# Efficacy of Lenvatinib as Second-Line Therapy After Atezolizumab Plus Bevacizumab for Hepatocellular Carcinoma

## TL;DR

Lenvatinib improves survival when used as second-line therapy after atezolizumab plus bevacizumab for advanced liver cancer.

## Contribution

This study provides evidence for lenvatinib's efficacy and identifies factors influencing outcomes after first-line immunotherapy failure.

## Key findings

- Lenvatinib as second-line therapy significantly improved median overall survival compared to no lenvatinib.
- Preserved hepatic reserve and a total lenvatinib dose of 400 mg or more were associated with better outcomes.
- The survival benefit of lenvatinib remained significant after adjusting for treatment selection bias.

## Abstract

Atezolizumab plus bevacizumab is used as first-line treatment for advanced hepatocellular carcinoma, but evidence regarding subsequent second-line therapy remains insufficient. This multicenter collaborative study retrospectively examined cases treated with lenvatinib as second-line therapy. Results showed that patients receiving lenvatinib had improved survival compared with those who did not receive it. Additionally, factors contributing to prognosis in patients receiving lenvatinib as second-line therapy included hepatic reserve before first-line treatment and a total lenvatinib dose of 400 mg or more. Maintaining hepatic reserve through appropriate dose management was considered important. These findings provide clinically useful information regarding the feasibility of sequential systemic therapy following atezolizumab plus bevacizumab treatment and highlight factors associated with preserved hepatic reserve and treatment continuation in routine clinical practice.

Background: Atezolizumab plus bevacizumab (ATZ/BEV) is widely used as first-line therapy for advanced hepatocellular carcinoma (HCC); however, optimal subsequent treatment after ATZ/BEV failure remains unclear. Methods: Between October 2020 and August 2024, 165 patients with unresectable HCC treated with first-line ATZ/BEV were retrospectively analyzed. After excluding patients with insufficient follow-up, outcomes were compared between those who received lenvatinib (LEN) as second-line therapy (n = 49) and those who did not (n = 95). Results: Median overall survival (OS) was significantly longer in the LEN group than in the non-LEN group (20.9 vs. 8.47 months, p < 0.01). LEN administration was independently associated with improved OS (hazard ratio 0.48), and this benefit remained significant after inverse probability weighting adjustment (adjusted hazard ratio 0.50). Among LEN-treated patients, a lower albumin–bilirubin score before ATZ/BEV and a total LEN dose ≥ 400 mg were independent prognostic factors. Conclusions: Lenvatinib as second-line therapy after ATZ/BEV was associated with improved survival in unresectable HCC. Preservation of liver function and the ability to maintain adequate lenvatinib exposure were associated with favorable outcomes, likely reflecting baseline prognosis and treatment feasibility rather than lenvatinib-specific predictive factors.