Background: Casdozo is the first in class and only clinical-stage IL-27 targeting antibody, which neutralizes IL-27 in the tumor microenvironment and stimulates antitumor response. A phase (Ph) 1 study demonstrated a favorable safety profile and antitumor activity alone and in combination with PD-1 blockade in indications known to have high levels of IL-27 pathway activation, such as HCC (NCT04374877). Casdozo induced increases in serum IFN-g and NK cell gene activation, indicating an immune response and reversal of IL-27-mediated immune suppression. IHC evaluation of HCC commercial tissue microarrays revealed that most HCC samples express the target: IL-27+ tumor-associated macrophages (TAMs, internal data). We present the safety and antitumor activity of this immunoregulatory cytokine antagonist given in combination with atezo/bev in uHCC in the open-label phase of a randomized Ph 2 trial. Methods: Patients (pts) with untreated uHCC received casdozo 10 mg/kg, atezo 1200 mg, and bev 15mg/kg IV every 3 weeks. Primary endpoints were safety and tolerability, with key secondary endpoints being investigator-assessed ORR by RECIST1.1 and mRECIST. Results: As of August 9, 2023, 30 pts were treated with casdozo/atezo/bev. Most pts were male (77%), Asian (67%), ECOG PS 1 (77%), had viral etiology (53% HBV, 17% HCV), and had poor-risk disease as evidenced by metastatic spread (70%) and macrovascular invasion (23%). 47% had AFP ≥400ng/mL. Median time on therapy was 28 wks (3-69). Most treatment-related adverse events (TRAEs) were low grade, with proteinuria (33%), fatigue (20%), decreased appetite (20%), and hypertension (20%) being most common. Grade 3/4 TRAEs occurred in 33%, with only hypertension (13%) arising in ≥10% of pts. TRAEs resulting in any study drug discontinuation was 20%. No deaths were attributed to study drugs. In the 29 response-evaluable pts, 67% experienced any tumor shrinkage with a 38% ORR (3 CRs, 5 confirmed PRs, 3 unconfirmed PRs). In the 28 pts evaluable for mRECIST, ORR was 43% (n=12). More than 50% of pts remain on therapy. Available archival tissue of responders (n=4) all expressed IL-27+ TAMs by IHC, including tumors of viral (n=3) and nonviral etiologies (n=1). Conclusions: Triplet blockade of the IL-27, VEGF, and PD-(L)1 pathways with casdozo/atezo/bev has an acceptable safety profile to date with promising antitumor activity in uHCC that warrants continued exploration. Toxicity was consistent with the known profiles of the agents, with no new safety signals identified. Biomarker analysis to evaluate immune response and associations of IL-27 pathway and clinical outcomes is ongoing. Additional clinical studies of casdozo in combination with the PD-1 inhibitor toripalimab are planned. Clinical trial information: NCT05359861.