Efficacy and safety of TACE plus lenvatinib with PD-1 inhibitor for unresectable huge hepatocellular carcinoma: a multicenter retrospective cohort study

PURPOSE: The combination of transarterial chemoembolization (TACE) plus lenvatinib and programmed death receptor-1 (PD-1) inhibitor has shown promising results for advanced hepatocellular carcinoma (HCC), but its benefits for unresectable huge HCC (maximum diameter ≥10 cm) are unknown. This study aimed to compare the efficacy between TACE combined with lenvatinib and PD-1 inhibitor (TACE + Len + PD-1) and TACE combined with lenvatinib (TACE + Len) for unresectable huge HCC. METHODS: This study analysed 147 and 241 patients in the TACE + Len and TACE + Len + PD-1 groups, respectively, from six hospitals. The PD-1 inhibitors used in this study (sintilimab, camrelizumab, pembrolizumab, toripalimab, tislelizumab and nivolumab) were administered at standard doses. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS) and tumor response. Propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and coarsened exact matching (CEM) were used to balance bias between the two groups. Tumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria based on a centralized and independent imaging review by blinded senior radiologists. A causal mediation analysis was employed to quantify the extent to which the survival benefit was mediated through early tumor response (objective response rate at 3- and 6-month) versus the direct effect of the treatment. RESULTS: The median PFS was 6.03 months [95% confidence interval (CI) 5.63-7.37] in the TACE + Len group and 8.37 months (95% CI 7.50-9.70) in the TACE + Len + PD-1 group. Overall, compared with the TACE + Len group, the TACE + Len + PD-1 group had better PFS [hazard ratio (HR) 0.67, 95% CI 0.54-0.83; s01] and OS (HR, 0.66; 95% CI 0.57-0.83; P <0.001), even after PSM, IPTW, and CEM. The objective response rate (ORR) was higher in the TACE + Len + PD-1 group than in the TACE + Len group (P <0.001). Furthermore, mediation analysis demonstrated that the survival benefit of the triple therapy operated principally through the enhancement of the early tumor response rate. CONCLUSION: Compared with TACE plus lenvatinib, triple therapy with TACE, lenvatinib, and PD-1 inhibitor resulted in better PFS and OS. These findings support the consideration of this triple combination as a promising first-line treatment option for unresectable huge HCC and warrant further validation in prospective studies.