Background Muzastotug is an anti-CTLA-4 IgG1 SAFEbody® with cleavable masking peptides that is preferentially activated in the tumor microenvironment and binds to a unique CTLA-4 epitope to prime T cells and deplete Tregs. We previously reported that repeated dosing of Muza as monotherapy had notably fewer Grade 3/4 irAEs than ipilimumab at ~7-fold higher doses (NCT04645069 and Study ADG126-1002), and that Muza/Pembro combination demonstrated promising clinical efficacy in 3L MSS CRC patients free of liver metastasis (NCT05405595). We report additional safety and efficacy data including further dose optimization for the combination 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 and PFS. Exposure-response assessment and mPBPK modeling were conducted.

Results As of 5/21/2024, 64 patients were dosed with Muza/Pembro (table 1). 26.6% patients had ≥ 3 prior therapies and 7.8% patients had prior IO therapies. No DLT or Grade 4/5 TRAE was observed and MTD was not reached. Grade 3 TRAEs at 10 mg/kg Q3W was 17% (7/42); TRAEs of ≥ 10% were pruritis (26.3%), hypothyroidism (15.3%), diarrhea (12.5%) and fatigue (11.1%). Repeat dosing at 20 mg/kg Q3W was associated with 3 TRAEs (3/5): 1 Grade 3 hemolytic anemia, 1 Grade 2 pneumonitis and 1 Grade 2 cough.

In MSS CRC EXP cohorts, Muza (10 mg/kg Q3W)/Pembro treatment resulted in 5 PRs [4 confirmed, ORR=17% (5/29)] and 86% DCR. The median treatment cycles for both Muza and Pembro were 5 (2–18). Subgroup analysis reveals that patients without liver and peritoneal metastasis (evaluable=22) showed a better response, resulting in 23% ORR (95% CI: 8–45%), 86% DCR, 36% CBR, 7-month mPFS, and >90% patients without survival event at data cutoff.

Integrated quantitative analysis supports the regimen of a single Muza 20 mg/kg loading dose followed by 10 mg/kg Q3W to optimize therapeutic index of the combination therapy. Evaluation of safety and efficacy with this regimen in MSS CRC is ongoing and will be reported.

Conclusions Muzastotug (up to 10 mg/kg Q3W)/Pembro continues to be well-tolerated with meaningful clinical benefits and durability in 3L MSS CRC. A higher dose Muza (20 mg/kg) allows for a rapid reaching of plasma cleaved drug exposure associated with clinical efficacy and an acceptable safety profile when combined with pembrolizumab. This regimen potentially can offer a best-in-class treatment option for patients with advanced/metastasis MSS CRC.