Topline data from Adagene’s Phase 1b/2 trial in late-line MSS metastatic colorectal cancer without liver metastases show a dose-dependent signal for muzastotug (ADG126) plus pembrolizumab: confirmed ORR was 31% (8/26) at the 20 mg/kg level versus 13% (5/39) at 10 mg/kg. Median PFS improved to 6.7 months at 20 mg/kg from 4.8 months at 10 mg/kg; in the 20 mg/kg loading-to-10 mg/kg Q3W cohort, median PFS reached 15.4 months. Median DOR was not reached at 20 mg/kg versus 6.2 months at 10 mg/kg. Safety featured a 4% discontinuation rate, no DLTs, and no treatment-related Grade 4/5 events; Grade 3 TRAEs were 38% at 20 mg/kg and 15% at 10 mg/kg. One-year OS was 80.8% at 20 mg/kg, while the 10 mg/kg cohorts posted a median OS of 19.8 months with 48% two-year survival.
The company reported the update alongside FDA Fast Track designation for the combination in adult MSS mCRC without active liver metastases. Enrollment is ongoing in a randomized Phase 2 (NCT05405595) comparing two induction/maintenance regimens that operationalize the observed dose-response: a 10 mg/kg induction followed by Q6W maintenance versus a higher 20 mg/kg induction with higher-dose Q6W maintenance. Up to 60 patients will be randomized 1:1, with ORR as the primary endpoint and results expected in the first half of 2027. Adagene intends to initiate a potential registration study after dose selection and further FDA feedback.
Strategically, this is a focused bid to reintroduce CTLA-4 activity into MSS CRC by widening the therapeutic window with tumor-activated masking and by narrowing the target population to patients without liver involvement—an enrichment approach that aligns with known immunotherapy headwinds in hepatic metastases. The induction/maintenance architecture appears designed to drive early tumor control at higher exposure while mitigating chronic toxicity in maintenance. The safety profile—low discontinuations and absence of high-grade life-threatening TRAEs—suggests the platform may support higher biologically active dosing than conventional CTLA-4 antibodies, but the 38% Grade 3 rate at the higher dose will be scrutinized for long-term tolerability and steroid-sparing management.
For stakeholders, the operational implications are specific. Sites must reliably exclude liver metastases at baseline, increasing reliance on high-quality imaging and potentially central review to avoid misclassification that could confound outcomes. Immune-related AE pathways, including readiness for GI toxicity and endocrinopathies, remain essential, though the reported infliximab use was low. Scheduling complexity spans Q3W and Q6W cycles; the maintenance-heavy Q6W plan could ease infusion chair demand if efficacy is preserved. CROs face a constrained recruitment pool and likely higher screen-failure rates, making referral networks and imaging adjudication critical. For sponsors monitoring the space, the program tests whether masked CTLA-4 can unlock an MSS CRC niche without biomarker testing, potentially simplifying trial logistics relative to genomic stratification.
Regulatory dynamics are clear: single-arm Phase 1b/2 signals will not carry an approval in this setting. The randomized Phase 2 must demonstrate a consistent dose-effect and credible activity benchmarked against current late-line standards such as fruquintinib, regorafenib, and TAS-102, where modest PFS gains are established. The notably high PFS reported in the loading cohort warrants confirmation and sensitivity analyses to rule out regimen- or assessment-driven artifacts.
What to watch next is dose selection and any interim consistency data across sites, as well as durability with extended exposure at higher doses where Grade 3 events were more frequent. The registrational design choice—comparator, endpoint hierarchy, and geographic footprint—will signal confidence and commercialization intent. If the randomized Phase 2 replicates the magnitude of response and durability with manageable toxicity, the path could include expedited interactions under Fast Track. The risk remains that a narrow, no-liver subset limits market impact unless regulators and payers accept site-of-disease enrichment as a durable precedent in MSS CRC.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
