Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical 
development for the treatment of tumors with the KRAS p.G12C mutation. A 
comprehensive nonclinical safety assessment package, including secondary/safety 
pharmacology and toxicology studies, was conducted to support the marketing 
application for sotorasib. Sotorasib was negative in a battery of genotoxicity 
assays and negative in an in vitro phototoxicity assay. Based on in vitro 
assays, sotorasib had no off-target effects against various receptors, enzymes 
(including numerous kinases), ion channels, or transporters. Consistent with the 
tumor-specific target distribution (ie, KRASG12C), there were no primary 
pharmacology-related on-target effects identified. The kidney was identified as 
a target organ in the rat but not the dog. Renal toxicity in the rat was 
characterized by tubular degeneration and necrosis restricted to a specific 
region suggesting that the toxicity was attributed to the local formation of a 
putative toxic reactive metabolite. In the 3-month dog study, adaptive changes 
of hepatocellular hypertrophy due to drug metabolizing enzyme induction were 
observed in the liver that was associated with secondary effects in the 
pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct 
effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat 
circulating metabolites, M24, M10, and M18, raised no clinically relevant safety 
concerns based on the general toxicology studies, primary/secondary pharmacology 
screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity 
assessment. Overall, the results of the nonclinical safety program support a 
high benefit/risk ratio of sotorasib for the treatment of patients with KRAS 
p.G12C-mutated tumors.