ST316, a first in class beta-catenin antagonist, demonstrates safety and efficacy in metastatic colorectal cancer (mCRC)

BACKGROUND Aberrant activation of the Wnt/beta-catenin pathway is a critical driver of tumor progression and immune evasion in tumors including colorectal cancer (CRC). Targeting this pathway is challenging for multiple reasons including its role in normal tissue physiology. BCL9 is a co-activator essential for oncogenic beta-catenin activity, but not its physiologic functions, highlighting the beta-catenin/BCL9 interaction as a therapeutic target. ST316 was designed to selectively disrupt the beta-catenin and BCL9/9L interaction, resulting in disruption of oncogenic Wnt/beta-catenin transcriptional activity and potent antitumor activity, with no negative impact on intestinal or bone physiology. METHODS A phase 1/2 study is ongoing to determine the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of ST316 alone in solid tumors likely to harbor abnormalities of the Wnt/beta-catenin signaling pathway, and in combination with standard of care FOLFIRI + bevacizumab (SOC) in patients (pts) with metastatic CRC who have progressed after first line chemotherapy-containing regimens. PD analysis was conducted on serial tumor biopsies and blood samples collected at baseline and on-study. RESULTS Here we report biomarker data from the phase I dose escalation and clinical data from the phase 2 study. As of January 5, 2026, 23 pts were enrolled in the dose escalation Ph1 (median age 62 yrs). Pts received a median of 18 weeks of ST316 monotherapy at doses of 0.5mg/kg/QW to 12mg/kg/QW. No DLTs were observed, and the RP2D for combination with SOC was 8 mg/kg. Spatial transcriptomics analysis identified significant decreases in Wnt/beta-catenin transcriptional signatures in tumor cells in 4/4 pts analyzed, confirming on-target pathway disruption. GSEA identified significant attenuation of EMT and TGF-beta signatures, consistent with potent Wnt/beta-catenin antagonism. In Ph2, 15 2L CRC pts (median age 53, range 22-62), 100% MSS, 73% RAS mut, were treated with ST316 + FOLFIRI/bevacizumab and evaluable for response. Confirmed ORR is 46.7% (7/15 pts), along with another 46.7% of pts with SD (7/15 pts, of which 3/7 pts display decreased target lesions). Adverse events occurring in ≥20% of pts include nausea, fatigue, ALT/AST elevations and neutropenia; G3 AEs were reported for ALT/AST elevation and neutropenia. ALT/AST elevations were reversible and managed by dose reductions or drug holidays. CONCLUSIONS ST316 monotherapy was well tolerated, with no Wnt-related AEs, and significant on-target suppression of tumor cell Wnt/beta-catenin transcriptional signatures. In 2L metastatic CRC, ST316 combined with FOLFIRI/bevacizumab reached a confirmed ORR of 46.7% and disease control rate of 93.4%, which compare favorably with 2L FOLFIRI/bevacizumab historical ORR of 11% (Iwamoto et al, EAGLE), supporting a clinically meaningful combination effect. Liver enzyme elevations were reversible and asymptomatic. Together, the data support further evaluation of ST316 in combination with SOC in early-stage CRC.