Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments

AbstractAmong 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 inhibitingKRAS or its signaling pathways,KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region ofKRASG12C has revolutionized the treatment ofKRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, directKRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treatedKRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment inKRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment withKRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. NewKRASG12C 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 ofKRAS, and outline different treatment approaches, focusing on the novel treatment ofKRASG12C-mutated NSCLC.
Source: Drugs - Category: Drugs & Pharmacology Source Type: research