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

<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.

<b><i>引言：</i></b> 1b期GO30140研究与3期IMbrave150研究评估了一线阿替利珠单抗（atezolizumab）联合贝伐珠单抗（bevacizumab）治疗不可切除肝细胞癌（hepatocellular carcinoma, HCC）的方案。本研究按肝功能损害状态及地域维度，评估了其药代动力学（pharmacokinetics, PK）特征与安全性。<b><i>方法：</i></b> 患者接受阿替利珠单抗1200mg联合贝伐珠单抗15mg/kg，每3周静脉输注。采用描述性统计与群体药代动力学分析药物浓度。按肝功能损害状态及地域，评估药代动力学参数与不良事件发生率。<b><i>结果：</i></b> 共有323例IMbrave150患者与162例GO30140患者可纳入药代动力学分析。相较于按美国国家癌症研究所器官功能障碍工作组（National Cancer Institute Organ Dysfunction Working Group, NCI-ODWG）标准判定为肝功能正常的IMbrave150患者（<i>n</i> = 123），轻度肝功能损害患者（<i>n</i> = 171）的阿替利珠单抗第1周期浓度-时间曲线下面积（area under the concentration-time curve, AUC）的几何均数比值（geometric mean ratio, GMR）为0.92；中度肝功能损害患者（<i>n</i> = 27）的GMR为0.88。亚洲患者（<i>n</i> = 162）与非亚洲患者（<i>n</i> = 161）相比，阿替利珠单抗第1周期AUC的GMR为1.25。相较于按NCI-ODWG标准判定为肝功能正常的GO30140患者（<i>n</i> = 61），轻度肝功能损害患者（<i>n</i> = 92）的贝伐珠单抗第1周期峰浓度的GMR为0.97；中度肝功能损害患者（<i>n</i> = 9）的GMR为0.94。亚洲患者（<i>n</i> = 111）与非亚洲患者（<i>n</i> = 51）相比，贝伐珠单抗第1周期峰浓度的GMR为0.94。采用其他肝功能评估标准（Child-Pugh分级或白蛋白/胆红素标准）或纳入日本受试者的亚组分析中，药代动力学结果总体可比。未观察到阿替利珠单抗药代动力学与肝细胞癌病因学存在关联。各组不良事件发生率相似。<b><i>结论：</i></b> 纳入不可切除肝细胞癌患者的IMbrave150与GO30140研究中，受试者基线肝功能损害程度存在差异，且亚洲地区受试者入组比例较高。药代动力学数据显示，各组间药物暴露量重叠度较高。各组治疗耐受性良好。基于本分析结果，无需根据轻度或中度肝功能损害情况或地域调整给药剂量。