e15622 Background: Aberrant activation of the Wnt/ß-catenin pathway is a critical driver of tumor progression and immune evasion in mCRC. Targeting this pathway is challenging due to its role in normal tissue physiology. BCL9 is a co-activator essential for oncogenic ß-catenin activity, but not its physiologic functions, highlighting the ß-catenin/BCL9 interaction as a therapeutic target. ST316 selectively disrupts the ß-catenin and BCL9/9L interaction, resulting in reduced oncogenic Wnt/ß-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/ß-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 1 dose escalation and clinical data from the phase 2 study. As of January 5, 2026, 23 pts were enrolled in the Ph1 (median age 62 yrs). Pts received a median of 18 weeks of ST316 monotherapy (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 indicates significantly decreased Wnt/ß-catenin transcriptional signatures in tumor cells, confirming on-target pathway disruption. GSEA identified significant attenuation of EMT and TGF-ß signatures, consistent with potent Wnt/ß-catenin antagonism. In Ph2, 15 2L mCRC 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 generally well tolerated, safe, and resulted in significant on-target suppression of tumor Wnt/ß-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 supports further evaluation of ST316 in combination with SOC in early-stage CRC. Clinical trial information: NCT05848739 .
El-Khoueiry et al. (Thu,) studied this question.