For patients with microsatellite-stable colorectal cancer (MSS CRC), immunotherapy has long remained a difficult challenge. While immune checkpoint inhibitors have transformed treatment for certain colorectal cancers, the majority of patients with MSS tumors have experienced limited benefit from these therapies.
Now, another investigational immunotherapy combination is moving closer to a potentially important clinical milestone.
On November 9, 2026, Adagene announced the completion of enrollment in its randomized Phase 2 trial evaluating muzastotug (ADG126) in combination with pembrolizumab in patients with previously treated MSS colorectal cancer without liver metastases.
The study has enrolled all 60 patients, with initial results expected in the first half of 2027. The findings will help determine the optimal dosing regimen for a planned Phase 3 registration trial.
Why Muzastotug in MSS Colorectal Cancer Matters
Microsatellite-stable colorectal cancer accounts for the majority of colorectal cancer cases and is generally resistant to conventional immune checkpoint blockade.
Unlike tumors with deficient mismatch repair or high microsatellite instability, MSS tumors often have a less immunogenic tumor microenvironment, limiting the effectiveness of PD-1 inhibitors when used alone.
Muzastotug is an investigational, next-generation anti-CTLA-4 antibody developed using Adagene’s proprietary masking technology. It is designed to become preferentially activated within the tumor microenvironment, potentially reducing systemic toxicity while preserving antitumor activity.
The approach also targets regulatory T cells (Tregs), which can suppress anticancer immune responses. By combining CTLA-4 blockade with pembrolizumab-mediated PD-1 inhibition, researchers hope to overcome some of the immune resistance associated with MSS colorectal cancer.
Phase 2 Trial Evaluates Two Dosing Strategies
The randomized Phase 2 study (NCT05405595) enrolled 60 patients, allocated equally between two treatment arms.
Both groups receive muzastotug plus pembrolizumab using an induction-maintenance strategy designed to establish sufficient drug exposure early in treatment and subsequently maintain antitumor activity.
- Arm A: Muzastotug 10 mg/kg every three weeks for four doses, followed by 10 mg/kg every six weeks during maintenance.
- Arm B: Muzastotug 20 mg/kg every six weeks for two doses, followed by 15 mg/kg every six weeks during maintenance.
The trial’s primary endpoint is overall response rate (ORR), while secondary endpoints include duration of response, progression-free survival, and overall survival.
The study specifically includes patients with late-line MSS colorectal cancer without liver metastases, including those with peritoneal involvement.
Earlier Results Showed Encouraging Antitumor Activity
The decision to advance muzastotug into randomized dose optimization follows encouraging findings from the earlier Phase 1b/2 study.
According to updated results released in April 2026, the combination demonstrated dose-dependent antitumor activity in patients with heavily pretreated MSS colorectal cancer without liver metastases.
Among efficacy-evaluable patients:
- 31% confirmed ORR (8/26) was observed in the combined 20 mg/kg cohorts.
- 13% ORR (5/39) was reported in the combined 10 mg/kg cohorts.
Median progression-free survival reached 6.7 months in the 20 mg/kg cohorts, compared with 4.8 months in the 10 mg/kg cohorts. - Median overall survival was 19.8 months in the 10 mg/kg cohorts, while it had not yet been reached in the 20 mg/kg cohorts.
The safety findings were also relevant to dose selection. Across 67 treated patients, the overall treatment discontinuation rate was 4%, with no dose-limiting toxicities or Grade 4–5 treatment-related adverse events reported. However, Grade 3 treatment-related adverse events occurred in 38% of patients in the combined 20 mg/kg cohorts versus 15% in the 10 mg/kg cohorts.
These results suggest potential antitumor activity, but the earlier dose cohorts were not randomized, and the differences cannot establish that one regimen is superior. The ongoing Phase 2 trial will provide a more structured comparison of efficacy and tolerability.
Preparing for a Phase 3 Trial
The Phase 2 study was developed following discussions with the US Food and Drug Administration (FDA) in 2025.
According to Adagene, the FDA agreed with the company’s proposed standard-of-care control arm for a future Phase 3 trial and confirmed that a muzastotug monotherapy arm would not be required.
The planned Phase 3 study will focus on overall survival as its primary endpoint, with progression-free survival, duration of response, and overall response rate evaluated as secondary endpoints.
In December 2025, the FDA also granted Fast Track designation to muzastotug in combination with pembrolizumab for adults with MSS metastatic colorectal cancer without current or active liver metastases.
Commenting on the latest milestone, Peter Luo, PhD, Chairman and President of R&D at Adagene, stated:
“Completing enrollment in this randomized trial is an important step toward identifying the dose regimen of muzastotug for the Phase 3 registration trial.”
The company also acknowledged an additional equity investment from Sanofi associated with the trial, supporting continued development of muzastotug in solid tumors.
Could Next-Generation CTLA-4 Inhibitors Change the Outlook for MSS CRC?
The development of muzastotug comes amid growing interest in next-generation CTLA-4 inhibitors as potential strategies for overcoming immunotherapy resistance in colorectal cancer.
Other investigational combinations, including botensilimab plus balstilimab, have also demonstrated encouraging activity in selected patients with MSS colorectal cancer, suggesting that more effective CTLA-4 targeting may help extend the benefits of immunotherapy to traditionally resistant tumors.
For muzastotug, however, important questions remain. The earlier efficacy signals must be confirmed, the optimal balance between efficacy and toxicity needs to be established, and any improvement in survival will ultimately require evaluation against standard treatment.
With enrollment now complete, the anticipated 2027 Phase 2 results represent the next critical step in determining whether muzastotug plus pembrolizumab can advance toward a new treatment option for patients with MSS colorectal cancer.
The milestone marks progress in clinical development, although the investigational combination has not yet demonstrated a survival benefit in a randomized trial.
You can also read: Agenus Reports 51% 18-Month Survival With BOT+BAL in MSS Colorectal Cancer
