Optimizing bevacizumab exposure in atezolizumab-based therapy for unresectable hepatocellular carcinoma: A nationwide real-world study

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab is administered for unresectable HCC, with bevacizumab dosed by body weight, which may not adequately reflect body composition. This study evaluated the association between body surface area (BSA)-adjusted bevacizumab dosing, expressed as the bevacizumab-BSA index (BBI), and outcomes. APPROACH AND RESULTS: This retrospective study included 1507 patients with unresectable HCC treated with atezolizumab plus bevacizumab at 30 Japanese institutions. BBI was the ratio of actual to standard dose per BSA. Restricted cubic spline analyses identified the optimal BBI range. Outcomes were compared among BBI groups. Spline analysis revealed a nonlinear association between BBI and overall survival (OS), with an optimal BBI range of 106%-121%. Accordingly, the patients were classified into under (n=924), target (n=522), and over (n=61) groups. The median progression-free survival was significantly longer in the target group than in the nontarget group (10.3 vs. 6.5 mo, p <0.001), and the median OS was prolonged (24.9 vs. 19.2 mo, p =0.008). Multivariable analysis demonstrated that the target BBI group was independently associated with improved progression-free survival (HR, 0.807; 95% CI: 0.715-0.910; p <0.001) and OS (HR, 0.850; 95% CI: 0.733-0.985; p =0.031). The objective response rate was significantly higher in the Target group ( p =0.023), while treatment-related adverse event rates were comparable across the BBI groups, with no significant differences in proteinuria, hypertension, or other toxicities. CONCLUSIONS: BSA-adjusted bevacizumab dosing was associated with improved efficacy without increased toxicity in patients with unresectable HCC treated with atezolizumab plus bevacizumab.