ADG126 (masked anti-CTLA-4) + pembrolizumab + fruquintinib drives 25–50% PRs in 4L MSS CRC (early Ph1b)

ADG126 (muzastotug) is a protease-activated “masked” anti-CTLA-4 IgG1 designed for tumor-selective CTLA-4 engagement, here combined with pembrolizumab (PD-1) and fruquintinib (VEGFR1/2/3 TKI) in a Phase 1b 4th-line MSS metastatic CRC dose-escalation study (NCT05405595) limited to patients with no liver metastases. As of Nov 29, 2025, 9 patients were treated (median follow-up 5 months); among efficacy-evaluable patients, PRs were seen in 25% (1/4) at ADG126 10mg/kg Q6W and 50% (2/4) at 15mg/kg Q6W, with DCR 75% at both doses (3/4 each). Grade 3 TRAEs occurred in 25% (1/4) and 40% (2/5) at 10 and 15mg/kg, respectively, with no Grade 4/5 TRAEs, no DLTs, and no discontinuations; fruquintinib dose reductions were common (67%, 6/9)—notably, this early ORR signal is far above fruquintinib monotherapy in refractory mCRC (FRESCO-2 ORR ~1.5%, DCR ~56%; mPFS 3.7 vs 1.8 months, HR 0.32; mOS 7.4 vs 4.8 months, HR 0.66).