PI-101 - AN OPEN-LABEL SINGLE-DOSE STUDY TO EVALUATE THE PHARMACOKINETICS OF SOTORASIB IN HEALTHY SUBJECTS AND SUBJECTS WITH MODERATE OR SEVERE HEPATIC IMPAIRMENT.

M. McComb, C. Terrio, J. Purkis, T. Varrieur, S. Dutta, B. Houk; Amgen Inc., Thousand Oaks, CA, USA.

Background: Sotorasib is a small molecule KRASG12C inhibitor approved for the treatment of KRASG12C-mutated locally advanced or metastatic NSCLC in adult patients. This study evaluated the need for dosing adjustments in subjects with moderate hepatic impairment (HI, Child-Pugh B) and severe HI (Child-Pugh C).

Methods: This Phase 1, parallel-arm, multi-center (US), open-label, non-randomized study enrolled 7 healthy, 8 moderate HI and 4 severe HI subjects. All subjects received a single oral dose of 960 mg sotorasib administered under fasted conditions. Blood samples were collected predose and up to 168 hours post dose. Total sotorasib plasma concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. PK parameters were estimated using non-compartmental methods. Safety and tolerability were monitored throughout the study.

Results: The geometric least squares means (GLSM) ratios and 90% confidence interval for test/reference of AUCinf, AUClast and Cmax for subjects with moderate HI compared to subjects with normal hepatic function (HF) were 0.746 (0.431, 1.29), 0.749 (0.431, 1.30), and 0.955 (0.512, 1.78), respectively. The GLSM ratios for subjects with severe HI compared to subjects with normal HF were 1.04 (0.545, 1.97), 1.04 (0.544, 1.99), and 1.43 (0.688, 2.96), respectively. Arithmetic mean t1/2 values for sotorasib were similar in subjects with normal HF and subjects with moderate or severe HI.
Single doses of sotorasib were safe and well tolerated when administered to healthy subjects with normal HF and subjects with moderate or severe HI.

Conclusion: The effect of moderate or severe HI on total sotorasib pharmacokinetics is minimal and no dose adjustments are required for sotorasib in moderate or severe HI patients.