Background: Immune checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 have become established treatments for advanced hepatocellular carcinoma (aHCC) but yield low objective response rates (ORRs) in treated patients (pts). Dual inhibition of LAG-3 and PD-1 pathways has demonstrated synergy in activating T-cells and improving immune response. Tebotelimab, also known as MGD013, is a bispecific tetravalent DART molecule that can bind both PD-1 and LAG-3. We initiated an open-label, single-arm, phase 1/2 dose escalation and expansion study to assess the safety and efficacy of tebotelimab in pts with aHCC. Methods: Eligible pts with aHCC who received ≥1 prior systemic treatment with or without prior CPI exposure were enrolled. The dose escalation phase evaluated doses at 120, 240, 400, and 600 mg. Tebotelimab was administered intravenously once every two weeks (Q2W) on days 1 and 15 of each 28-day cycle. The dose expansion phase consisted of one CPI-experienced cohort and one CPI-naïve cohort, both treated at recommended phase 2 dose (RP2D). Primary endpoints were safety for the escalation phase, and safety and ORR per RECIST v1.1 for the expansion phase. Investigator-assessed efficacy results are reported. Results: At data cut-off as of 27 April 2022, 13 pts received tebotelimab in the escalation phase. No dose-limiting toxicity was observed and RP2D was determined as 600 mg Q2W. In the expansion phase, 69 pts (CPI-experienced 33, CPI-naïve 36) were enrolled (median age, 57.0 years; male, 87.0%; ECOG 1, 58.0%; BCLC Stage C, 89.9%; and HBV etiology, 84.1%). Thirteen (18.8%) pts had Grade ≥3 treatment-related adverse events (TRAEs), most commonly hepatic function abnormal (n=3), amylase increased (n=2), and aspartate aminotransferase increased (n=2). Serious TRAEs occurred in nine (13.0%) pts, immune-related adverse events in 30 (43.5%), TRAEs leading to treatment discontinuation in five (7.2%), and treatment-related death in one (1.4%). Of the 30 evaluable pts in the CPI-experienced cohort, one achieved confirmed partial response (PR) and 14 achieved stable disease (SD), with a 3.3% ORR and a 50.0% disease control rate (DCR); of the 30 evaluable pts in the CPI-naïve cohort, four achieved confirmed PR and 10 achieved SD, with a 13.3% ORR and a 46.7% DCR. Median progression-free survival was 2.4 and 3.1 months for CPI-experienced and CPI-naïve cohorts, respectively, with median overall survival not reached in both. Conclusions: Tebotelimab demonstrated a manageable safety profile in pts with aHCC. Antitumor activity, mainly as disease stabilization, was observed in both the CPI-naïve setting and the CPI-experienced setting. No additional clinical trials are planned at this time. Clinical trial information: NCT04212221.