At a recent major international oncology conference, Dr. Matthew D. Galsky from Mount Sinai presented updated data from a Phase 1 clinical trial (Late-Breaking Abstract, LBA639) and associated biomarker analysis of FX-909, a first-in-class peroxisome proliferator-activated receptor gamma (PPARG) inhibitor, in patients with advanced urothelial carcinoma (UC). The study data were simultaneously published in the top-tier journal Nature Medicine.01 Targeting PPARG:
A Novel Mechanism to Overcome Luminal Urothelial Carcinoma PPARG is a transcription factor and a core driver of normal urothelial luminal differentiation. Multiple lines of evidence suggest that hyperactivated PPARG signaling drives the development of luminal urothelial cancers. Specifically, PPARG gene amplifications and mutations in its obligate heterodimeric receptor partner, RXR-alpha, are highly enriched in luminal urothelial carcinomas.
Based on this evidence, pharmacologic strategies to repress PPARG transcriptional activity hold potential therapeutic value in these tumors. However, previously developed PPARG antagonists have been unsuccessful to date, largely because they failed to completely inhibit ligand-activated PPARG signaling and could not repress basal PPARG transcriptional activity.
As a first-in-class PPARG inverse agonist, FX-909 binds to PPARG and induces a conformational change that biases the structure toward co-repressor binding, thereby achieving potent dual inhibition of both ligand-activated and basal PPARG transcriptional activities.
02 Study Design and Baseline Characteristics:
Focusing on Heavily Pretreated Advanced UC This Phase 1 study consists of two parts: a Phase 1a dose-escalation phase and a Phase 1b dose-expansion phase. The current report primarily focuses on the data from the Phase 1a dose-escalation phase.
The study enrolled patients with advanced solid tumors who had progressed despite standard therapies, utilizing an enrollment strategy that enriched for UC. Among the 56 patients enrolled in total, 46 had UC. Baseline characteristics revealed a heavily pretreated patient population, with the vast majority having previously received immune checkpoint blockade (ICB) and the antibody-drug conjugate (ADC) enfortumab vedotin (EV).
03 Safety Analysis: 30 mg and 50 mg Identified for Further Exploration During the Phase 1a phase, the study utilized a standard “3+3” dose-escalation design to evaluate the safety of 100 mg, 70 mg, 50 mg, and 30 mg dose cohorts.
- 100 mg Cohort: Two dose-limiting toxicities (DLTs) were observed (hyperglycemia and proteinuria).
- 70 mg Cohort: One DLT was observed (anemia).
Dr. Galsky pointed out that the aforementioned adverse events (including thrombocytopenia and hyperglycemia) primarily occurred in the higher-dose cohorts and were reversible upon discontinuation of the study drug. Based on safety considerations, the lower doses of 30 mg and 50 mg were selected for further evaluation and are currently being explored in randomized cohorts in the Phase 1b portion of the study.
04 Efficacy and Biomarker Exploration:
Precision Screening via High PPARG Expression To precisely identify patients who might benefit from FX-909, the research team developed a PPARG immunohistochemistry (IHC) assay. By evaluating different tumor proportion score (TPS) cutoffs (0%, 50%, 100%) and analyzing the correlation between PPARG IHC expression and RNA sequencing (RNA-seq)-defined luminal/non-luminal lineages, the study established a provisional cutoff of TPS ≥ 60% to define luminal tumors.
Regarding efficacy, the data demonstrated significant antitumor activity for FX-909:
- Clinical Response: Antitumor activity was observed across all evaluated dose levels, including 30 mg and 50 mg, with many patients achieving durable responses.
- ctDNA Dynamics: The majority of patients exhibiting on-treatment declines in circulating tumor DNA (ctDNA) levels had PPARG-high tumors (TPS ≥ 60%).
- Multi-omics Integration: An integrated heatmap analysis of DNA, RNA, and protein data showed a strong correlation among PPARG IHC (≥ 60%), PPARG mRNA expression levels, the luminal subtype (compared to the basal subtype), and clinical responses. Notably, all clinical responses occurred exclusively in patients with PPARG-high (i.e., entirely luminal lineage) tumors.
Furthermore, an analysis of immune cell infiltration inferred from RNA-seq revealed that these luminal tumors had generally decreased immune infiltration compared to basal tumors. This finding provides a mechanistic rationale for exploring future combination treatment strategies involving FX-909 (e.g., in combination with immunotherapy).
05 Summary and Clinical Implications
In his conclusion, Dr. Galsky emphasized that Part A of this Phase 1 study establishes FX-909 as the first pharmacologic agent capable of effectively inhibiting PPARG in humans.
The study observed encouraging preliminary antitumor activity in patients with advanced UC characterized by high PPARG expression, successfully validating PPARG as a viable therapeutic target for luminal UC. This milestone discovery positions PPARG alongside the androgen receptor (AR) in prostate cancer and the estrogen receptor (ER) in breast cancer as successfully targeted nuclear receptors serving as key therapeutic targets in oncology.
Currently, the Phase 1b expansion cohort is ongoing, randomly assigning patients to receive either 30 mg or 50 mg daily, specifically enriching for advanced UC patients with high PPARG expression. It is highly anticipated that this agent will bring a new targeted treatment standard to this difficult-to-treat patient population.
