The therapeutic landscape of advanced hepatocellular carcinoma (aHCC) has evolved with the advent of targeted therapies and immune checkpoint inhibitors (ICIs). While ICI-based regimens such as atezolizumab and bevacizumab are widely adopted as first-line therapy, emerging evidence indicates reduced effectiveness in patients with non-viral etiologies such as metabolic dysfunction-associated steatohepatitis (MASH) and steatotic liver disease (MASLD). With viral HCC declining and non-viral cases increasing, lenvatinib, a potent multi-kinase inhibitor, has gained attention for its favorable efficacy in this subgroup. A thorough literature search was conducted across PubMed, MEDLINE (Medical Literature Analysis and Retrieval System Online), Google Scholar, Web of Science, and Science Direct, for English-language studies published from 2014 to 2025. Relevant randomized controlled trials, observational studies, real-world evidence, and registered clinical trials were reviewed. Our review indicates that lenvatinib may outperform ICI-based regimens in overall survival (OS) and progression-free survival (PFS) among patients with non-viral aHCC, particularly those with MASLD/MASH; however, this observation is based predominantly on retrospective studies. Its mechanisms, including angiogenesis inhibition and immune modulation, offer advantages in the immunosuppressive tumor microenvironment of non-viral HCC. Safety data suggest a manageable profile, with adverse events comparable to those in viral HCC. Emerging data also support lenvatinib-based combination therapies to enhance efficacy. Moreover, we have also discussed the existing challenges in managing HCC in clinical practice. Lenvatinib is a promising first-line option in non-viral aHCC in patients with MASH or MASLD. Given the etiology-specific response to therapy, future research and clinical guidelines should consider stratified approaches. Evidence suggests superior survival outcomes compared with ICIs. Etiology-specific responses highlight the need for stratified therapeutic approaches and consideration of lenvatinib-based combination therapies.
Sonone et al. (Fri,) studied this question.