Management of KRAS-mutated non-small cell lung cancer.

ABSTRACT

Kirsten rat sarcoma virus (KRAS) is the most frequently mutated oncogene in human cancers, particularly in non-small cell lung cancer (NSCLC), where mutations are present in 32% of lung adenocarcinoma and 4% of squamous cell lung cancer. The most common KRAS variant is KRAS G12C, which accounts for nearly 40% of all KRAS mutations. Although it is the most common oncogenic driver in NSCLC, KRAS was considered a "nondruggable target" until recently, owing to the lack of any progress in developing targeted therapies for this oncogene. With the recent development and approval of selective KRAS G12C inhibitors such as sotorasib and adagrasib for the treatment of advanced or metastatic NSCLC in the second-line setting and beyond, the standard of care for managing these tumors has undergone a significant change. Mechanisms of resistance to KRAS G12C inhibitors are highly heterogeneous, including both on-target and off-target resistance as well as morphologic switching, thus limiting the activity of these drugs when used as monotherapy. New-generation inhibitors and different combination strategies are being developed in early-phase trials to overcome or delay the onset of resistance as well as to target non-G12C mutations. Owing to the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualized based on factors such as co-occurring mutations.