Transarterial chemoembolization (TACE) combined with immunotherapy and anti-angiogenic agents in intermediate-stage hepatocellular carcinoma (CHANCE2202): a target trial emulation study

Background: This study aimed to assess the clinical outcomes of transarterial chemoembolization (TACE) with immune checkpoint inhibitors (ICIs) plus vascular endothelial growth factor (VEGF) inhibitors or tyrosine kinase inhibitors (TKIs) (combination therapy) versus TACE monotherapy as a first-line treatment for intermediate-stage hepatocellular carcinoma (HCC). Methods: This nationwide, retrospective cohort study employed a target trial emulation framework with a cloning-censoring-weighting approach. Patients with intermediate-stage HCC receiving either combination therapy or TACE monotherapy between January 2018 and December 2022 in China were included. Co-primary outcomes were overall survival (OS) and progression-free survival (PFS) per modified Response Evaluation Criteria in Solid Tumors (mRECIST), assessed using restricted mean survival time (RMST). Hazard ratio (HR) was additionally estimated using Cox proportional hazards models for reference. For both RMST and HR, 95% CIs were obtained by bootstrapping. Secondary outcomes included PFS per RECIST 1.1, objective response rate (ORR) per both mRECIST and RECIST 1.1, and safety. This study is registered at ClinicalTrials.gov (NCT05332496). Findings: A total of 941 patients were included in the study, with 308 (32.7%) receiving combination therapy, and 633 (67.3%) receiving TACE monotherapy. Median OS was 32.9 with combination therapy versus 23.0 months with TACE monotherapy, with an RMST difference of 9.2 months (95% CI 4.5-14.3, bootstrapped p < 0.001; HR 0.57 [95% CI 0.43-0.70]). Median PFS was 18.0 and 12.9 months in the respective groups, with an RMST difference of 6.7 months (95% CI 3.3-10.7, bootstrapped p = 0.001; HR 0.70 [95% CI 0.58-0.82]). Combination therapy also yielded a higher ORR per mRECIST (60.5% versus 44.3%; p < 0.001). Similar results for PFS and ORR were observed when assessed using RECIST 1.1. Grade ≥3 adverse events occurred in 64 (20.8%) and 43 (6.8%) patients, respectively. Interpretation: Combining TACE with ICIs and VEGF inhibitors or TKIs was associated with improved OS and PFS than TACE monotherapy, with an acceptable safety profile, supporting its potential as a first-line treatment strategy for intermediate-stage HCC. Funding: National Natural Science Foundation of China (82130060, 82502493), China Postdoctoral Science Foundation (2025M772071), Jiangsu Provincial Basic Research ProgramNatural Science Foundation-Frontier Leading Technology Basic Research Project (BK20232008), Jiangsu Provincial Medical Innovation Center (CXZX202219), Postdoctoral Fellowship Program of CPSF (GZC20251385), and Natural Science Foundation of Jiangsu Province (BK20251687).