Update of phase 1b/2 study of muzastotug (ADG126, an anti-CTLA-4 SAFEbody) in combination with pembrolizumab in advanced/metastatic MSS CRC.
Authors: Daneng Li, Sun Young Kim, Hee Kyung Kim, Sunil Sharma, Sang Joon Shin, Jeeyun Lee, Sae-Won Han, Marwan Fakih, Luke Euichul Chung, Yan Li, Ping Xiao, Songmao Zheng, Kristine Xiaohong She, Dana D. Hu-Lowe, Jiangchun Xu, Stanley R. Frankel, Michael Jon Chisamore, Peter Luo, Jiping Zha, Manish R. Patel
Journal: Journal of Clinical Oncology (2025)

193 Background: ADG126 is an anti-CTLA-4 IgG1 masked antibody with cleavable masking peptides that is preferentially activated in the tumor microenvironment, which in turn binds to a unique epitope to block CTLA-4 function, prime T cells and deplete Tregs. We previously reported that repeated dosing of the IO doublet therapy ADG126 plus pembrolizumab (Pembro) was well-tolerated with promising clinical efficacy in 3L MSS CRC patients (pts) free of liver metastasis (NCT05405595) 1,2 . Here we update clinical safety and efficacy of the study as result of continued dose optimization for the IO doublet therapy. Methods: This is a Phase 1b/2, open-label, multicenter dose escalation (DE) and expansion (EXP) study. Primary endpoints were safety and tolerability. Secondary endpoints were PK, ADA, ORR, DCR, DOR, PFS and OS. Results: A total of 72 pts were dosed with ADG126/Pembro (Table). 27.8% pts had ≥ 3 prior therapies and 6.9% pts had prior IO therapies. There was no Grade 4/5 TRAE, and MTD was not reached. Grade 3 TRAEs were 5.9% (1/17), 16.2% (6/37), 33% (4/12) for 10 mg/kg Q6W, 10 mg/kg Q3W and 20 mg/kg loading dose (LD) &amp; cohorts, respectively. Repeated dosing of ADG126 at 20 mg/kg (Q3W)/Pembro was not well-tolerated. In MSS CRC EXP cohorts, ADG126 of 10 mg/kg Q3W/Pembro treatment resulted in 4 confirmed PRs (n=24 EE), 17% ORR (95% CI: 5-37%), 75% DCR, 4.7-mon mPFS and OS rate of 88% (6 mons) and 75% (9 mons). Subgroup analysis revealed that in pts without liver and peritoneal metastasis (NLPM), ADG126 of 10 mg/kg Q6W/Pembro (10 EE) showed 70% SD and ~ 100% OS (6 and 9 mons); ADG126 of 10 mg/kg Q3W/Pembro (17 EE) showed 24% ORR (4 PR (95% CI: 7-50%)), 88% DCR, 47% CBR, 8.5-mon mPFS and OS rate of 89% (6 mons) and 83% (9 mons). Detailed safety and efficacy results, including those from ADG126 20 mg/kg LD cohort, will be reported. Conclusions: Extensive effort on ADG126 dose optimization, aided by PK-informed dosing strategy, suggested that ADG126 10 mg/kg Q6W and Q3W are appropriate dose/regimen for the IO doublet; this is supported by the well-balanced safety and efficacy (ORR, PFS and OS) profile observed in MSS CRC. ADG126 20 mg/kg Q3W appears to have reached safety ceiling for the IO doublet. The totality of the data further verifies that ADG126 possesses potential best-in-class therapeutic index, and provides basis for continued development of the IO doublet in MSS CRC and for additional exploration of the IO doublet in combination with SOCs/other anti-cancer agents in broader patient populations. Clinical trial information: NCT05405595 . Patient number for safety and efficacy evaluation. Evaluated for ADG126 Dose/Pembro* 10 mg/kg Q6W 10 mg/kg Q3W 20 mg/kg Q3W 20 mg/kg LD &amp; Overall Safety (all pts of DE &amp; EXP) 17 37 6 12 72 Efficacy (MSS CRC NLM, EXP) 10 24 / 5 39 *200mg, Q3W, IV; &amp; 20 mg/kg LD: 20 mg/kg x1 cycle followed by 10 mg/kg Q3W. NLM: liver metastasis-free; DE: Dose Escalation; EXP: Dose Expansion; EE: efficacy evaluable. Data cut date: Aug 30, 2024.