Development of KRAS Inhibitors and Their Role for Metastatic Colorectal Cancer

Colorectal cancer (CRC) is a heterogeneous group of diseases comprising several molecular subtypes. Comprehensive DNA sequencing is now standard practice to identify these subtype. Until recently, KRAS mutation status in metastatic CRC was primarily used as a biomarker to predict resistance to EGFR inhibition. However, with up to 40% of CRC cases harboring KRAS mutations, therapeutic targeting of RAS has been an area of great need. The development of KRAS G12C inhibitors has led to the FDA approval of drugs for treating non–small cell lung cancer. Recently, these and other newly developed inhibitors have been investigated as monotherapies and in combination for metastatic KRAS G12C -mutant CRC. This review examines the development of these inhibitors and highlights data supporting the inclusion of sotorasib and adagrasib, in combination with either panitumumab or cetuximab, in the NCCN Guidelines for CRC for the treatment of refractory metastatic disease.