Comparison of Efficacy between Lenvatinib and Bevacizumab in Combination of Immune Checkpoint Inhibitor and Interventional Triple Therapy in Chinese Advanced Hepatocellular Carcinoma: The CLEAP 2302 Study.

Background: The conversion therapy for advanced hepatocellular carcinoma (HCC) shows promise with a triple therapy approach that combines interventional therapy, immune checkpoint inhibitors, and molecular targeted therapy (primarily small-molecule TKIs and the large-molecule bevacizumab). This combination has achieved the highest objective response rates (ORR) along with acceptable safety profiles. The aim of this study was to compare the clinical efficacy of lenvatinib versus bevacizumab, when combined with immune checkpoint inhibitors and interventional triple therapy, as first-line treatments for Chinese patients with unresectable HCC (uHCC).

Method: This retrospective multicenter study involved 371 consecutive patients from 21 centers in China, observed between April 2017 and December 2023. The study focused on patients with uHCC at Chinese liver cancer stages IIb to IIIb (Barcelona Clinic Liver Cancer stage B or C) who received lenvatinib or bevacizumab combined with anti-PD-1/L1 and interventional therapy (including TACE and/or HAIC) as first-line treatment. Of the 371 patients, 258 received lenvatinib-based triple therapy, while 113 received bevacizumab-based triple therapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS). To balance baseline clinical characteristics, propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied. Subgroup analysis was also performed based on different clinicopathological characteristics of the enrolled uHCC patients.

Results: The median OS in the lenvatinib group was significantly longer than in the bevacizumab group, both before (36.0 vs. 27.9 months; hazard ratio [HR]: 0.536; 95% confidence interval [CI]: 0.344-0.835; = 0.0016) and after PSM (HR: 0.524; 95% CI: 0.305-0.900; = 0.01), as well as after IPTW (HR: 0.549; 95% CI: 0.331-0.908; = 0.01). Before adjustment, PFS in the lenvatinib group was also significantly longer than in the bevacizumab group (20.0 vs. 12.1 months; HR: 0.649; 95% CI: 0.457-0.922; = 0.0078). However, after PSM (HR: 0.808; 95% CI: 0.535-1.222; = 0.33) and IPTW, there was no significant difference in PFS between the two groups. Multivariate analysis showed that lenvatinib-based triple therapy was independently associated with improved OS compared to bevacizumab-based triple therapy. Subgroup analysis indicated that patients with age ≤65 years, no history of hepatitis B virus infection, Barcelona Clinic Liver Cancer stage C (BCLC-C), ALT levels ≤40 U/L, platelets ≥100 × 10/L, or log 10 AFP ≥1.40 benefited more from lenvatinib-based triple therapy.

Conclusion: Lenvatinib-based triple therapy tends to prolong OS compared to bevacizumab, although the PFS was similar between the two groups. Patients aged ≤65 years, without a history of hepatitis B virus infection, with BCLC-C stage, ALT ≤40 U/L, platelets ≥100 × 10/L, or log 10 AFP ≥1.40 are likely to benefit more from lenvatinib-based triple therapy.