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

Abstract

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 (<i>n</i> = 123), patients with mild impairment (<i>n</i> = 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 (<i>n</i> = 27) had a GMR of 0.88. Patients in Asia ([<i>n</i> = 162] vs. outside [<i>n</i> = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [<i>n</i> = 61]), patients with mild impairment (<i>n</i> = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (<i>n</i> = 9) had a GMR of 0.94. Patients in Asia (<i>n</i> = 111) versus outside Asia (<i>n</i> = 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. <b><i>Conclusions:</i></b> 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.

Adverse Events of Immune Checkpoint Inhibitor-Based Therapies for Unresectable Hepatocellular Carcinoma in Prospective Clinical Trials: A Systematic Review and Meta-Analysis

“…The indirect comparison of safety data between CheckMate 040 cohort 5 (Child-Pugh B7/8 patients, except 1 Child-Pugh A6 patient in the sorafenib-naïve arm; nivolumab monotherapy) and CheckMate 040 cohorts 1 and 2 (98% Child-Pugh A) did not show a significant difference in trAE incidence between Child-Pugh A or B patients (Child-Pugh B cohort vs. Child-Pugh A cohort all-grade trAE incidence: 51 vs. 59%) [ 22 ]. Similar results were reported in a post hoc analysis for GO30140 and IMbrave150 trial (atezolizumab plus bevacizumab), where the investigators found patients with moderate hepatic impairment have similar trAE incidence compared to overall population (moderate hepatic impairment vs. overall population: 96.4 vs. 98.2%) [ 53 ]. There are currently no published articles on the impact of baseline liver function on trAE in patients under dual ICI therapy or ICIs plus oral targeted agents, but analyses focusing on oral targeted agent monotherapies indicate that impaired liver function would raise important safety issues in this subpopulation [ 54 , 55 , 56 ].…”

Efficient and relevant stepwise covariate model building for pharmacometrics

“…CRCL was calculated from the baseline serum creatinine using the Cockcroft–Gault formula 10 capping CRCL at 150 ml/min. The NCI liver function classification was based on bilirubin and ALT levels 11 …”

“…The NCI liver function classification was based on bilirubin and ALT levels. 11 In addition, food intake and formulation were considered as covariates and their values were given by the designs of the studies. Altogether, each subject was associated with 13 covariates.…”

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies

“…According to the IMbrave150 trial, atezolizumab in combination with bevacizumab showed greater benefits compared with sorafenib in advanced HCC patients and suggested that this combination strategy could be used as the first-line standard of care. [310][311][312][313] Additionally, a combination of ICB with other targeted therapeutic approaches, including ATR kinase inhibition and androgen receptor blockade resulted in synergistic therapeutic response in prostate cancer. [314][315][316] Combining chemotherapy with ICB can be used to extend a synergistic therapeutic effect.…”