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

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.

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Publication Details

Journal
JHEP Reports
Published
2025-09-24
DOI
https://doi.org/10.1016/j.jhepr.2025.101595
Citations
4
Primary Topic
Hepatocellular Carcinoma Treatment and Prognosis
Type
article
Field-Weighted Citation Impact
5.29

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article

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

David James Pinato, Brooke Wietharn, Tiziana Pressiani, Ho Yeong Lim et al.
4 citations
JHEP Reports
Hepatocellular Carcinoma Treatment and Prognosis
5.29
article

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

David James Pinato, Brooke Wietharn, Tiziana Pressiani, Ho Yeong Lim, Antonio D’Alessio, Ciro Celsa, Giuseppe Cabibbo, Alessandro Parisi, Johann von Felden, Fabio Piscaglia, Masatoshi Kudo, Pasquale Lombardi, Bernhard Scheiner, Claudia Angela Maria Fulgenzi, Matthias Pinter, Thomas U. Marron, Gianluca Masi, Lorenza Rimassa, Giulia Francesca Manfredi, Hong Jae Chon, Peter R. Galle, Martin Schönlein, Beodeul Kang, Mario Pirisi, Chun‐Yen Lin, Bernardo Stefanini, Emily Warmington, Marianna Silletta, Andrea Dalbeni, Wei‐Fan Hsu, Jung Sun Kim, Nidhi Doshi
article en
4 citations

Abstract

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.

JHEP ReportsVol. 7(12)
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), University of Verona (IT), Marche Polytechnic University (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Mount Sinai Hospital (US), Humanitas University (IT), Universität Hamburg (DE), Chang Gung University (TW), China Medical University (TW), Johannes Gutenberg University Mainz (DE), Hammersmith Hospital (GB), Agostino Gemelli University Polyclinic (IT), Chang Gung Memorial Hospital (TW), University Medical Center of the Johannes Gutenberg University Mainz (DE), The University of Kansas Cancer Center (US), University Medical Center Hamburg-Eppendorf (DE), Azienda USL di Bologna (IT), Azienda Ospedaliero Universitaria Maggiore della Carita (IT), China Medical University Hospital (TW), CHA University Bundang Medical Center (KR), Campus Bio Medico University Hospital (IT), CHA University (KR), IRCCS Humanitas Research Hospital (IT), Azienda Ospedaliera Universitaria Pisana (IT), Imperial College London (GB), Medical University of Vienna (AT), University of Palermo (IT), Kindai University (JP), University of Bologna (IT)
Amgen, Eli Lilly and Company, AstraZeneca, Gilead Sciences, Incyte, National Research Foundation, National Research Foundation of Korea, Eisai, European Society for Medical Oncology, Ministry of Science and ICT, South Korea, Ipsen
Openalex Percentile: Top 4%
Hepatocellular Carcinoma Treatment and Prognosis
5.29
DOIOpen Access PDFOpenAlex
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