Targeting KRAS^G12C in Non-Small-Cell Lung Cancer: Current Standards and Developments

Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRAS^G12C has revolutionized the treatment of KRAS^G12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRAS^G12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRAS^G12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRAS^G12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRAS^G12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRAS^G12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRAS^G12C-mutated NSCLC.