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 KRASG12C 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.
Submitted February 14, 2024; final revision received August 5, 2024; accepted for publication August 15, 2024. Published online January 3, 2025.
Disclosures: Dr. Deming has disclosed receiving grant/research support from Merck, Genentech, Bristol Myers Squibb, Aadi Bioscience, Pfizer, Curegenix, Promega Corporation, Natera, Strata Oncology, Cornerstone Pharmaceuticals, Arcus Biosciences, Guardant Health, Ipsen, Takeda Pharmaceuticals, Eli Lilly, Revolution Medicines, and Mirati Therapeutics; and serving as a scientific advisor for Bayer, Pfizer, Seagen, Eli Lilly, Foundation Medicine, Illumina, Regeneron Pharmaceuticals, and Aadi Bioscience.
Funding: This study was funded by the JD Fluno Colorectal Cancer Precision Medicine Program and the ACI/Schwenn Family Professorship.