999P Donafenib combined with hepatic artery infusion chemotherapy (HAIC) and sintilimab for unresectable hepatocellular carcinoma (uHCC): A prospective, single-arm phase II trial (DoHAICs study)

Both donafenib and anti-PD-1 antibodies are indicated for uHCC, HAIC significantly improved treatment response over TACE in patients (pts) with large uHCC in a phase III trial. Considering the different mechanisms, this study aimed to investigate the safety and efficacy of donafenib combined with HAIC and sintilimab in pts with uHCC. This is a prospective, single-arm phase II study. Pts with histologically diagnosed uHCC, no previous systemic treatment, Child-Pugh A5-B7, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Enrolled pts received donafenib (200 mg, bid), sintilimab (200 mg, q3w) and HAIC (oxaliplatin 85 mg/m2 2h, leucovorin 400 mg/m2 2h, fluorouracil bolus 400 mg/m2 in the first 10 minutes, and fluorouracil infusion 1200 mg/m2 for 23 hours, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). From Dec 2021 to Apr 2023, 30 pts were enrolled: BCLC stage A/B/C: 4/10/16; Child-Pugh class A/B: 29/1; ECOG PS 0/1: 29/1. The median tumor size was 7.9 cm, 46.7% pts presented macro vascular invasion, 10.0% had extrahepatic metastasis. As of May 6, 2023, the median follow-up time was 102 days, the median number of HAIC was 3 times (range, 1-8). Based on mRECIST, the ORR was 82.1% (95% CI, 63.1% - 93.9%) with 4 (14.3%) complete responses (CR) and 19 (67.8%) partial responses (PR). The disease control rate (DCR) was 96.4% (95% CI, 81.7% - 99.9%). Of 28 pts evaluable for response, the conversion success rate was 64.3% (18/28), 13 of them received hepatectomy, 5 cases (38.5%) achieved complete pathological response and 6 cases (46.2%) achieved major pathological response. The median time to response (TTR) was 2.1 months. The median progression-free survival (PFS) was 10.2 months (95% CI, NR). The most common treatment-emergent adverse events (TEAEs) were thrombocytopenia, anemia and neutropenia. Grade 3-4 TEAEs occurred in 33.3% of pts. No grade 5 TEAEs were observed. Combination treatment with donafenib and HAIC plus sintilimab showed promising clinical benefits and acceptable toxic effects in pts with uHCC. The enrollment and follow-up are continuing.