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 alphafetoprotein <-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. (c) 2025 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study
Rimassa, Lorenza;
2025-01-01
Abstract
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 alphafetoprotein <-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. (c) 2025 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
