Checkpoint inhibitors in microsatellite instability-high metastatic colorectal cancer: treatment strategies, specificities, and care management questions

For patients with metastatic colorectal cancer (mCRC), defective mismatch repair (dMMR) or microsatellite instability-high (MSI-H) status strongly predicts benefit from immune checkpoint inhibitors (ICIs). Based on the phase III KEYNOTE-177 and CheckMate 8HW trials, first-line treatment with ICIs, either anti-PD-1 monotherapy or anti-PD-1 + anti-CTLA-4 combination therapy, has become the standard of care for these patients. Combination ICIs offer superior efficacy compared with anti-PD-1 monotherapy, at the cost of a moderate increase in toxicity, particularly endocrine-related toxicities. However, 10%-30% of patients exhibit primary resistance, and secondary resistance may develop during or after treatment, highlighting the urgent need for reliable predictive biomarkers and diagnostic tools to guide personalized treatments. In case of early disease progression occurs during ICI treatment, initial priorities include confirming the MSI-H/dMMR status and identifying pseudo-progression. This review addresses the major challenges in the clinical management of patients with MSI-H/dMMR mCRC. Key questions include: What are the specificities of care for these patients? What is the optimal ICI treatment duration, and what is the role of surgery/local treatment in case of residual mass after ICI treatment? Which therapeutic options should be proposed in case of progression under ICI and in patients with tumoral BRAF V600E mutation? Are there biological, molecular, genetic, or clinical factors that can predict response? Does circulating tumor DNA hold promise for guiding personalized immunotherapy decisions? This review aims to address these questions, while acknowledging that many remain unanswered and are the focus of numerous ongoing studies.