Updated clinical results and associated biomarkers from an ongoing phase 1 study of FX-909, a first-in-class peroxisome proliferator-activated receptor gamma (PPARG) inhibitor, in patients (pts) with advanced urothelial carcinoma (adv UC).

Abstract

LBA639 Background: PPARG is a master regulator of luminal lineage in UC with two-thirds of adv tumors classified as luminal. FX-909 is a first-in-class oral small molecule that potently and selectively inhibits both ligand-mediated and basal PPARG activity, offering a novel approach to targeting key cancer cell-intrinsic biology. Preliminary phase 1A data have demonstrated objective responses with FX-909 monotherapy (Gao, AACR Targets 2025). Here we report updated safety, tolerability, antitumor activity and predictive biomarker discovery to identify pts most likely to benefit from FX-909. Methods: 56 pts enrolled in a phase 1A open-label dose escalation study (30-100 mg PO QD, 28-day cycles), including additional 10 adv UC patients in 30 mg PO and 50 mg PO QD backfill cohorts. Baseline archival tissue (<30 months old) or a fresh biopsy collected for PPARG IHC (SP500 clone) and NGS correlative biomarker analysis. A provisional PPARG TPS cutoff was determined using linear regression modeling leveraging molecular real-world data (RWD) (N=2609 adv UC pts, Tempus xT). Serial blood samples collected for ctDNA analysis. Results: As of Nov 10, 2025, 46 pts with adv UC have been treated across four dose levels; 30 mg (17); 50 mg (16); 70 mg (11); and 100 mg (2). Median age was 71 (range 44-86), 71.7% ECOG PS 1, and 100% had mUC. Median lines of prior therapy was 3 (range, 1-8), including prior EV and anti-PD(L)1 treatment in 69.6%. Concordance between PPARG mRNA and TPS (r = 0.88, p<0.001) supported linear regression modeling, which inferred a provisional TPS cutoff of ≥60% (PPARG high ). Among 40 efficacy-evaluable adv UC pts, 35 had PPARG IHC results. 18/26 PPARG high pts showed tumor regressions, including 5 confirmed and 1 unconfirmed partial response. Decreases in ctDNA VAF occurred in 7/8 PPARG high pts with available results at cycle 2 (3 PR, 3 SD). Additional data demonstrating the relationship between PPARG high status, luminal subtype, and specific genomic alterations (PPARG(CN≥3), RXRA S427F and FGFR3) will be presented. At 30mg and 50mg doses, the most common ≥Gr3 TRAEs were anemia (18.9%), thrombocytopenia (16.2%) and fatigue (10.8%). Other common TEAEs were diarrhea (32.4%), hypertriglyceridemia (27%) and hyperglycemia (24.3%). The 30 mg dose was associated with fewer Gr3 TRAEs (35.3%), longer time to TRAE onset (52 days, range 44, 85), and fewer dose interruptions (29.4%) and dose reductions (11.8%). Conclusions: FX-909, a first-in-mechanism orally bioavailable PPARG inhibitor, demonstrates clinical proof-of-concept for targeting the master regulator of luminal lineage in heavily pretreated adv UC pts and may offer a novel therapeutic strategy for PPARG high adv UC. A randomized phase 1B expansion study is ongoing (NCT05929235). A combination study of FX-909/anti-PD1 is planned for early 2026. Clinical trial information: NCT05929235 .