Abstract
BACKGROUND: Lenvatinib (LEN) is the recommended first-line therapy for unresectable hepatocellular carcinoma (uHCC), but resistance frequently develops, and limited data exist on second-line treatments. This study evaluated the efficacy and safety with a focus on the sorafenib (SOR) or regorafenib (REG)- based monotherapy or combination therapy in patients with uHCC after failure of first-line LEN. METHODS: Patients with first-line LEN failure between May 2018 and December 2023 were retrospectively collected. Based on second-line regimens, 70 patients were divided into two groups: the TKI group (n = 21) and the TKI-ICI group (n = 49). Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to identify prognostic factors. RESULTS: In the TKI-ICI group, median PFS was 5.27 months and median OS was 12.53 months. In the TKI group, median PFS was 3.10 months and median OS was 7.50 months. The objective response rate (ORR) was 19.1% in the TKI group and 16.3% in the TKI-ICI group. The disease control rate (DCR) was 85.7% in the TKI-ICI group and 61.9% in the TKI group. In the TKI-ICI cohort, multivariable Cox analysis revealed the high albumin to neutrophil ratio index (ANRI) was an independent predictor for PFS, while alpha-fetoprotein > 400 ng/mL was the independent predictor for OS. Safety profiles in both cohorts showed manageable toxicity, with no treatment-related deaths. CONCLUSIONS: The combination of TKI and ICI presents a promising second-line treatment option after LEN failure, regardless of the specific second-line TKI used.