Background: The combination therapies of anti-angiogenic with anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, is approved for treatment of several malignancies in China. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results demonstrated good efficacy and tolerable safety of the combined regimen. Here we updated the results with more enrolled patients and longer follow-up duration. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 pts without prior systemic treatment to receive anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR according to mRECIST and irRECIST. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: By the cutoff date of September 18, 2021, 31 pts were enrolled and treatment duration ranged from 0.23+ to 14.65+ months. Among 26 evaluable pts, the confirmed ORR and DCR according to mRECIST was 34.6% (95% Cl 17.2%-55.7%) and 92.3% (95% Cl 17.2%-55.7%), respectively. The DoRs ranged from 1.38 month to 9.69 month. The preliminary median PFS was 10.2m (95% Cl 6.1-14.3) and the median OS have not reached yet. 28 of 31 pts (90.3%) occurred treatment-related adverse events (TRAEs). Grade 3-5 TRAEs were recorded in 14 pts (45.2%). Immune-Related TRAEs (irTRAEs) occurred in 21 pts (67.7%), while 5 patients (16.1%) had grade 3-5 irTRAEs. The most common grade 3 TRAEs included hypertension (n = 3, 9.7%), hand-foot skin reaction (n = 2, 6.5%), arthralgia (n = 2, 6.5%), total bilirubin increased(n = 2, 6.5%) and fatigue (n = 2, 6.5%). The grade 3 irTRAEs were total bilirubin increased (n = 2, 6.5%), AST increased (n = 1, 3.2%), fever (n = 1, 3.2%), arthralgia (n = 1, 3.2%) and fatigue (n = 1, 3.2%). No grade 4 TRAEs occurred.1 patient had an irTRAE that led to death (immune-related pneumonitis). Conclusions: This combination therapy of anlotinib plus toripalimab in the first-line treatment for uHCC yielded satisfactory anti-tumor efficacy and manageable toxicity. The study is still ongoing and detailed data will be presented. Clinical trial information: ChiCTR1900028295.