Efficacy and Safety of Lenvatinib Versus Sorafenib in Recurrent HCC After Liver Transplant: A Multi‐Center Real‐World Study

Introduction: Liver transplantation (LT) indications for hepatocellular carcinoma (HCC) have broadened, increasing the need for systemic therapy in post-transplant recurrence. Because of the risks of graft rejection and uncertain efficacy, immunotherapy remains controversial, making tyrosine kinase inhibitors (TKIs) such as lenvatinib and sorafenib the preferred first-line treatments. However, their comparative efficacy in this setting remains unclear, warranting further research. Methods: We conducted a retrospective, multicenter study of HCC recurrence after LT treated with either lenvatinib or sorafenib as first-line systemic treatment. Primary objectives were to compare overall survival (OS), progression-free survival (PFS) and treatment response assessed per RECIST 1.1. A meta-analysis incorporating prior studies was carried out to enhance the robustness of findings. Safety was evaluated as the rate of adverse events onset graded as per CTCAE v5.0. Results: In a cohort of 64 patients (lenvatinib: 40, sorafenib: 24), lenvatinib significantly improved median OS (19.5 vs. 11.4 months, HR 0.31, p = 0.003), as confirmed in a meta-analysis with another recent report (HR 0.43, p = 0.0012). Although PFS was longer with lenvatinib (7.3 vs. 4.6 months), the difference was not significant (HR 0.91, p = 0.73). Both treatments had comparable safety profiles, with lenvatinib linked to higher hypertension and proteinuria rates, and sorafenib associated with more hand-foot syndrome and diarrhea. Conclusions: This study provides real-world evidence that lenvatinib confers superior overall survival over sorafenib in recurrent HCC post-LT, with manageable toxicity. As LT indications expand, these findings support lenvatinib as a preferred first-line treatment. Further prospective studies are needed to confirm these results and optimize post-LT treatment strategies.