Immunotherapy

Approximately 4% of patients with stage IV colorectal cancer have tumors that are mismatch repair deficient (dMMR) or microsatellite unstable/MSI-H. The MSI-H phenotype is associated with germline defects in the MLH1, MSH2, MSH6, and PMS2 genes and is the primary phenotype observed in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Patients can also have the MSI-H phenotype because one of these genes was silenced via DNA methylation. Testing for microsatellite instability can be done with molecular genetic tests, which look for microsatellite instability in the tumor tissue, or with immunohistochemistry, which looks for the loss of mismatch repair proteins. MSI-H status has historically been prognostic of increased survival for patients with earlier-stage disease and since 2015, has also been found to predict tumor response to checkpoint inhibition.

The FDA approved pembrolizumab for use in patients with treatment-naïve, metastatic, dMMR/MSI-H colorectal cancer in 2020. Studies regarding first-line treatment with dual checkpoint inhibitors are ongoing. The FDA approved the anti-programmed cell death protein 1 (PD-1) antibodies pembrolizumab in 2017 and nivolumab in 2017 for the treatment of patients with microsatellite-unstable tumors who had previously received 5-FU, oxaliplatin, and irinotecan-based therapy. In 2018, the FDA granted accelerated approval for the combination of nivolumab with ipilimumab (a CTLA-4 inhibitor) to treat MSI-H colorectal cancers that progressed after prior 5-FU, oxaliplatin, and irinotecan-based therapies.