Immunotherapy in Colorectal Cancer: Novel Perspectives and Next Steps

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the second leading cause of cancer-related mortality. Currently, only about 15% of newly diagnosed CRC cases and 5% of metastatic cases are classified as being microsatellite instability-high (MSI-H) and can benefit significantly from immune checkpoint blockade, while the majority of patients are microsatellite stable (MSS) and typically show limited responses to this strategy. This review aims to describe recent advances and emerging perspectives regarding the use of novel checkpoint inhibitors for MSS CRC. We conducted a structured review and critical analysis of the most relevant evidence on immunotherapy in CRC. Particular focus was placed on response outcomes in MSS CRC populations treated with enhanced anti-CTLA-4 antibody botensilimab (BOT) and the anti-PD-1 antibody balstilimab (BAL). The combination of BOT+BAL has shown promising efficacy in heavily pretreated or refractory CRC, with objective response rates up to 20% and disease control rates around 60%. In the neoadjuvant setting, the BOT+BAL regimen has produced unprecedented pathologic complete response (pCR) rates for MSS CRC tumors, achieving a pCR rate of up to 40% and partial responses up to 71%. Treatment was associated with manageable toxicity and no surgical delays, resulting in downstaging levels that may spare surgery and/or adjuvant chemotherapy. Current evidence suggests a potential shift in the therapeutic landscape of CRC. Immunotherapy benefits may extend beyond MSI-H tumors, offering new possibilities for the broader population of patients with MSS CRC.