Background: Sintilimab plus bevacizumab has been approved as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC). Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 plus sintilimab has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the efficacy, tolerability, and safety of IBI110 in combination with sintilimab and lenvatinib as first-line treatment in pts with advanced HCC. Methods: This phase Ib study enrolled pts with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W, in combination with lenvatinib (weight <60kg: 8mg, weight ≥60 kg: 12mg) orally administered once daily, until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As the data cutoff date on January 9^th 2023, 28 pts were enrolled (median age: 59 years; ECOG PS=0: 6 pts; stage C per Barcelona Clinic Liver Cancer [BCLC]: 13 pts). All 28 pts were included for safety analysis. Treatment-related adverse events (TRAEs) of any grade occurred in 27 pts (96.4%) and the most frequent TRAEs included hypertension (50%), hypothyroidism (42.9%), neutrophil count decreased (39.3%). Grade ≥ 3 TRAEs occurred in 16 pts (57.1%) and grade ≥3 irAEs occurred in 4 (14.3%) pts. Two (7.1%, 2/28) pts experienced TRAE leading to drug discontinuation. One pt experienced investigator-assessed treatment related death. As of data cutoff, for 27 pts with at least one efficacy evaluation, the objective response rate (ORR) was 29.6% (95% CI, 13.8-50.2). The disease control rate (DCR) was 85.2% (95% CI, 66.3-95.8), and 11 pts were still in treatment. With a median follow up of 12.2 months (95%CI, 11.0-12.6), the median progression-free survival (PFS) was 9.9 months (95%CI, 5.7-NC) and the 9-month PFS rate was 54.5% (95%CI, 33.8-71.2). The median overall survival (OS) was not reached. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and lenvatinib as first line therapy demonstrated robust response and survival benefit with manageable safety profile in patients with advanced hepatocellular carcinoma. This combination therapy need to be further explored in this population. Clinical trial information: NCT04085185.