Abstract B031: A phase 1/2 trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor, preliminary safety and efficacy in patients with solid tumors bearing Wnt pathway-activating mutations (WPAM+)

Abstract BACKGROUND: Dysregulation of the WNT-signaling pathway is associated with the development and progression of various tumors. Wnt-β-catenin pathway activating mutations are nearly universally present in selected solid tumors (e.g. desmoid) and in more than 80% of microsatellite stable (MSS) colorectal cancer (CRC). There are no approved agents targeting this pathway. FOG-001 is a Helicon™ peptide that competitively inhibits the interaction between β-catenin and TCF transcription factors in the Wnt-signaling pathway. FOG-001 monotherapy inhibits tumor growth in WPAM+ CRC and other solid tumor patient-derived xenograft (PDX) models. When co-administered with 5-fluorouracil (5-FU), or inhibitors of VEGF or PD-1, FOG-001 showed additive to synergistic efficacy in PDX models. Here we present safety, efficacy, and pharmacokinetic (PK)/pharmacodynamic (PD) results of FOG-001 in patients (pts) with advanced solid tumors. METHODS: This is a first-in-human, phase 1/2, study of FOG-001 alone or in combination in pts with locally-advanced or metastatic solid tumors (NCT05919264). Eligible pts must have received ≥1 prior systemic therapies and either progressed or were unfit for available therapies. Pts with MSS CRC should have received prior 5-FU, oxaliplatin, and irinotecan in the metastatic setting. The primary objective is safety and tolerability. Secondary objectives include anti-tumor activity, PD in paired tumor biopsies and PK. Circulating tumor DNA (ctDNA) assessment is exploratory. RESULTS: As of May 11, 2025, 83 (N=63 MSS CRC, N=20 other WPAM+ solid tumors) pts have received FOG-001 monotherapy at doses ranging from 36–480 mg/m2. Median age was 53 (range 19–79) and 63.9% were male. In pts with MSS CRC, median number of prior treatment lines was 4, with 87.3% and 69.8% of pts having lung and liver metastases, respectively. Grade (Gr) 3 and serious treatment-related adverse events (TRAEs) were uncommon, reported in 20.5% and 2.4% of pts, respectively, primarily at doses at or above 360 mg/m2. There were no Gr 4 or 5 TRAEs and no treatment discontinuations due to TRAEs. FOG-001 showed dose linear exposure with low variability. Anti-tumor activity was assessed in the efficacy-evaluable population. In Wnt-β-catenin driven solid tumors (N=14), objective response rate (ORR) was 43%. Disease control rate (DCR) in this population was 79%. In pts with desmoid tumors (N=5), ORR and DCR were 60% and 100%, respectively. In MSS CRC, the DCR was 50% at the higher dose levels (240–480 mg/m2) with molecular responses (≥50% ctDNA reduction) in 60% of these pts. CONCLUSIONS: FOG-001 monotherapy is well tolerated with a manageable safety profile in pts with desmoid, other WPAM+ tumors and heavily pre-treated MSS CRC. Favorable PK, on-target PD effect, and encouraging anti-tumor activity demonstrate that FOG-001 is a bona fide β-catenin inhibitor with biologic and clinical impact supporting ongoing expansion in desmoid tumors, and evaluation in combination with standard chemotherapy or nivolumab in MSS CRC. Citation Format: Samuel J. Klempner, Michael Cecchini, Moh’d Khushman, Shivaani Kummar, Meredith Pelster, Jordi Rodon, Sunil Sharma, Rona Yaeger, Jonathan Rojo, Amber L. Wells, Megan Tipps, Wade Berry, Amanda Garofalo, Lalith Akella, Laura Strong, Xinwei Han, Ziyang Yu, Jorge D. Ramos, Marie Huong Nguyen, Jonathan Hurov, Keith Orford, Kyriakos P. Papadopoulos. A phase 1/2 trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor, preliminary safety and efficacy in patients with solid tumors bearing Wnt pathway-activating mutations (WPAM+) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B031.