{
  "abstract": "Background In urothelial carcinoma (UC), peroxisome proliferator-activated receptor gamma (PPARG) is a master regulator of luminal lineage, driving tumor initiation and progression. 1 Clinically, high PPARG expression is associated with lack of response to anti-PD-1 therapy2 3 and a ‘cold’ tumor microenvironment (TME).2 We hypothesize that FX-909, an oral first-in-class inhibitor of PPARG, exerts antitumor activity by targeting PPARG-expressing luminal cancer cells, while promoting a systemic immune activation. Exploratory biomarker analyses from a Phase 1 study of FX-909 (NCT05929235)4 were conducted to test this hypothesis.Methods The Phase 1A open-label dose escalation study utilized a 3+3 design (30-100 mg QD, in 28-day cycles) with backfilling of up to 30 patients. As of August 26, 2025, 36 advanced UC patients had been treated across four dose levels. 5 Longitudinal plasma samples from 20 UC patients were analyzed by Olink Explore HT at Cycle 1 Day 1 (C1D1) and Cycle 2 Day 1 (C2D1). Peripheral blood mononuclear cells (PBMCs) from a subset of these patients (n =11) were analyzed by single cell RNAseq at screening and C2D1 following established methods.6 Best Overall Response (BOR) was assessed per RECIST v1.1.Results Of the 20 UC patients, 17 had received prior immunotherapy, either alone or in combination. Twelve patients were of luminal lineage with high PPARG expression by validated immunohistochemistry. Among these 12 PPARG highpatients, 8 experienced tumor regressions, including 3 with confirmed partial response (PR). FX-909 treatment led to increased IFNγ-inducible chemokines and cytokines relative to baseline (figure 1). Immune single-cell analysis revealed expansion of T-cell populations in patients with PRs (screening: 33% vs. C2D1: 62%), indicating a potentially enhanced systemic immune activation in responders (figure 2). A corresponding decrease in circulating monocytes was also seen in PR patients compared with PD patients (36% vs. 17%). These immunologic changes were exclusively observed in PPARGhighpatients with luminal lineage, where PPARG has previously been correlated to lack of response in IO-treated advanced UC patients.2 3 These findings support further exploration of FX-909 as a potential inducer of a more IO-responsive TME. Gene signatures linked to peripheral inflammation and immune cell populations will be presented.Conclusions Phase 1A data indicate that FX-909 directly targets tumor cells with immune modulation, inducing pro-inflammatory cytokines and chemokines and driving T-cell expansion in circulation. These results support PPARG inhibition as a potential strategy to overcome immune resistance in advanced UC and further warrant exploring the potential of FX-909 in combination with anti-PD-1.Acknowledgements We thank the patients and their families for their participation in this study. We are grateful to the clinical investigators, site staff, and study coordinators for their dedication and contributions. We also thank Flare Therapeutics staff, CROs and Consultants.References Tate T, Xiang T, Wobker SE, Zhou M, Chen X, Kim H, Batourina E, Lin CS, Kim WY, Lu C, Mckiernan JM, Mendelsohn CL. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat Commun. 2021 Oct 25;12(1):6160.Gjini E, Kirov S, Bowden M. PPARG amplification is associated with lack of response to anti-PD1 in muscle-invasive urothelial cancer. 2023 Society for Immunotherapy of Cancer (SITC) 38th Annual Meeting.Nguyen PA, Zhang G, Kakrecha B, Marable R, Kirov S, Bowden M, Gjini E. PPARG-high circulating monocytes exhibit an immunosuppressive phenotype in urothelial cancer patients treated with anti-PD1. 2024 AACR Annual Meeting.Iyer G, Gao X, Milowsky M, Garmezy B, Rodrigues Rivera I, Tepper J, Moles M, Gjini E, Bowden M, Meyers ML, Bellmunt J, Galsky M. A phase 1, first-in-human, dose-escalation and expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma 2024 ASCO genitourinary cancers symposium.Gao X, Milowsky MI, Mantia CM, Garmezy B, Iyer G, Petrylak D, Mikhailov Y, Joshi A, Gjini E, Tepper J, Meyers ML, Bowden M, Bellmunt J, Galsky MD. Safety and clinical activity of FX-909, a first-in-class oral small molecule inhibitor of peroxisome proliferator-activated receptor gamma (PPARG), a master regulator of luminal lineage in patients with advanced urothelial carcinoma. 2025 AACR-NCI-EORTC International Conference (LBA submission – pending).Wang L, Sfakianos JP, Beaumont KG, Akturk G, Horowitz A, Sebra RP, Farkas AM, Gnjatic S, Hake A, Izadmehr S, Wiklund P, Oh WK, Szabo PM, Wind-Rotolo M, Unsal-Kacmaz K, Yao X, Schadt E, Sharma P, Bhardwaj N, Zhu J, Galsky MD. Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing. Clin Cancer Res. 2021 Aug 1;27(15):4287–4300.Ethics Approval This study was conducted in accordance with Good Clinical Practice guidelines. Institutional Review Board approval was obtained at each participating site, and all participants provided written informed consent.Abstract 1318 Figure 1FX-909 promotes IFNy- induced inflammatory responses in patients with advanced urothelial cancerAbstract 1318 Figure 2FX-909 induces T-cell expansion selectively in responding patients that are enriched for luminal lineage C2D1: Cycle 2 Day 1",
  "authors": [
    {
      "affiliations": [
        "University of North Carolina, Chapel Hill, NC, USA"
      ],
      "name": "Matthew Milowsky"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Charlene Mantia"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Evisa Gjini"
    },
    {
      "affiliations": [
        "Tisch Cancer Institute At Mount Sinai Medical Center, New York, NY, USA"
      ],
      "name": "Matthew Galsky"
    },
    {
      "affiliations": [
        "Massachusetts General Hospital, Boston, MA, USA"
      ],
      "name": "Xin Gao"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Gopa Iyer"
    },
    {
      "affiliations": [
        "Sarah Cannon Cancer Institute Nashville, Nashville, TN, USA"
      ],
      "name": "Benjamin Garmezy"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Bijal Kakrecha"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Memphis, TN, USA"
      ],
      "name": "Phuong Nguyen"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Peter Szabo"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Michael L Meyers"
    },
    {
      "affiliations": [
        "Flare Therapeutics, Cambridge, MA, USA"
      ],
      "name": "Michaela Bowden"
    },
    {
      "affiliations": [
        "Dana-Farber Cancer Institute, Boston, MA, USA"
      ],
      "name": "Joaquim Bellmunt"
    },
    {
      "affiliations": [
        "Yale School of Medicine, New Haven, CT, USA"
      ],
      "name": "Daniel P Petrylak"
    }
  ],
  "title": "1318 Phase 1 clinical data show FX-909, a first-in-class oral PPARG inhibitor, drives immune modulation and pro-inflammatory cytokine induction in IO-experienced patients with advanced urothelial carcinoma",
  "uid": "e8b253b8-032f-5245-914d-a1891ba8d3c4"
}