Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer: Current Status, Recent Advances, and Future Directions

Immune checkpoint inhibitors have shown very promising outcomes in the subset of metastatic colorectal cancers (CRCs) that are mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H). We reviewed the existing literature on immune checkpoint inhibitors in colorectal cancers to highlight the recent advances and future directions. The significance of immune check point inhibitors in dMMR/MSI-H metastatic CRCs has been validated by several studies employing anti-programmed death cell receptor (anti-PD1) and anti-PDL1 antibodies single agent or in combination with anti-CTLA4 antibodies (“KEYNOTE” and “CHECKMATE” studies). This has led to FDA approval of these drugs. At present, its approval is limited to those who have failed traditional chemotherapy (5-FU, oxaliplatin, and irinotecan). The trials for the dMMR/MSI-H CRCs are now being moved up in terms of first-line, neoadjuvant, and adjuvant settings. The results of various studies favor the excellent antitumor activity and safety profile of anti PD-1 monoclonal antibodies that include pembrolizumab and nivolumab in MSI-H colorectal cancer. Combination immunotherapy with nivolumab and ipilimumab has also shown significant clinical benefit in dMMR/MSI-H metastatic CRC patients. These have now been FDA-approved. Multiple ongoing studies assessing the safety and efficacy of other anti-PD/PD-L1 agents (e.g., durvalumab, atezolizumab) alone or in combination therapy with classes of drugs are in progress. The goal ideally would be to identify approaches to expand activity of immune checkpoint inhibitors beyond the dMMR/MSI-H subset of CRC, which represent 4–5% of metastatic CRC patients. These are also being moved up in terms of usage in earlier lines of therapy and neoadjuvant/adjuvant approaches.