Background: PD-1 inhibitor with Lenvatinib were reported to improve ORR in patients with metastatic HCC. KN046 was a bispecific antibody that target both PD-1/PD-L1 and CTLA-4/B7 immune checkpoints pathway. Preliminary report already showed good efficacy and tolerable safety of the KN046+Lenvatinib regimen. Here we updated the efficacy and safety results with more enrolled patients and longer follow-up duration. Methods: This is an open-label, single-arm, multicenter, phase II trial in pts with unresectable or metastatic HCC. Enrolled patients (pts) with Barcelona Clinic Liver Cancer (BCLC) stage B or C who were not suitable for curative surgery or local therapy had received Lenvatinib 12 mg/day (bodyweight [BW] ≥60 kg) or 8 mg/day (BW<60 kg) orally and KN046 5 mg IV on Day 1 of a 21-day cycle until disease progression or intolerable toxicity or 2-year treatment. Primary endpoints were safety and ORR by RECISTv1.1 per investigators. Results: As data cutoff (January 7, 2022) date, 55 enrolled pts received combination treatment with median duration of 25 weeks. For 52 evaluable pts, ORR was 51.9% (95% CI 37.6-66.0) (RECIST v1.1) and DCR was 86.5% (95% CI 74.2-94.4) (RECIST v1.1). Median PFS was 9.3 months (95% CI 7.0–not estimable [NE]), The median OS and DOR of pts were not reached. The overall incidence of KN046 related treatment-emergent adverse events(TRAEs) was 98.2%, with 27.3% Gr3. The most common Grade ≥ 3 TRAEs included platelet count decreased (7.3% of pts) and aspartate aminotransferase increased (3.6% of pts). The immune related adverse events (irAE) occurred in 14.5% of pts (grade ≥3 5.5%). 3 pts discontinued KN046 treatment due to ≥3 Gr TRAE, which was infusion related reaction, platelet count decreased and interstitial lung disease. 4 (7.2%) pts died from KN046 TRAEs (Hyponatremia, n=1; Interstitial lung disease, n=2; Cause of death unknown, n=1). Conclusions: KN046+Lenvatinib demonstrated a promising efficacy in ORR and PFS and the manageable safety profile in the first-line advanced unresectable or metastatic HCC treatment. These result support the KN046 plus Lenvatinib as a potential new treatment option for this population. Clinical trial information: NCT04542837.