Immune Checkpoint Blockade Therapy in Patients With Colorectal Cancer Harboring Microsatellite Instability/Mismatch Repair Deficiency in 2022

Abstract

Immune checkpoint inhibitors (ICIs) are shown to be effective among patients with metastatic colorectal cancer (mCRC) harboring high microsatellite instability (MSI-H) and/or mismatch repair deficiency (dMMR), with U.S. Food and Drug Administration approvals for all lines of therapy. In Europe, only pembrolizumab in the first line and the combination of nivolumab and ipilimumab beyond the first line are approved. Many questions remain about the clinical management of MSI-H/dMMR CRC. Biomarkers predictive of immune checkpoint inhibitor resistance among MSI-H/dMMR tumors are needed (1) to select the best treatment for patients with CRC (anti–PD-[L]1 monotherapy alone or combined with anti–CTLA-4 or chemotherapy) and (2) to develop new treatment strategies for patients whose disease progressed after immune checkpoint inhibitor monotherapy. The development of immune checkpoint inhibitors in the adjuvant and neoadjuvant settings is also of great interest for patients harboring MSI-H/dMMR, especially as a substantial proportion have Lynch syndrome or are at high risk of developing cancers in their lifetime and sporadic MSI-H/dMMR cancers occur most frequently in elderly and frail patients. Thus, CRC is not one, but two different diseases: (1) MSI-H/dMMR CRC (seen in 5% of mCRC and 15% of non-mCRC), which is genetically unstable with a high mutational load and many neoantigens, and for which immune checkpoint inhibitors radically changed clinical management, and (2) microsatellite stable CRC with chromosomal instability, for which immune checkpoint inhibitors are not proven efficient.