Transcatheter arterial chemoembolization plus donafenib and sintilimab for unresectable hepatocellular carcinoma: A prospective, single-arm, phase II study.

e16186 Background: Although combination therapy with anti-angiogenic agents and immune checkpoint inhibitors has become the standard treatment for unresectable hepatocellular carcinoma (uHCC), the progression-free survival and objective response rate still unmet clinical need. Transarterial chemoembolization (TACE) may prime adaptive immunity and enhance immunotherapy efficacy, anti-angiogenic agents may optimize the embolization effect by promoting tumor vascular normalization. Therefore, we aimed to evaluate the efficacy and safety of TACE plus donafenib and sintilimab for uHCC. Methods: This prospective study was performed from August 2022 to December 2024 at Nanfang Hospital, Southern Medical University. Eligible uHCC patients without prior systemic treatment were planned to receive up to four cycles of TACE within 16 weeks,donafenib and sintilimab were started ≤7 days after first TACE until disease progression or unacceptable toxicity for up to 2 year. The first up to 6 patients entered the safety run-in period and treated with donafenib 200 mg bid for determination of dose-limiting toxicities (DLT). The primary endpoint was the objective response rate (ORR) as assessed according to modified RECIST (mRECIST). The secondary endpoints included ORR (RECIST 1.1), overall survival (OS), and progression-free survival (PFS) and safety. Results: After the safety run-in period, donafenib was adjusted to 100 mg bid. 30 patients were enrolled at the time of the primary analysis (December 31, 2024): median age was 61 years; 93.3% had HBV; BCLC B and C stage were 14 (46.7%) and 16 (53.3%) respectively; median tumor size was 48.5 mm (IQR, 33.9-58.5); 18 (60.0%) beyond up-to-seven criteria; 22 (73.3%) received one TACE (range, 1 to 3); 7 (23.3%) had prior locoregional treatment. The median follow-up was 8.4 months, the ORR were 90.0% and 56.7% per mRECIST and RECIST 1.1, respectively. The median PFS was 10.2 months (95%CI, 6.8-NA), with a 1-year PFS rate of 44.3% (95%CI, 24.9%-79.0%). The median OS was not reached, and 1-year OS rate was 87.2% (95%CI, 74.6%-100.0%). The median time to response was 1.8 months (range, 1.0-4.7). Grade 3 or 4 adverse events occurred in 14 (46.7%) of patients, and the most frequent was increased AST (16.7%) . Conclusions: In patients with uHCC, TACE plus donafenib and sintilimab resulted in promising preliminary antitumor efficacy and tolerable safety profile. Clinical trial information: NCT05507632 .