Background: Atezo + bev is the current first-line standard of care for uHCC based on the IMbrave150 study, which demonstrated superior overall survival, progression-free survival (PFS), and objective response rate (ORR) vs sorafenib (Finn, et al. New Engl J Med 2020; Cheng, et al. J Hepatol 2022). TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergize with other immunotherapies, such as PD-L1/PD-1 inhibitors. The MORPHEUS platform comprises multiple phase Ib/II trials to identify early efficacy signals and safety of treatment combinations across cancers. Here we report data from a cohort of the MORPHEUS-liver study (NCT04524871) evaluating the combination of tira + atezo + bev vs a control arm (atezo + bev) in patients with uHCC. Methods: Patients with previously untreated uHCC were randomized to receive atezo (1200mg IV) + bev (15mg/kg IV) with or without tira (600mg IV) every three weeks. The primary endpoint was investigator-assessed ORR by RECIST V1.1. Secondary endpoints included PFS and safety. Results: A total of 58 patients were randomized (tira + atezo + bev, n=40; atezo + bev, n=18). As of 28 November 2022, median follow up was 14.0 months in the tira + atezo + bev arm and 11.8 months in the control arm. Confirmed ORR was higher in the tira + atezo + bev arm (42.5%) vs the control arm (11.1%). Median PFS was longer with tira + atezo + bev (11.1 months; 95% CI: 8.2–NE) vs control (4.2 months; 95% CI: 1.6–7.4), corresponding to a PFS hazard ratio (HR) of 0.42 (95% CI: 0.22–0.82). A similar pattern of increased ORR and PFS was observed for the treatment arms in both PD-L1+ (n=23) and PD-L1– (n=27) subgroups. For tira + atezo + bev vs control arm, grade 3/4 treatment-related AEs were 27.5% vs 33.3% and AEs leading to any treatment discontinuation were 22.5% vs 22.2%, respectively. Conclusions: The addition of tira to atezo + bev resulted in higher ORR and longer PFS compared with atezo + bev, and no new safety signals were identified. These data suggest that tira + atezo + bev may be a promising novel first-line treatment option for patients with uHCC, and support further study in this setting. Clinical trial information: NCT04524871.