Second-Line Durvalumab plus Tremelimumab versus Lenvatinib after Atezolizumab plus Bevacizumab Failure in Hepatocellular Carcinoma: A Multi-Center Retrospective Study

Abstract Background The optimal second-line treatment after atezolizumab plus bevacizumab (Atezo + Bev) failure in unresectable hepatocellular carcinoma (HCC) remains uncertain. We compared durvalumab plus tremelimumab (Dur + Tre) with lenvatinib in this setting. Methods We retrospectively analyzed 108 patients with unresectable HCC who experienced treatment failure during first-line Atezo + Bev and subsequently received Dur + Tre ( n = 22) or lenvatinib ( n = 86) as second-line therapy between January 2021 and March 2025 across eight Japanese institutions. Overall survival (OS), progression-free survival (PFS), tumor response, treatment-related adverse events (TRAEs), liver function at discontinuation, subsequent therapy, and post-treatment survival (PTS) were evaluated. Group comparisons were performed using the Mann–Whitney U test and Fisher’s exact test, and survival outcomes were analyzed using Kaplan–Meier methods, log-rank tests, and Cox proportional hazards models. Results Baseline characteristics were generally balanced, except for more prior Atezo + Bev courses in the Dur + Tre group. Median OS was 16.1 versus 10.4 months (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.19–1.04; p = 0.063), median PFS was 2.8 versus 4.0 months (HR, 1.00; 95% CI, 0.52–1.91; p = 0.995), and median PTS was 13.6 versus 5.8 months (HR, 0.50; 95% CI, 0.20–1.16; p = 0.106). Objective response rates were 13.6% versus 10.5%, and disease control rates were 31.8% versus 52.3%. Any-grade TRAEs were less frequent with Dur + Tre (54.5% vs. 89.5%; p < 0.001). Changes in Child–Pugh and albumin–bilirubin scores and subsequent systemic therapy rates did not differ significantly between the groups among evaluable patients. Conclusions Dur + Tre was associated with fewer any-grade TRAEs and nonsignificant trends toward longer OS, whereas lenvatinib achieved numerically higher disease control. Further studies are warranted to identify patients most likely to benefit from Dur + Tre therapy.