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

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.

Fig. 1

Phase 3 IMbrave150 (a) and phase 1 GO30140 (b) study designs and flowcharts of the analysis populations. The hepatic function refers to that defined by the NCI-ODWG criteria. For purposes of PK and safety assessments, the current analysis includes patients in Japan as part of the Asia subgroup (for geographic region). AFP, α-fetoprotein; BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; ITT, intention to treat; MVI, microvascular invasion; NCI-ODWG, National Cancer Institute Organ Dysfunction Working Group; PK, pharmacokinetic; Q3W, every 3 weeks; ROW, rest of world. ^aTwo patients with severe hepatic impairment were not included in subgroup analyses.

Fig. 2

PK of atezolizumab and bevacizumab by hepatic function (a, c) and geographic region (b, d) following single and multiple administrations of atezolizumab 1,200 mg with bevacizumab 15 mg/kg Q3W in patients with HCC. Box plots include the median, 25th, and 75th percentiles for values at indicated visits, and whiskers refer to 10th and 90th percentiles, with outliers (open circles) plotted as single points vertically. C_max, maximum concentration; HCC, hepatocellular carcinoma; PK, pharmacokinetics; Q3W, every 3 weeks.