FX-909 demonstrates early activity in PPARγ-high advanced urothelial carcinoma

FX-909, a novel peroxisome proliferator–activated receptor gamma (PPARγ) inverse agonist, demonstrated preliminary antitumor activity in a biomarker-defined subset of patients with advanced urothelial carcinoma (UC), according to data from the phase 1 CLINPRO-1 study (NCT05929235).¹

The results were presented by Matthew D. Galsky, MD, of the Icahn School of Medicine at Mount Sinai, during a late-breaking session at the 2026 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California. The findings were also concurrently published in Nature Medicine.²

Encouraging responses were observed among heavily pretreated patients with advanced UC, particularly in those whose tumors demonstrated high PPARγ expression by immunohistochemistry (IHC). According to the authors, the findings provide early clinical validation of PPARγ as a therapeutic target in luminal UC.

Trial overview

FX-909 is described as a first-in-class PPARγ inverse agonist designed to repress both ligand-activated and basal PPARγ transcriptional activity. Galsky explained that, unlike prior PPARγ antagonists, which were unable to fully suppress receptor signaling, FX-909 induces a conformational shift favoring corepressor binding, thereby more completely inhibiting transcriptional output.

The ongoing phase 1 study includes a dose-escalation phase (part A) followed by a randomized dose-expansion phase (part B). The data presented at ASCO GU focused on part A. Using a standard 3+3 design, investigators evaluated escalating oral dose levels in patients with advanced solid tumors refractory to standard therapy; enrollment was enriched for UC. To be eligible for enrollment, patients needed to have an ECOG performance score of 0 to 2, measurable or nonmeasurable disease per RECIST v1.1, archival tumor tissue or fresh tumor biopsy, and hemoglobin A_1c levels of 7.0% or lower. The median age of patients was 70 years (range, 44-86).

In total, 56 patients were treated, including 46 with advanced UC. Most had received multiple prior lines of therapy (3 or more, 54.2%), including anti–PD-L1 blockade (95.7%) and enfortumab vedotin monotherapy (43.5%). Patients were assigned to 1 of 4 dose levels (30 mg, n = 17; 50 mg, n = 20; 70 mg, n = 13; or 100 mg, n = 6) and received FX-909 orally once daily in 28-day cycles.

Safety profile

Dose-limiting toxicities (DLTs) were observed at higher dose levels. At 100 mg, 2 DLTs occurred (hyperglycemia and proteinuria). At 70 mg, 1 DLT (anemia) was reported. The 30-mg and 50-mg dose levels are being further evaluated in part B.

Grade 3 or higher treatment-related adverse events occurred in 58.9% of patients across all dose levels, which included anemia (26.8%), thrombocytopenia (21.4%), fatigue (10.7%), and hyperglycemia (7.1%). Notable adverse events included thrombocytopenia and hyperglycemia; both were reversible upon treatment interruption and appeared less frequently and at lower grade at reduced dose levels, according to Galsky.

Biomarker development and antitumor activity

There was evidence of antitumor activity across all dose levels. Overall, objective responses were observed in 17.5% of patients. Several responses were ongoing at data cutoff.

To identify patients who might respond better to FX-909, investigators developed a companion IHC assay to quantify tumor PPARγ expression. A provisional tumor proportion score (TPS) cutoff of at least 60% was identified to define PPARγ-high tumors, based on correlations between protein expression and mRNA thresholds. Luminal tumors demonstrated higher PPARγ mRNA expression than nonluminal tumors (mean, 8.09 vs 5.47 log₂ [transcripts per million + 1]; P < .0001), as well as higher PPARγ protein expression (mean, 93.5% vs 30.8% TPS).

In an integrated analysis incorporating DNA, RNA, and protein data, all confirmed partial or complete responses occurred in patients whose tumors met the PPARγ-high threshold and were classified as luminal lineage. Additionally, circulating tumor DNA declines during treatment were more commonly observed in patients with PPARγ-high tumors.

RNA sequencing–based inference suggested decreased immune cell infiltration in luminal tumors compared with basal tumors. According to Galsky, these findings raise the possibility of combination treatment strategies.

Next steps

According to Galsky, these early data from the study support continued clinical investigation of PPARγ inhibition in biomarker-defined luminal UC. Part B of the study is ongoing and will randomly assign patients with advanced UC and PPARγ-high tumors to 30 mg or 50 mg daily to refine dose selection and further characterize efficacy and safety.

Overall, Galsky concluded, “Part A of this phase 1 study establishes FX-909 as the first pharmacological agent capable of effectively inhibiting PPARγ in humans. Promising preliminary antitumor activity is observed in patients with advanced urothelial cancer with increased PPARγ expression. These findings validate PPARγ as a therapeutic target in luminal urothelial cancer, positioning it alongside the androgen receptor and estrogen receptor as successfully targeted nuclear receptors that serve as key therapeutic targets in oncology.”

REFERENCES

1. Galsky MD, Bellmunt J, Mantia C, et al. 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). Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, CA. Abstract LBA639. https://www.asco.org/abstracts-presentations/256844/abstract

2. Galsky MD, Mantia C, Bowden M, et al. A small-molecule inverse agonist of PPARγ for advanced solid tumors: a phase 1 trial. Nat Med. Published online February 28, 2026. doi:10.1038/s41591-026-04263-3