Abstract Background: Muzastotug (ADG126) is a masked, tumor-activated, Treg-depleting anti-CTLA-4 IgG1 antibody engineered for protease-mediated activation within the tumor microenvironment. Upon activation ADG126 binds a unique CTLA-4 epitope, blocks CTLA-4 signaling, soft-primes effector T cells, and selectively depletes regulatory T cells (Tregs) with ∼10-fold greater antibody-dependent cellular cytotoxicity (ADCC) than ipilimumab. Given the role of Treg-mediated immunosuppression in HCC and the established benefit of atezolizumab (Atezo) and bevacizumab (Bev), the triplet regimen ADG126 + Atezo + Bev may further amplify antitumor immunity. We report interim results from a randomized cohort of the MORPHEUS-Liver platform study (NCT04524871) for the triple combo. Methods: Patients with previously untreated, unresectable locally advanced or metastatic HCC were randomized to Atezo (1200 mg IV) + Bev (15 mg/kg IV) Q3W with or without ADG126 (6 mg/kg IV) Q6W. The primary endpoint was investigator-assessed objective response rate (ORR; RECIST v1. 1). Secondary endpoints included duration of response (DOR), safety, PFS and OS. Results: As of July 11, 2025, 6 patients were randomized to ADG126 + Atezo + Bev arm and 40 to Atezo + Bev. Median follow-up was 18. 8 and 17. 2 months for the ADG126 and control arm, respectively. Confirmed ORR was 50% with ADG126 + Atezo + Bev individual patient target tumor size at baseline and BOR as follows: 52 mm to 8. 5 mm (-84%), 65 mm to 36 mm (-45%), 20 mm to 7. 4 mm (-63%), 76. 8 mm to 54. 8 mm (-28. 6%), 82. 62 mm to 83. 83 mm (+1. 5%), 71. 2 mm to 71. 7 mm (+0. 7%) versus 17. 5% with Atezo + Bev; DCR was 83% versus 53% per RECIST v1. 1. Median DOR was not reached (individual DORs: 18. 1 months, 13. 8 months, and 4 months). PFS and OS were longer for the triple combo. Grade ≥3 treatment-related adverse events (AEs) were similar (50% vs 45%), with no fatal AEs and no ADG126 dose reduction (G3 AEs for triplet arm: 1 hypertension, proteinuria; 1 infusion related reaction; 1 aspartate aminotransferase increased, pyrexia). Two patients discontinued Bev due to toxicity yet remained on ADG126 + Atezo with one remaining on treatment 630 days. Serious AEs occurred in 33% of cases for the ADG126 arm compared to 55% for control. Conclusions: The initial 6 patients treated with ADG126 + Atezo + Bev demonstrated enhanced antitumor activity, PFS and OS, and comparable safety profile compared to the control arm. Observations from two patients for which ADG126 + Atezo therapy continued following Bev discontinuation underscores the potential importance of the ADG126 + Atezo doublet, which is an effective regimen on its own and allows flexibility in treatment after toxicity. These findings support further investigation of ADG126-based combinations for first-line immunotherapy strategies for HCC and beyond. Citation Format: Daneng Li, Edward Gane, Chih-Hung Hsu, Adam Burgoyne, Peter Luo, Songmao Zheng, Yan Li, Xiaohong She, Stanley Frankel, Jiping Zha, Ann-Lii Cheng. Results from the phase 1b/2 Morpheus liver study in patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC): Muzastotug (ADG126: masked anti-CTLA-4 Ab) combination arm abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT054.
Li et al. (Fri,) studied this question.