Clinical Significance of Anti-Atezolizumab Antibodies in Patients With Unresectable Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

[AIM] Systemic therapy is required for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab (ATZ/BEV) is the recommended first-line treatment for HCC; however, the development of anti-drug antibodies (ADAs) against ATZ may impair its therapeutic efficacy. Although ADAs have been reported in other cancers treated with immune checkpoint inhibitors, the incidence and clinical relevance in HCC remain unclear.

[METHODS] We retrospectively analyzed 50 patients with unresectable HCC who received ATZ/BEV between April 2020 and December 2024. Serum samples were obtained at baseline and after treatment initiation, primarily at the third cycle, and ATZ-ADA levels were measured using ELISA. Tumor response was assessed by modified RECIST, and survival was evaluated by the Kaplan-Meier method and Cox regression analysis.

[RESULTS] Median ATZ-ADA levels after treatment initiation were higher in patients with progressive disease than in those with disease control (0.46 vs. 0.37, p = 0.02). Longitudinal analysis demonstrated a greater increase in ATZ-ADA levels from baseline in the progressive group (p = 0.04) than that in the other groups. ROC analysis identified a cutoff of 0.40 for predicting progression (AUC = 0.69), and 17 patients (34%) were classified as ATZ-ADA-positive (OD value ≥ 0.40). Progression-free survival (PFS) was significantly shorter in the ATZ-ADA-positive group than in the ATZ-ADA-negative group (3.8 vs. 9.4 months, HR = 2.24, p = 0.03), whereas no difference was observed in overall survival.

[CONCLUSIONS] ATZ-ADAs were detected in 34% of patients with unresectable HCC and were associated with inferior PFS. ATZ-ADAs may serve as a promising biomarker for predicting treatment response and optimizing therapeutic strategies in HCC.