Efficacy and safety of hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and PD-1 inhibitors for unresectable hepatocellular carcinoma: a meta-analysis

Background The triplet combination of hepatic arterial infusion chemotherapy (HAIC), a tyrosine kinase inhibitor (TKI), and a programmed cell death-1 (PD-1) inhibitor has emerged as a highly promising strategy for unresectable hepatocellular carcinoma (uHCC). This study aimed to comprehensively evaluate the efficacy and safety of this triple-therapy compared with the dual-therapy of a TKI plus a PD-1 inhibitor. Methods We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials or comparative cohort studies that assessed HAIC plus a TKI and a PD-1 inhibitor (H-T-P) versus a TKI plus a PD-1 inhibitor (T-P) for uHCC. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The secondary endpoint was treatment-related adverse events (AEs). A random-effects model was employed to pool data, calculating hazard ratios (HRs) or relative risks (RRs) with their 95% confidence intervals (CIs). Results A total of 12 studies involving 2,386 patients with uHCC were included. Compared with T-P dual therapy, the H-T-P triple therapy was associated with significantly improved OS (HR, 0.51; 95%CI, 0.47-0.56; P < 0.001) and PFS (HR, 0.59; 95%CI, 0.51-0.68; P < 0.001). Furthermore, the H-T-P group demonstrated a significantly higher ORR (RR, 1.97; 95%CI, 1.73-2.24; P < 0.001) and DCR (RR, 1.19; 95%CI, 1.11-1.28; P < 0.001). Regarding safety, while no significant difference was observed in the overall incidence of all-grade AEs ( P = 0.238), the incidence of grade ≥3 AEs was significantly higher in the triple-therapy arm (RR, 1.29; 95%CI, 1.13-1.48; P = 0.004), consisting primarily of manageable hepatotoxicity and hematologic toxicities. Conclusion Our findings indicate that for patients with uHCC, the H-T-P triple-therapy regimen is superior to dual therapy in terms of survival benefits and tumor response. The associated increase in severe toxicity is considered predictable and clinically manageable. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420251113276.