Real-World Efficacy and Safety of TACE Combined with Lenvatinib and PD-1 Inhibitor in Conversion Therapy for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study

Introduction: Transarterial chemoembolization (TACE) combined with lenvatinib has demonstrated efficacy for unresectable hepatocellular carcinoma (HCC). However, real-world evidence on the additional benefit of PD-1 inhibitors in conversion therapy remains limited. This study aimed to investigate the efficacy and safety of triple therapy (TACE, lenvatinib, and PD-1 inhibitors) versus dual therapy (TACE and lenvatinib) in conversion therapy for initially unresectable HCC. Methods: This multicenter study was conducted in 20 Chinese tertiary hospitals. Patients received either triple therapy (TLP group, n=289) or dual therapy (TL group, n=132). Inverse probability of treatment weighting (IPTW) was used to control for confounding. Multivariate models compared overall survival (OS) and progression-free survival (PFS). Results: From January 2019 to June 2023, 421 consecutive patients were enrolled. After IPTW adjustment, baseline characteristics were well-balanced. The TLP group showed superior efficacy: objective response rate 55.1% versus 34.7% (P < 0.001), complete response rate 24.9% versus 14.9% (P = 0.010), and conversion surgery rate 35.5% versus 15.7% (P < 0.001). Median OS was prolonged (31.67 vs 25.00 months; adjusted HR 0.60, 95% CI: 0.42-0.85, P = 0.001) and median PFS extended (16.47 vs 12.00 months; adjusted HR 0.65, 95% CI: 0.47-0.93, P = 0.008). Sensitivity analyses including propensity score matching (HR 0.61), landmark analysis (HR 0.64), and time-varying covariate analysis (HR 0.58) confirmed the findings. E-value analysis (2.72) suggested unmeasured confounding alone is unlikely to explain the benefit. Treatment effects were consistent across subgroups. Grade 3-4 adverse events were similar (35.6% vs 36.4%, P = 0.885), though immune-related adverse events were more frequent in the TLP group. Conclusions: Adding PD-1 inhibitors to TACE plus lenvatinib was associated with improved tumor response, prolonged survival, and higher conversion surgery rates, with an acceptable safety profile. Given the heterogeneity of PD-1 inhibitors and inherent limitations of retrospective design, these findings should be considered hypothesis-generating and require verification in prospective randomized controlled trials.