PD-1 inhibition alone or combined with CTLA-4 blockade in MSI-H/dMMR metastatic colorectal cancer: refining treatment intensity

Abstract

Abstract Immune checkpoint inhibition has revolutionized the management of microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), a biologically distinct subgroup characterized by high tumor mutational burden, neoantigen richness, and marked immune infiltration. Programmed death-1 (PD-1) inhibitors, such as pembrolizumab and nivolumab, have demonstrated durable responses and improved outcomes compared with historical chemotherapy, including in the first-line setting. Nevertheless, a clinically relevant proportion of patients exhibit primary resistance or early progression on PD-1 monotherapy. This unmet need has driven interest in dual immune checkpoint blockade combining PD-1 and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibition. Mechanistically, CTLA-4 blockade enhances T-cell priming and repertoire diversification, complementing PD-1–mediated reinvigoration of tumor-infiltrating effector T cells. Clinical studies indicate that nivolumab plus ipilimumab is associated with higher objective response rates and longer progression-free survival compared to PD-1 monotherapy. Recent randomized data from the Checkmate 8HW trial suggest a clinically meaningful trend toward improved overall survival with combination therapy; however, overall survival data are not yet mature and definitive conclusions regarding survival benefit cannot be drawn.