The Pharmacologic Inhibition of KRAS Mutants as a Treatment for Cancer: Therapeutic Principles and Clinical Results.

Abstract

Mutations of the KRAS oncogene are found in up to 20% of all cancers, and particularly in non-small-cell lung cancer (NSCLC) (20-40%) and colorectal cancer (CRC) (30-50%). Inhibitors of specific KRAS mutants have recently become available and are now a part of routine care. This review is based on articles published in the past 5 years that were retrieved by a selective search in PubMed for clinical trials of the pharmacological inhibition of KRAS. Sotorasib and adagrasib have already been approved, on the basis of two randomized phase III trials, as specific inhibitors of the KRASG12C mutant for palliative second-line treatment. Compared to standard chemotherapy with docetaxel, both drugs significantly prolonged progression-free survival (PFS): 5.6 months (95% confidence interval [4.3; 7.8]) for sotorasib versus 4.5 [3.0; 5.7] for docetaxel, and 5.5 months [4.5; 6.7] for adagrasib versus 3.8 [2.7; 4.7] for docetaxel. Sotorasib was also found to cause fewer severe adverse drug events (33%, versus 40% with docetaxel). The most common ones were diarrhea and elevated liver enzymes. For already treated CRC, sotorasib combined with the anti-epidermal growth factor receptor (anti-EGFR) antibody panitumumab was found, in a randomized phase III trial, to prolong progression-free survival significantly compared to standard therapy with triflurdin/tipiracil or regorafenib (5.6 months [4.2; 6.3] versus 2.2 months [1.9; 3.9]), while also improving patients' quality of life. Approval by the European Medicines Agency is pending. Further KRAS and pan-RAS inhibitors are now in early clinical development. Pharmacological KRAS inhibition is a promising new approach to the treatment of many kinds of cancer.