Tackling KRASG12C-mutated non-small-cell lung cancer: iteration and exploration

Despite rat sarcoma virus (RAS) oncogenes being the first identified, RAS-driven cancers have remained one of the greatest challenges in oncological drug development. The landmark discovery by Shokat and colleagues 1 Ostrem JM Peters U Sos ML Wells JA Shokat KM K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013; 503: 548-551 Crossref PubMed Scopus (1606) Google Scholar of an allosteric drug-binding pocket in GDP-bound KRASG12C (ie, Gly12Cys) has led to accelerated approvals by the US Food and Drug Administration for the use of two covalent inhibitors, sotorasib and adagrasib, post chemoimmunotherapy in advanced KRASG12C-mutated non-small-cell lung cancers (NSCLCs). This breakthrough has ushered in a new era of RAS drug discovery. 2 Luo J Ostrem J Pellini B et al. Overcoming KRAS-mutant lung cancer. Am Soc Clin Oncol Educ Book. 2022; 42: 1-11 PubMed Google Scholar Garsorasib in patients with KRASG12C-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 2 trialThe results show that garsorasib has a high response rate, long duration of response, and an acceptable and manageable safety profile in patients with previously treated KRASG12C-mutated NSCLC. Garsorasib potentially provides a promising treatment option for this patient population. Full-Text PDF