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

ABSTRACT 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.