Efficacy and safety of donafenib combined with hepatic artery infusion chemotherapy and sintilimab as neoadjuvant therapy for hepatocellular carcinoma: A prospective, single-arm phase II trial (Neo-DoHAICs study).

e16176 Background: Recurrence is a major cause of treatment failure in hepatocellular carcinoma (HCC), especially for tumors with high-risk features such as multiplicity or vascular invasion. Yet, a standardized neoadjuvant regimen for resectable HCC is lacking. This study evaluates the efficacy and safety of a neoadjuvant combination of donafenib, sintilimab, and hepatic artery infusion chemotherapy (HAIC) in patients with resectable HCC at high risk of recurrence. Methods: This is a prospective, single-arm phase II study (NCT06512467). Patients with technically resectable CNLC IIb or IIIa HCC were included, provided they also had high-risk features such as an anticipated surgical margin < 1 cm or the presence of ipsilateral portal or hepatic vein tumor thrombus. Patients received 2-4 cycles of neoadjuvant therapy with donafenib (200 mg, bid), sintilimab (200 mg, q3w) and HAIC (oxaliplatin 85 mg/m 2 2h, leucovorin 400 mg/m 2 2h, fluorouracil bolus 400 mg/m 2 in the first 10 minutes, and fluorouracil infusion 1200 mg/m 2 for 23 hours, q3w) prior to elective surgical resection. The primary endpoint was the major pathological response (MPR) rate. Results: A total of 17 patients were enrolled from August 2024 to July 2025. 94.1% of patients were CNLC IIIa. The median maximum tumor diameter was 99.0 mm. 76.4% presented with Vp3/Vp4 portal vein tumor thrombus. 29.4% had hepatic vein tumor thrombus. To date, 16 patients have undergone surgical resection. Pathological assessment revealed the following rates: 31.3% for pathological complete response (pCR), 43.8% for MPR, 100.0% for R0 resection, and 25.0% for microvascular invasion. The objective response rate was 88.2% (2 complete responses, 13 partial responses PRs) per mRECIST and 52.9% (9 PRs) per RECIST 1.1, the corresponding median times to response were 1.6 months and 2.0 months, respectively. The disease control rate was 100.0% for both criteria. A association was found between radiographic and pathological response: 85.7% of radiographic responders achieved pCR or MPR, compared to none among non-responders ( P = 0.05). The 1-year event-free survival rate was 84.4%, while the 1-year recurrence-free survival rate was 73.9%. Both AFP and PIVKA-II levels decreased significantly from baseline to surgery. The albumin-bilirubin score did not show a significant change before surgery compared to baseline (-2.82 vs -2.86, P = 0.75). Treatment-emergent adverse events (TEAEs) occurred in 94.1% of patients. Grade 3-4 TEAEs were reported in two cases. The most common AEs were decreased platelet count and elevated ALT. Conclusions: Preliminary analysis indicates that the neoadjuvant combination of donafenib, HAIC, and sintilimab demonstrates favorable efficacy and safety in patients with HCC. The enrollment and follow-up are continuing. Clinical trial information: NCT06512467 .