Hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitors as first-line treatment for hepatocellular carcinoma with high tumor burden and portal vein tumor thrombus: A target trial emulation study (CHANCE 2416).

4132 Background: Patients with advanced hepatocellular carcinoma (HCC) characterized by high tumor burden (beyond up-to-seven criteria) and portal vein tumor thrombus (PVTT) have a median overall survival (OS) of lower than 4 months without intervention. Global guidelines rely on Phase III trials that often under-represented this high-risk subgroup, creating a therapeutic gap. While systemic combinations are standard, they may lack the rapid cytoreductive potency required to prevent liver failure in this subgroup. We emulated a target trial to evaluate if adding hepatic arterial infusion chemotherapy (HAIC) to lenvatinib and PD-1 inhibitors (H+L+P) improves outcomes compared to lenvatinib and PD-1 inhibitors (L+P) alone. Methods: Using multicenter data from 22 centers in the Chinese Liver Cancer Clinical Study Alliance (CHANCE) registry, we compared first-line H+L+P (n = 127) vs. L+P (n = 117) in patients with advanced HCC (BCLC stage C without extrahepatic spread) and PVTT (Vp1-4). To minimize selection and immortal time biases, we employed stabilized inverse probability of treatment weighting (sIPTW) and a cloning-censoring-weighting framework. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), site-specific PFS, objective response rate (ORR), and safety. Results: Baseline covariates were well-balanced after weighting (SMD < 0.1). After sIPTW adjustment, H+L+P demonstrated a significant survival benefit: median OS was 25.6 months (95% CI: 22.0–33.7) vs. 15.9 months (95% CI: 12.6–21.3) for L+P (adjusted HR, 0.60; 95% CI: 0.43–0.82; p = 0.0015). Crucially, a favorable survival trend was preserved even in the high-risk Vp3-4 subgroup (HR 0.77). Median PFS (RECIST v1.1) was 13.0 vs. 6.8 months (adjusted HR, 0.58; p = 0.0002). H+L+P significantly delayed progression in intrahepatic lesions (median 14.8 vs. 7.8 months; p = 0.0006) and PVTT (median 24.9 vs. 15.5 months; p = 0.0183). Intrahepatic ORR (mRECIST) was 87.4% for H+L+P vs. 28.9% for L+P (p < 0.0001), with a PVTT response rate of 81.6% vs. 22.1% (p < 0.0001). Grade ≥3 adverse events (AEs) occurred in 37.0% of the H+L+P group vs. 9.4% in the L+P group. Common Grade ≥3 AEs in the H+L+P arm included abdominal pain (20.5%) and leukopenia (5.5%); no treatment-related deaths occurred in the H+L+P group. Conclusions: In this target trial emulation, adding HAIC to lenvatinib and PD-1 inhibitors significantly improved OS and PFS in patients with high-risk HCC and PVTT. The survival advantage was driven by rapid and profound locoregional control, particularly of the tumor thrombus, with a manageable safety profile. Clinical trial information: NCT06631326 .