Abstract CT083: Ph1b evaluation of ADG126 (muzastotug, an anti-CTLA-4 masking antibody) pembrolizumab (Pembro) IO doublet in combination with fruquintinib (Fruq) in advanced and metastatic microsatellite stable colorectal cancer

Abstract Background: ADG126 is a masked anti-CTLA-4 IgG1 antibody with a widened therapeutic index (TI), designed for tumor-selective activation via protease-mediated cleavage. Upon activation, ADG126 binds a unique CTLA-4 epitope, partially blocks CTLA-4 signaling, slightly primes effector T cells, and selectively depletes intratumoral regulatory T cells. Fruquintinib is a current 3/4L standard of care treatment for MSS CRC, while ADG126 + Pembro showed promising efficacy for those with no liver metastasis (NLM) in this setting1. Triple combo of ADG126 + Pembro + Fruq may further improve therapeutic outcomes by leveraging potential synergy of these pathways in MSS CRC patients, including those with liver metastasis (LM). Here we present the initial dose escalation results evaluating this triple combo in 4L MSS CRC (NCT05405595). Methods: 4L MSS CRC patients with NLM received ADG126 (10 or 15 mg/kg Q6W IV) + Pembro (400 mg Q6W IV) + Fruq (5 mg/day PO, 3 weeks on and 1 week off). Primary endpoints include safety and tolerability, and ORR/DOR. Secondary endpoints include PK, ADA, PFS and OS. Results: As of Nov. 29, 2025, 9 MSS CRC Pts were treated with ADG126 + Pembro + Fruq, with median follow up of 5 months. Early efficacy signals were observed, with 25% (1/4) and 50% (2/4) PRs, and 75% (3/4) and 75% (3/4) DCR for efficacy evaluable patients at 10 and 15 mg/kg ADG126 dose levels, respectively. G3 TRAEs were 25% (1/4) for 10 mg/kg and 40% (2/5) for 15 mg/kg cohorts, respectively, with no G4/5 TRAEs and DLT for safety evaluable patients. MTD was not reached. Fruq was dose-reduced in 67% (6/9) of patients. There were no discontinuations due to safety at either dose level. Updated data will be presented. Conclusions: The favorable safety profile of ADG126 + Pembro IO doublet allows its safe combination with Fruq, with ADG126 dosage ∼10-15 fold higher than some approved ipilimumab combination dosages (e.g., 1 mpk Q6W, IO doublet only) in other indications. Despite the safety profile of Fruq, this triple combo shows manageable safety with no new safety signals identified compared with IO doublet. The triple combo provides options to manage safety by dropping individual components, such as Fruq. Given that Fruq is indicated for LM Pts and may allow such Pts to remain on treatment long enough for IO therapy to induce durable efficacy, future studies including MSS CRC patients with LM are warranted to further investigate the therapeutic effects of the triplet.Reference: 1. Daneng Li et al., Abstract #3579, ASCO, Jun. 2025 Citation Format: Marwan Fakih, Sunil Sharma, Manish R. Patel, Daneng Li, Yan Li, Luke Chung, Songmao Zheng, Xiaohong She, Stanley Frankel, Michael J. Chisamore, Peter Luo, Jiping Zha. Ph1b evaluation of ADG126 (muzastotug, an anti-CTLA-4 masking antibody) pembrolizumab (Pembro) IO doublet in combination with fruquintinib (Fruq) in advanced and metastatic microsatellite stable colorectal cancer [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(8_Suppl):Abstract nr CT083.