Abstract A024: Genomic peroxisome proliferator-activated receptor gamma (PPARG) study: A sponsored testing program to identify patients harboring genetic alterations in advanced UC in support of the FX-909 Phase 1 study
Authors: Bijal Kakrecha, Adarsh Joshi, Kenneth Eagle, Rodney Marable, Michael Meyers, Stefan Kirov, Evisa Gjini, Michaela Bowden
Journal: Clinical Cancer Research (2024)

Abstract The transcription factor PPARG is associated with the luminal lineage subtype representing ~65% of advanced urothelial cancer (UC) patients. Recurrent genetic alterations in PPARG, fibroblast growth factor receptor 3 (FGFR3), and the heterodimeric binding partner for PPARG, retinoid X receptor alpha (RXRA), are characteristic of this luminal subtype. FX-909, a covalent PPARG inverse agonist, represents a promising first-in-class therapy for patients with advanced UC. FX-909-CLINPRO-1 [NCT05929235] is an open-label Phase 1 study to evaluate the safety, tolerability, pharmacokinetics, biologic activity, and preliminary clinical activity of FX-909. This study includes a Phase 1b expansion cohort, which will enroll advanced UC patients with genetic alterations in PPARG, RXRA, and/or FGFR3. FlareTx is sponsoring a testing program called Genomic PPARG Study (GPS) to enable investigators to identify patients with these relevant genetic alterations. Tumors collected from patients with advanced UC were sequenced using the Tempus xT assay (DNA-seq of 648 genes at 500x coverage; RNA-seq). A clinical report is generated and returned to the physician to guide selection of approved therapies, and if appropriate to support eligibility for inclusion in the study. FlareTx is provided with de-identified genomic data, where assessment of the prevalence of genetic alternations such as copy number variation (CNV), fusions and mutations (single nucleotide variants) in PPARG, RXRA and FGFR3 are undertaken. Additionally, luminal molecular classification is performed using the Robertson method [1]. PPARG mean expression value are normalized by transcripts-per-million (TPM) and reported as Log2[TPM+1]. In the initial data set of 27 patients, 3 patients had PPARG amplification (CN &amp;gt;/= 3), 3 patients had RXRA hotspot mutation (S427F) [2], 6 patients had FGFR3 mutation(s), and 1 patient had both PPARG amplification and a FGFR3 mutation. Twenty of 27 patients tested had sufficient starting material of good quality to also perform whole transcriptome analysis. The mean mRNA expression level of PPARG was 6.77 Log2[TPM+1] (range 2.91 Log2[TPM+1] – 9.22 Log2[TPM+1]). Consistent with the Robertson subtype distribution, 65% of patients were luminal and 35% were non-luminal (basal-squamous and neuronal); 10 of 13 luminal patients had one or more genetic alteration in PPARG, RXRA and/or FGFR3. High PPARG expression was associated with luminal subtype compared to non-luminal subtype (7.90 Log2[TPM+1] vs 4.67 Log2[TPM+1]; p=0.00042). GPS is open at two active Phase 1 sites, with several more planned as the study advances towards the Phase 1B dose expansion stage. GPS runs concurrently with the FX-909 study and is a novel precision strategy to maximize identifying advanced UC patients with actionable genetic alterations to potentially enroll in the clinical study. References:1. Robertson AG et al. (2017) Cell 171:540-556. 2. Korpal M et al. (2017) Nat Commun 8:103 Citation Format: Bijal Kakrecha, Adarsh Joshi, Kenneth Eagle, Rodney Marable, Michael Meyers, Stefan Kirov, Evisa Gjini, Michaela Bowden. Genomic peroxisome proliferator-activated receptor gamma (PPARG) study: A sponsored testing program to identify patients harboring genetic alterations in advanced UC in support of the FX-909 Phase 1 study [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A024.