KRASG12C inhibition in colorectal cancer

For years, patients with metastatic colorectal cancer were considered and treated as a single biological entity. Since the association between activated RAS mutations and low efficacy of anti-epidermal growth factor receptor (EGFR) therapy became evident, it has been recommended that all patients with metastatic colorectal cancer are routinely tested for RAS mutations. Mutations in RAS are one the most frequent oncogenic drivers in human cancers, with a frequency of nearly 50% in patients with metastatic colorectal cancer dominated by mutations in KRAS codon 12, but KRASG12C is only present in 3% of patients with metastatic colorectal cancer. 1 Henry JT Coker O Chowdhury S et al. Comprehensive clinical and molecular characterization of KRASG12C-mutant colorectal cancer. JCO Precis Oncol. 2021; 5: 613-621 Crossref Scopus (16) Google Scholar In metastatic colorectal cancer, RAS mutations indicate poor prognosis, but patients with KRASG12C might have an even shorter overall survival than those with non-KRASG12C mutations. 1 Henry JT Coker O Chowdhury S et al. Comprehensive clinical and molecular characterization of KRASG12C-mutant colorectal cancer. JCO Precis Oncol. 2021; 5: 613-621 Crossref Scopus (16) Google Scholar Until recently, abnormal RAS proteins were regarded as undruggable. However, in 2013, a breakthrough reported the development of small molecules that selectively and irreversibly bind to KRASG12C, and so far, early results of phase 2 studies of the two KRASG12C inhibitors, sotorasib and adagrasib, have been reported. 2 Ostrem JM Peters U Sos ML et al. (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013; 503: 548-551 Crossref PubMed Scopus (1201) Google Scholar Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trialAlthough the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. Full-Text PDF