FDA Fast-Tracks Muzastotug Combo in MSS Metastatic Colorectal Cancer

The FDA has granted fast track designation to the combination of muzastotug (ADG126) plus pembrolizumab (Keytruda) in microsatellite-stable metastatic colorectal cancer (MSS mCRC).¹

Muzastotug is a novel anti–CTLA-4 IgG1 masked antibody utilizing a proprietary masking technology from Adagene which enhances regulatory T-cell depletion and preferentially activates antibody binding within the tumor microenvironment, thereby enabling tumor-specific targeting of antibodies.^1,2 The selective targeting can also help minimize off-target toxicities, potentially enhancing patient quality of life.

The designation, granted to agents designed to fill serious unmet medical needs,³ reflects the FDA’s acknowledgement of this novel approach coupled with the combination’s promising early efficacy and safety profile observed in a phase 1b/2 study (NCT05405595).

Data from the dose-expansion portion shared during the 2025 European Society for Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Asia Congress showed evidence of deep, durable responses with the combination, offering higher response rates than historical anti–CTLA-4 benchmarks. Overall response rates (ORRs) across different dosing regimens ranged from 0% to 29%. Among confirmed responses, the median duration of response was 8 months (95% CI, 4.2–not available).

Overall, no dose-limiting toxicities or grade 4 or 5 treatment-related adverse events were observed, additionally highlighting the manageable safety profile of the combination.

“Receiving [f]ast [t]rack [d]esignation… further validates the promise of our SAFEbody^® technology to unlock CTLA-4 biology in a fundamentally safer and more effective way,” said Peter Luo, PhD, CEO of Adagene, 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 [p]hase 1b/2 clinical data over the next few months as we continue advancing this program with urgency and purpose.”

Muzastotug’s Clinical Development Trajectory

Through enhanced communications with the FDA, the designation will help facilitate the ongoing development and regulatory pathway of the therapy.

Muzastotug’s therapeutic potential is presently being explored in combination with pembrolizumab in the open-label, multicenter phase 1b/2 study involving heavily pretreated patients with advanced or metastatic solid tumors, with a focus on MSS mCRC.⁴ The study is specifically investigating the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination alone or with trifluridine/tipiracil-bevacizumab (Lonsurf plus Avastin) or fruquintinib (Fruzaqla).

With 62 patients with MSS mCRC enrolled and evaluated as of April 2025, the study is recruiting patients for its ongoing randomized phase 2 dose-optimization portion. Here, patients will be randomized to receive either 10 mg/kg or 20 mg/kg of muzastotug plus pembrolizumab (up to 30 patients per arm). The treatment will be administered as an induction-maintenance regimen, with no cycle limits on muzastotug administration.

Looking ahead, the FDA has also confirmed the study design and end points for a phase 3 trial of the combination, slated for 2027. This trial will involve patients with late-line MSS mCRC who do not have liver metastases, including those with peritoneal metastasis or involvement. Designed as a registrational trial, this study will be instrumental in confirming whether the encouraging early responses ultimately translate into meaningful clinical benefits.

REFERENCES

1. Adagene announces FDA fast track designation for muzastotug (ADG126). News release. Adagene. December 16, 2025. Accessed December 16, 2025. https://tinyurl.com/55c6h9rm

2. Li D, Kim SY, Kim HK, et al. Update of phase 1b/2 study of muzastotug (ADG126, an anti-CTLA-4 SAFEbody) in combination with pembrolizumab in advanced/metastatic MSS CRC. J Clin Oncol. 2025;43(4_suppl):193-193. doi:10.1200/jco.2025.43.4_suppl.193

3. Fast track. US FDA. Updated August 13, 2024. Accessed December 16, 2025. https://tinyurl.com/ms2695jn

4. 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