An evaluation of sotorasib for the treatment of patients with non–small cell lung cancer with KRASG12C mutations

Abstract

ABSTRACT Introduction Improving the clinical outcomes of patients with KRASG12C -mutated non-small cell lung cancer (NSCLC), the majority of whom are current or former smokers, has been a barrier to improving population-level outcomes in NSCLC. Novel and effective KRASG12C inhibitors are emerging, and sotorasib is the first member of that class to achieve commercial availability. Areas covered In this review, we survey the epidemiology of KRASG12C -mutated NSCLC, as well as sotorasib’s chemistry, pharmacology, and clinical trial data. Expert opinion While sotorasib’s development has been unique and exciting, questions persist regarding its intracranial penetrance, optimal dose, and efficacy relative to standard-of-care therapy. Improvements in the clinical activity of KRAS inhibition will hinge on better understanding of resistance mechanisms, the development of broad-spectrum inhibitors with activity beyond G12C mutations, and combination therapy targeting multiple mediators of KRAS signaling and alternative pathways. From a regulatory perspective, sotorasib’s development may, in time, prove to be an instructive example for early-phase clinical trialists and regulators focused on dose optimization.