Real-World Effectiveness of Sorafenib versus Lenvatinib Combined with PD-1 Inhibitors in Unresectable Hepatocellular Carcinoma

SIMPLE SUMMARY: Immunotherapy using immune checkpoint inhibitors (ICIs) (e.g., programmed cell death protein-1 (PD-1) inhibitors) combined with molecular targeted agents has been evaluated in clinical trials and has shown potential synergic effects and superior efficacy in unresectable hepatocellular carcinoma (uHCC). The optimal regimen for uHCC of combination therapy with a PD-1 inhibitor plus an MTKI remains controversial. A head-to-head comparison is still lacking regarding combination strategies involving the administration of PD-1 inhibitors with different MTKIs in uHCC. This highly original study evaluates the efficacy and safety of PD-1 inhibitors in combination with sorafenib or lenvatinib in a cohort of patients with uHCC. We observed that PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Our data on efficacy and tolerability may enable clinicians to select optimal treatment strategies for HCC therapy. ABSTRACT: Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39, p = 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.