Donafenib and sintilimab plus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: A phase II, biomarker exploratory study (DosinTACE).

549 Background: Despite the combination of anti-angiogenics and immune checkpoint inhibitors being the standard for unresectable hepatocellular carcinoma (uHCC), further improvements are needed to prolong overall survival (OS), progression-free survival (PFS) and increase the objective response rate (ORR). This study evaluated the efficacy, safety, and biomarkers of donafenib and sintilimab plus TACE as the first-line treatment for uHCC. Methods: DosinTACE is a single-arm phase II study that includes a safety run-in and an expansion phase. The safety run-in phase determined the recommended dose of donafenib. Systemic treatment-naive uHCC patients received up to four cycles of TACE within 16 weeks, along with donafenib and sintilimab until progression or intolerable toxicity. Primary endpoint was the ORR per mRECIST. Single-nucleus RNA sequencing (snRNA-seq) of tumor biopsy samples was performed to characterize the tumor microenvironment (TME). Results: Donafenib was adjusted to 100 mg bid for the expansion phase. A total of 44 patients were enrolled and analyzed: median age, 59.1 years; 90.9% with HBV infection; 52.3% BCLC stage C and 47.7% BCLC stage B; 79.5% had multiple tumors; 68.2% exceeded the up-to-seven criteria. At a median follow-up of 15.2 months, according to mRECIST, the ORR and disease control rate (DCR) were 81.8% and 90.9%, respectively, with a time to response (TTR) of 1.7 months. The median PFS was 17.3 months (95% CI, 7.3-NA), with a 1-year PFS rate of 51.8% (95% CI, 35.5%-75.7%). In comparison, per RECIST 1.1 criteria, the ORR and DCR were 50.5% and 90.9%, respectively. The median PFS was 10.6 months (95% CI, 6.8-NA), with a 1-year PFS rate of 49.8% (95% CI, 33.8%-73.4%). The median overall survival (OS) was not reached, and the 1-year OS rate was 83.5% (95% CI, 72.1%-96.6%). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 40.9% of patients. No treatment-related deaths occurred. snRNA-seq revealed TME heterogeneity may drive treatment response differences. Non-responders had hypoxia/glycolysis/proliferation-enriched tumor cells and CAF-driven pro-fibrotic, immune-cold microenvironments, while responders exhibited active immune-tumor crosstalk. Conclusions: DosinTACE study demonstrates that the combination of TACE, donafenib, and sintilimab shows promising efficacy and a manageable safety profile in patients with uHCC. Moreover, tumor-intrinsic metabolic and immune disparities drive treatment response variability. Clinical trial information: NCT05507632 .