-related adverse events, clinical benefit, protocol completion (2 years), surgery, or pregnancy. Among patients who discontinued without progression, treatment cessation did not negatively impact progression-free survival or overall survival. Patients who achieved radiologic response and stopped without progression rarely relapsed. Liquid biopsy analysis using circulating tumor DNA (ctDNA) was available from 48 patients. Among those who stopped per protocol, nearly 80% had negative ctDNA at discontinuation, with only 7% of them progressing during follow-up. Conversely, among those patients who progressed, 78.3% had positive liquid biopsy results at treatment discontinuation, underscoring the complexity of molecular monitoring. CONCLUSIONS: These findings support the safety of early ICI discontinuation (<2 years) in responding patients and suggest that ctDNA may aid in identifying optimal stopping points. However, due to the retrospective design and limited sampling, these results should be interpreted as hypothesis-generating. Prospective studies are required to define the precise role of ctDNA in guiding ICI duration in dMMR/MSI mCRC.