Clinical Impact of Hepatic Impairment on the Pharmacokinetics of Sotorasib and its Major Metabolites: Implications for Dose Adjustment

Abstract Sotorasib is a small molecule KRAS G12C inhibitor approved for the treatment of KRAS G12C mutated locally advanced or metastatic non‐small cell lung cancer in adult patients. The effect of hepatic impairment on the pharmacokinetics (PK) of sotorasib and major metabolites M10, M18, and M24, safety, and tolerability after a single oral dose of 960 mg was assessed in a phase 1, parallel‐arm, multi‐center (US), open‐label study. Sotorasib AUC inf ratio for subjects with moderate (n = 7) or severe (n = 4) hepatic impairment relative to normal hepatic function (n = 7) was 0.746 (90% CI: 0.431–1.29) and 1.04 (0.545–1.97), respectively. C max ratio for moderate and sever hepatic impairment was 0.955 (0.512–1.78) and 1.43 (0.688–2.96), respectively. Mean t 1/2 values for sotorasib were similar in subjects with normal hepatic function and subjects with moderate or severe hepatic impairment. C max and AUC inf of M10 and M24 increased, while M18 decreased with increasing severity of hepatic impairment. Treatment‐emergent adverse events were mild in severity and no serious adverse events were reported. Overall, moderate or severe hepatic impairment did not considerably affect the exposure of sotorasib, M10, M18, and M24. This data supports that adjustments to sotorasib dosing are not indicated for moderate or severe hepatic impairment.