Second-Line and Subsequent Therapies after Atezolizumab Plus Bevacizumab Treatment in Hepatocellular Carcinoma: A Multicenter Prospective Cohort Study

Background/Aims: Optimal second-line (2L) and third-line (3L) systemic therapies after first-line (1L) atezolizumab plus bevacizumab (AtezoBev) for advanced hepatocellular carcinoma (HCC) remain undefined. This prospective multicenter study evaluated the efficacy and safety of various 2L and 3L systemic therapies following AtezoBev. Methods: We enrolled 94 patients with advanced HCC who were intolerant of or progressed to 1L AtezoBev treatment from four hospitals in Korea. Five patients who did not receive 2L therapy were excluded, and the remaining 89 patients were analyzed. Survival outcomes were analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Results: Among the 89 analyzed patients, median progression-free survival (PFS) was significantly longer in those who received 2L-lenvatinib compared to 2L-sorafenib (5.5 months vs 3.2 months: hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.24 to 0.77; p=0.005) or 2L-regorafenib (4.7 months), while median overall survival (OS) did not differ significantly. Among 48 patients receiving 3L therapy, regorafenib showed a trend toward improved OS over sorafenib (HR, 0.33; 95% CI, 0.11 to 1.02; p=0.051), supported by restricted mean survival time analysis (p=0.028). Adverse events differed across therapies, with skin reactions and proteinuria notably linked to regorafenib and lenvatinib. Sequential 2L-lenvatinib followed by 3L-sorafenib yielded significantly better PFS than 2L-sorafenib followed by 3L-regorafenib (5.49 months vs 2.99 months: HR, 0.26; 95% CI, 0.10 to 0.65; p=0.003). Longer AtezoBev exposure prior to 2L treatment was associated with improved OS (HR, 1.05; 95% CI, 1.00 to 1.11; p=0.041). Conclusions: In advanced HCC following 1L AtezoBev failure, 2L lenvatinib prolonged PFS, and 3L regorafenib improved OS. These findings underscore the need to optimize sequential systemic therapies to enhance survival.