Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region

Colby S Shemesh; Phyllis Chan; Hui Shao; Derek-Zhen Xu; Daniel Combs; Shweta Vadhavkar; René Bruno; Benjamin Wu

doi:10.1159/000515817

Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region

Liver Cancer. 2021 Jun 10;10(5):485-499. doi: 10.1159/000515817. eCollection 2021 Sep.

Authors

Colby S Shemesh¹, Phyllis Chan¹, Hui Shao², Derek-Zhen Xu³, Daniel Combs¹, Shweta Vadhavkar¹, René Bruno⁴, Benjamin Wu¹

Affiliations

¹ Department of Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA.
² Safety Science, F. Hoffmann-La Roche Ltd., Beijing, China.
³ Product Development Oncology, F. Hoffmann-La Roche Ltd., Shanghai, China.
⁴ Clinical Pharmacology, Genentech-Roche, Marseille, France.

Abstract

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region.

Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region.

Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups.

Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

Keywords: Atezolizumab; Bevacizumab; Clinical pharmacology; Geographic region; Hepatic impairment.