TACE-HAlC combined with donafenib and immune checkpoint inhibitors for BCLC stage C HCC patients (THEME study): A retrospective IPTW adjusted cohort study.

4090 Background: Transarterial chemoembolization (TACE) combined with hepatic arterial infusion chemotherapy (HAIC) has demonstrated superior objective response rate (ORR) and progression-free survival (PFS) compared to TACE alone, particularly in patients with unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombosis (PVTT), as shown in previous studies. Additionally, Donafenib exhibited significant survival benefits and better safety profiles compared to Sorafenib in a Phase III clinical trial. We aimed to retrospectively compare the efficacy and safety of TACE-HAIC combined with Donafenib and immune checkpoint inhibitors (Quadruple Therapy Group) versus the standardized targeted therapy (TKIs or bevacizumab) plus immune checkpoint inhibitors (Targeted-Immunotherapy Group) in patients with BCLC stage C hepatocellular carcinoma (HCC). Methods: We conducted a retrospective analysis of patients with BCLC stage C hepatocellular carcinoma (HCC) who received quadruple therapy or targeted-immunotherapy at the Harbin Medical University Cancer Hospital between September 2019 and October 2024. To minimize baseline imbalances between the groups, we applied stabilized inverse probability of treatment weighting (sIPTW) methods. Results: A total of 195 patients were included in the study, of whom 125 were assigned to the Quadruple Therapy Group and 70 to the Targeted-Immunotherapy Group. Within the Targeted-Immunotherapy Group, 44 patients received TKIs combined with immune checkpoint inhibitors, while 26 patients received bevacizumab combined with immune checkpoint inhibitors. After applying sIPTW to balance the baseline characteristics between the two groups, patients in the Quadruple Therapy Group demonstrated a significantly higher median overall survival (OS) compared with the Targeted-Immunotherapy Group(29.4 months [95% CI: 23.9–NA] vs 18.0 months [14.7–31.8]; P = 0.045). Additionally, the median progression-free survival (PFS) assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was longer in the Quadruple Therapy Group(16.4 months [95% CI: 12.7–NA] vs 10.0 months [3.3–31.8]; P = 0.013). The objective response rate (ORR) evaluated according to mRECIST was also higher in the Quadruple Therapy Group(68.4% vs 28.2%, P < 0.001).The incidence of any adverse events in the Quadruple Therapy Group was 95.2%, compared with 97.1% in the Targeted-Immunotherapy Group.Among these the incidence of grade ≥3 adverse events was 40.8% in the Quadruple Therapy Group and 38.6% in the Targeted-Immunotherapy Group. Conclusions: Compared with Targeted-Immunotherapy Group, patients with BCLC stage C HCC treated with TACE-HAIC combined with Donafenib and immune checkpoint inhibitors therapy demonstrated superior efficacy and acceptable safety.