Non–small-cell lung cancer (NSCLC) accounts for 85% of the 2.2 million new cases of lung cancer diagnosed in 2020. At the time of diagnosis, 75% of these cases are in the advanced stage, which has historically been associated with poor survival. Recently, key driver mutations of this cancer type have been discovered along with small molecules that inhibit these drivers. This has improved treatment options and outcomes of subsets of patients with advanced NSCLC.
The first targetable driver mutation discovery was the tyrosine kinase domain of the epidermal growth factor receptor gene (EGFR). Other targetable driver mutations were subsequently discovered, including the anaplastic lymphoma kinase gene (ALK), the c-Ros-1 proto-oncogene (ROS1), the B-Raf proto-oncogene (BRAF), the c-Met proto-oncogene (MET), the Ret proto-oncogene (RET), and gene fusions in the neurotrophic tyrosine receptor kinase gene (NTRK). The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend testing for these mutations in patients with advanced NSCLC to direct treatment with targeted therapies. However, there are low testing rates despite this recommendation.
The NCCN also recommends testing be performed for the Kirsten rat sarcoma viral oncogene (KRAS), as this is the most common oncogenic driver in advanced NSCLC. KRAS is found in 30% of tumors in Western countries. KRAS G12C accounts for 44% of KRAS mutations. KRAS G12C is found in 10% to 13% of all patients with advanced NSCLC. An article by Veluswamy and colleagues summarized recent discoveries in KRAS biology that have led to the development of KRAS-targeted therapies.
KRAS G12C is more common in former or current smokers and can co-occur with other mutations, creating KRAS subtypes that may impact response to therapy and clinical outcomes. Patients with KRAS G12C have a significantly worse 2-year survival compared with patients with non-KRAS G12C subtypes. With recent advances in the understanding of KRAS biology and structure, novel therapy strategies have been developed for treating NSCLC harboring the KRAS mutation. Two small-molecule inhibitors that selectively and irreversibly bind to the pocket of KRAS G12C have shown efficacy in treating KRAS G12C-mutant NSCLC.
Sotorasib has recently received US Food and Drug Administration approval, and adagrasib is being evaluated in phase 1 and 2 clinical trials. Rigosertib, which functions as a KRAS mimetic, disrupts RAF/MEK, PI3K, and RalGDS signaling, inhibiting tumor growth. Rigosertib combined with nivolumab is in an early-phase trial and is demonstrating promising results.
These promising new therapies indicate a need for routine testing for KRAS mutations in patients with this lung cancer subtype to better target frontline therapy.
Veluswamy R, Mack PC, Houldsworth J, et al. KRAS G12C-mutant non-small cell lung cancer: biology, developmental therapeutics, and molecular testing. J Mol Diagn. 2021;23:507-520.