Muzastotug has been granted fast track designation by the FDA for use in combination with pembrolizumab as treatment for patients with MSS mCRC.
The FDA has granted fast track designation to the combination of muzastotug and pembrolizumab (Keytruda) for the treatment of patients with adult patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) without current or active liver metastases.1
The designation was based on growing data illustrating encouraging efficacy and safety with the regimen. The combination is under investigation in an ongoing phase 2 trial (NCT05405595) updated results from which were presented at the 2025 ASCO Annual Meeting.2
“Receiving fast track designation marks an important milestone for Adagene and further validates the promise of our SAFEbody® technology to unlock CTLA-4 biology in a fundamentally safer and more effective way,” Peter Luo, PhD, chief executive officer and president of R&D at Adagene, stated in a news release.1 “We are deeply encouraged by the responses we are seeing with muzastotug in combination with pembrolizumab and believe this therapy has the potential to reshape the treatment paradigm by offering patients an opportunity for extended survival with an improved quality of life. We look forward to sharing updated topline phase 1b/2 clinical data over the next few months as we continue advancing this program with urgency and purpose.”
Topline News
The FDA awarded fast track status to muzastotug plus pembrolizumab for adult patients with MSS mCRC without active liver metastases based on encouraging efficacy and safety signals from an ongoing phase 2 trial presented at the 2025 ASCO Annual Meeting.
Muzastotug is a masked anti–CTLA-4 SAFEbody designed to enhance antitumor immune activation while reducing off-tumor toxicity, addressing the unmet need in MSS mCRC where checkpoint inhibitors have limited benefit.
Following FDA feedback, the randomized phase 2 study is evaluating 10-mg/kg vs 20-mg/kg dosing with pembrolizumab, without a muzastotug monotherapy arm, and a registrational phase 3 trial with OS as the primary end point is planned to begin in 2027.
What is the need for muzastotug in MSS mCRC?
Muzastotug is a masked anti–CTLA-4 IgG1 SAFEbody with cleavable masking peptides engineered to be preferentially activated in the tumor microenvironment.2 It binds to a unique epitope to block CTLA-4 function, primes T cells, and depletes Tregs through epitope-enhanced antibody-dependent cellular cytotoxicity/phagocytosis. Muzastotug can be given at higher doses in combination with anti–PD-1 antibodies with predicted higher drug exposures with reduced on-target, off-tumor toxicities, positioning it as an attractive option for patients with MSS CRC who generally experience poor responses with first-generation checkpoint inhibition.
Where does muzastotug stand in the development pipeline?
On July 15, 2025, Adagene released an overview of the written feedback received from their Type B meeting with the FDA regarding their development plans for muzastotug plus pembrolizumab.3 Key learnings included that the phase 2 trial will randomly assign patients to either 10 mg/kg or 20 mg/kg of indefinite treatment with muzastotug in combination with pembrolizumab, using an induction-maintenance regimen. Additionally, per the trial design, investigators would be responsible for enrolling approximately 30 patients into each arm of the study, without a requirement for a muzastotug monotherapy arm.
The phase 2 trial enrolled patients at least 18 years old following a wash-out period from prior therapy with MSS mCRC, an ECOG performance status of 0 or 1, at least 1 measurable lesion at baseline according to RECIST 1.1 criteria, adequate organ function, and an archival tumor biopsy taken within 2 years of enrollment.4
The primary outcome measures included establishing the maximum-tolerated dose and recommended phase 2 dose of muzastotug in combination with pembrolizumab and trifluridine/tipiracil (Lonsurf; TAS-102)/bevacizumab (Avastin), safety and tolerability, and preliminary activity.
What data have been previously presented with muzastotug?
Findings presented at the ASCO meeting from the muzastotug/pembrolizumab arms revealed that the objective response rate (ORR) in the cohort that received the agent at 10 mg/kg every 3 weeks (n = 29) was 17% (95% CI, 6%-36%).2 The disease control rate (DCR) was 76% (95% CI, 56%-90%), and the 6-month clinical benefit rate (CBR) was 38% (95% CI, 21%-58%). The median progression-free survival (PFS) was 4.8 months (95% CI, 2.6-6.7) and the 6-month PFS rate was 39.5% (95% CI, 21.8%-56.7%). The median duration of response (DOR) was 6.2 months (95% CI, 4.2-not available [NA]). In the combined 20-mg/kg cohort (n = 21), the ORR was 29% (95% CI, 11%-52%).2 The DCR was 81% (95% CI, 58%-95%). The 6-month CBR data were not mature. The median PFS was not reached (NR), and the 6-month PFS rate was 50.4% (95% CI, 20.7%-74.2%). The median DOR was NR.
At a median follow-up of 17.8 months (95% CI, 15.7-20), the median overall survival (OS) was 19.4 months (95% CI, 13.5-NA).
With respect to safety, any-grade treatment-related adverse effects (TRAEs) occurred in 83% of patients in the combined 10-mg/kg cohort (n = 41) and 81% of patients in the combined 20-mg/kg cohort (n = 26). TRAEs that occurred in at least 10% of patients included pruritus (82.1%), diarrhea (34.3%), hypothyroidism (13.4%), fatigue (11.9%), and adrenal insufficiency (10.4%).
Study authors noted that no dose-limiting toxicities or grade 4 or 5 TRAEs occurred. Low treatment discontinuation was also noted at 4%.
What are the next planned steps?
The registrational phase 3 trial is expected to launch in 2027.1 The primary end point will be OS. Secondary end points will include PFS, DOR, and ORR. In accordance with FDA feedback, Adagene will move forward with their suggested standard-of-care control arm.
References
Adagene announces FDA fast track designation for muzastotug (ADG126). News release. Adagene. December 16, 2025. Accessed December 16, 2025. https://investor.adagene.com/news-releases/news-release-details/adagene-announces-fda-fast-track-designation-muzastotug-adg126
Li D, Kim SY, Patel MR, et al. Safety and efficacy of ADG126 (an anti-CTLA-4 masking antibody) in combination with pembrolizumab: updated results of phase 1b/2 study in advanced MSS CRC. J Clin Oncol. 2025;43(suppl 16):3579. doi:10.1200/JCO.2025.43.16_suppl.3579
Adagene announces regulatory update on clinical development plan for muzastotug in microsatellite stable colorectal cancer following productive type B (end of phase 1) meeting with FDA. News release. Adagene. July 15, 2025. Accessed December 16, 2025. https://investor.adagene.com/news-releases/news-release-details/adagene-announces-regulatory-update-clinical-development-plan
ADG126 in combination with pembrolizumab in patients with advanced/metastatic solid tumors. ClinicalTrials.gov. Updated June 4, 2025. Accessed December 16, 2025. https://www.clinicaltrials.gov/study/NCT05405595
