Donafenib plus sintilimab combined with TACE or HAIC for unresectable hepatocellular carcinoma: A prospective single-arm phase II study.

e16179 Background: The combination of targeted therapy and immunotherapy has shown promising efficacy in patients (pts) with unresectable hepatocellular carcinoma (uHCC). Interventional therapy is an effective locoregional treatment for uHCC. The purpose of this study is to evaluate the efficacy and safety of donafenib combined with sintilimab in conjunction with TACE, HAIC, or a combination of TACE and HAIC in pts with uHCC. Methods: This is a prospective, single-arm phase II study (ChiCTR2300076993). Pts with uHCC who had not received any previous systemic treatment were included, provided they had an ECOG PS of 0-1 and Child-Pugh class A or B. Enrolled pts received donafenib (200 mg, bid), sintilimab (200 mg, q3w) along with TACE (administered as needed, conventional TACE or drug-eluting bead TACE) or HAIC (administered as needed, oxaliplatin 85 mg/m² over 2h, leucovorin 400 mg/m² over 2h, fluorouracil bolus 400 mg/m² in the first 10 minutes, and fluorouracil infusion 1200 mg/m² for 23 hours, q3w), or a combination of TACE and HAIC, until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Results: From Dec 2023 to Aug 2025, 27 pts were enrolled: BCLC stage A/B/C: 1/5/21; Child-Pugh class A/B: 25/2; ECOG PS 0/1: 15/12. The median tumor size was 7.9 cm. Macro vascular invasion was present in 77.8% of pts, and 74.1% had Vp3/Vp4 portal vein tumor thrombus. As of Jan 2026, the median follow-up time was 11.4 months. The ORR was 59.3% (4 complete responses CRs, 12 partial responses PRs) per mRECIST and 40.7% (1 CR, 10 PRs) per RECIST 1.1. The disease control rate was 96.3% for both criteria. The median progression-free survival was 10.5 months (95% CI, 10.5-NA). The 1-year overall survival rate was 96.0% (95% CI, 88.6%-100.0%). Of the 7 pts (25.9%) who achieved successful conversion therapy, 6 underwent radical surgery (all achieving R0 resection, with 5 exhibiting a major pathological response and 1 achieving a pathological complete response), and 1 received radical ablation. Currently, 3 pts have experienced recurrence. Following combination therapy, both AFP and PIVKA-II levels declined significantly. The quality of life (QoL) scores showed a slight decrease from baseline post-treatment, but this change did not meet the threshold for a minimal clinically important difference (defined as a ≥10-point decrease). Throughout treatment, the score remained stable ( P > 0.05). The incidence of any treatment-emergent adverse event (TEAE) was 100%. The most common TEAEs were thrombocytopenia, anemia, and elevated bilirubin, grade 3-4 TEAEs occurred in 18.5% of pts. No grade 5 adverse events were reported. Conclusions: This study preliminarily indicates that the combination of donafenib, sintilimab, with TACE, HAIC, or TACE-HAIC shows encouraging efficacy and acceptable toxicity in uHCC. Enrollment and follow-up are continuing. Clinical trial information: ChiCTR2300076993.