Phase 0 intratumoral microdevice study of FX-909 in bladder cancer demonstrates on-target anti-tumor activity and immune modulation, enhanced in combination with anti-PD-1

INTRODUCTION Luminal advanced urothelial carcinoma (UC), defined by high PPARG expression, represents ~65% of UC cases and is associated with poor clinical outcomes 1,2 . FX-909, a first-in-class oral PPARG inhibitor, demonstrated early clinical activity and acceptable safety in Phase 1a, with correlative biomarker analyses indicating immune activation 3,4 . Here, we report Phase 0 results (NCT06204614) assessing intratumoral effects of FX-909 alone and with anti-PD-1 using intratumoral microdevice (IMD) 5 implantation and retrieval in primary bladder cancer. METHODS Participants had localized bladder cancer (T2-T3 N0) with tumors containing a ≥1 cm lesion and were planned for cystectomy. Eligibility required clinical stability and sufficient tumor volume. Data are shown from two patients (Pt1, Pt2), with IMDs remaining in situ for 48-72 hours. Two FX-909 doses (D1, 200 mg; D2, 350 mg) were tested. Intratumoral drug penetration was assessed by MALDI-TOF, PPARG 6 and cleaved caspase-3 (CC3) by immunohistochemistry (IHC), CD3 and CD8 by cyclic immunofluorescence (cIF), and spatial transcriptomics (ST) using NanoString CosMx. RESULTS FX-909 tissue penetration showed a dose- and distance-dependent concentration gradient, highest near the device-tissue interface. FX-909 concentrations plateaued at 100-400 μm from the device, with similar histomorphology in exposed and unexposed control-regions. In both patients, FX-909 showed a dose-dependent decrease in the proportion of PPARG expressing cells (Pt1: 32.1% at D1, 71.4% at D2; Pt2: 69.9% at D1, 86.0% at D2). Apoptosis assessment demonstrated dose-dependent increases in CC3+ cells in FX-909 alone (Pt1: 16% at D1, 44% at D2; Pt2: 12% at D1, 18% at D2), with substantially higher levels observed in FX-909 and anti-PD-1 combination (Pt1: 120% at D1, 142% at D2; Pt2: 136% at D1, 289% at D2). ST analyses showed FX-909 suppressed proliferation and cell cycle pathways in tumor cells, while in macrophages it modulated expression changes in key genes associated with a pro-inflammatory state. cIF showed dose-dependent increases in CD8⁺ T-cell infiltration with FX-909, with higher levels observed in FX-909 and anti-PD-1 combination. CONCLUSIONS In this Phase 0 study, FX-909 showed intratumoral penetration and on-target activity in primary bladder cancer, with dose-dependent PPARG modulation, increased tumor apoptosis and CD8 + T-cell infiltration. Combined with anti-PD-1, FX-909 enhanced immune activation and tumor proliferation suppression, supporting further clinical evaluation of this combination in UC 4 . REFERENCES 1. Robertson et al, Cell 2017:171 2. Motley et al, Eur J Cancer 2022:174S1 3. Gao et al, AACR-NCI-EORTC 2025 4. Milowsky et al, J Immunother Cancer 2025:13(Suppl 3) 5. Peruzzi et al, Sci Transl Med 2023:15 6. Gjini et al, J Clin Oncol 2025:43