Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study

Background & Aims: Atezolizumab plus bevacizumab (A+B) is a standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, optimal sequencing strategies after A+B failure remain undefined. Methods: LEVIATHAN is a multicentre, observational study evaluating efficacy and survival outcomes in patients who progressed on A+B and subsequently received either lenvatinib or sorafenib as second-line therapy. Of 1,210 patients treated with first-line A+B between May 2018 and August 2024, 230 eligible patients were included (lenvatinib, n = 125 [54.3%]; sorafenib, n = 105 [45.7%]). Propensity score matching was applied to adjust for baseline imbalances, incorporating independent predictors of overall survival (OS) and response to prior treatment. Results: In the overall second-line cohort, lenvatinib was associated with superior median progression-free survival (5.5 vs. 2.6 months, hazard ratio [HR] 0.41, p <0.001) and median OS (11.9 vs. 7.4 months, HR 0.67, p = 0.018) compared to sorafenib. From the start of A+B, the A+B-lenvatinib sequence achieved a median OS of 22.4 months vs. 14.3 months with A+B-sorafenib (HR 0.54, p <0.001). These differences persisted in the propensity score-matched cohort (median OS: 19.6 vs. 13.9 months, HR 0.67, p = 0.024). Multivariate analysis identified treatment with lenvatinib as an independent predictor of improved OS alongside alpha-fetoprotein ≤400 ng/ml, neutrophil-to-lymphocyte ratio <3, and absence of portal vein thrombosis. Conclusions: The LEVIATHAN study supports lenvatinib as a more effective second-line option than sorafenib following A+B in unresectable HCC, including in patients with primary resistance to immunotherapy. While limited by the observational study design, these findings highlight the importance of treatment sequencing to optimise outcomes in advanced HCC. Impact and implications: Continuing active treatment after progression on frontline atezolizumab plus bevacizumab (A+B) can benefit patients with advanced hepatocellular carcinoma (HCC), but evidence to guide second-line therapy remains limited. The LEVIATHAN study addresses this gap by evaluating real-world outcomes in a large, prospective, multinational cohort treated with lenvatinib or sorafenib after A+B discontinuation. Our findings show that lenvatinib provides significantly longer progression-free and overall survival than sorafenib, even after adjusting for baseline imbalances with propensity scores. Lenvatinib also achieved higher disease control rates, including in patients with primary resistance to immunotherapy. These results challenge the assumption that all VEGFR-targeting TKIs are equivalent post-ICI and suggest lenvatinib may be superior to sorafenib following anti-VEGF–based immunotherapy. While prospective randomised trials are still needed, these real-world data offer valuable guidance for clinicians and help refine treatment sequencing in advanced HCC.