# Mono‐TKI and TKI Plus ICI in Unresectable Hepatocellular Carcinoma Progression on First‐Line Treatment of Lenvatinib: A Real‐World Study

## TL;DR

This real-world study compares second-line treatments for hepatocellular carcinoma after lenvatinib failure, finding that combining TKI with immunotherapy improves survival and disease control.

## Contribution

The study provides real-world evidence on the efficacy and safety of TKI-based monotherapy versus TKI-ICI combination therapy after lenvatinib failure in unresectable hepatocellular carcinoma.

## Key findings

- TKI-ICI combination therapy showed better progression-free and overall survival than monotherapy.
- High ANRI predicted better progression-free survival, while elevated alpha-fetoprotein predicted worse overall survival.
- Combination therapy had a higher disease control rate and manageable toxicity.

## Abstract

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.

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.

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.

The combination of TKI and ICI presents a promising second‐line treatment option after LEN failure, regardless of the specific second‐line TKI used.

The combination of TKI and ICI for uHCC after LEN failure demonstrated great survival benefits and was well tolerated, irrespective of the second‐line TKI administered.