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

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Pharmacological KRAS inhibition is a promising new approach to the treatment of many kinds of cancer.