Lenvatinib vs. sorafenib as second-line treatment post atezolizumab plus bevacizumab for hepatocellular carcinoma: The LEVIATHAN study
Pasquale Lombardi, Jung Sun Kim, Giulia Francesca Manfredi, Ciro Celsa, Claudia Angela Maria Fulgenzi, Antonio D’Alessio, Bernardo Stefanini, Nidhi Doshi, Emily Warmington, Thomas U. Marron, Matthias Pinter, Bernhard Scheiner, Beodeul Kang, Ho Yeong Lim, Wei‐Fan Hsu, Brooke Wietharn, Marianna Silletta, Alessandro Parisi, Chun‐Yen Lin, Andrea Dalbeni, Gianluca Masi, Martin Schönlein, Johann von Felden, Fabio Piscaglia, Peter R. Galle, Masatoshi Kudo, Tiziana Pressiani, Lorenza Rimassa, Mario Pirisi, Giuseppe Cabibbo, Hong Jae Chon, David J. Pinato
Abstract
Background 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 the efficacy and survival outcomes of patients who progressed on A+B and subsequently received either lenvatinib or sorafenib as second-line therapy. Of 1210 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 (PSM) 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 (PFS) (5.5 vs 2.6 months, 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 versus 14.3 months with A+B-sorafenib (HR 0.54, p<0.001). These differences persisted in the PSM 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 AFP ≤400 ng/ml, NLR <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. Although constrained by the observational design of our study, these findings underscore the importance of treatment sequencing in optimizing outcomes for patients with advanced HCC. Implication for practice While continuing active treatment in patients with advanced hepatocellular carcinoma (HCC) who progress following frontline atezolizumab plus bevacizumab (A+B) has shown clinical benefit, there remains a lack of definitive evidence to guide optimal second-line strategies. The LEVIATHAN study addresses this critical gap by evaluating real-world survival outcomes in a large, prospective, multinational cohort of patients treated with either lenvatinib or sorafenib after A+B discontinuation. Our findings show that lenvatinib is associated with significantly improved progression-free and overall survival compared to sorafenib, even after adjustment for imbalances of baseline features using propensity scores. Importantly, lenvatinib achieved superior disease control rates, including in those patients with primary resistance to immunotherapy. These results challenge the assumption that all VEGFR-targeting TKIs are equivalent in the post-ICI setting and lenvatinib may be superior to sorafenib following anti-VEGF-based immunotherapy. While prospective randomized trials are still needed, these real-world data offer valuable guidance for clinicians and contribute to refining treatment sequencing in advanced HCC.