Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers

Simple Summary Non-small-cell lung cancers (NSCLCs) are commonly diagnosed malignancies with poor prognosis. Kirsten rat sarcoma virus (KRAS) mutations are often observed in NSCLC and have classically been proven difficult to target. New targeted therapies for KRAS mutations (sotorasib, adagrasib) have become available to patients with NSCLC as of 2020. In this review, we assess the current evidence for these medications in terms of efficacy and safety, as well as future directions for these therapies.Abstract Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.