Sotorasib is a first-in class KRASG12C covalent inhibitor in clinical 
development for the treatment of tumors with the KRAS p.G12C mutation. In the 
nonclinical toxicology studies of sotorasib, the kidney was identified as a 
target organ of toxicity in the rat but not the dog. Renal toxicity was 
characterized by degeneration and necrosis of the proximal tubular epithelium 
localized to the outer stripe of the outer medulla (OSOM), which suggested that 
renal metabolism was involved. Here, we describe an in vivo mechanistic rat 
study designed to investigate the time course of the renal toxicity and 
sotorasib metabolites. Renal toxicity was dose- and time-dependent, restricted 
to the OSOM, and the morphologic features progressed from vacuolation and 
necrosis to regeneration of tubular epithelium. The renal toxicity correlated 
with increases in renal biomarkers of tubular injury. Using mass spectrometry 
and matrix-assisted laser desorption/ionization, a strong temporal and spatial 
association between renal toxicity and mercapturate pathway metabolites was 
observed. The rat is reported to be particularly susceptible to the formation of 
nephrotoxic metabolites via this pathway. Taken together, the data presented 
here and the literature support the hypothesis that sotorasib-related renal 
toxicity is mediated by a toxic metabolite derived from the mercapturate and 
β-lyase pathway. Our understanding of the etiology of the rat specific renal 
toxicity informs the translational risk assessment for patients.