On November 3, 2023 Flare Therapeutics Inc., a clinical-stage biotechnology company targeting transcription factors to discover precision medicines for cancer and other diseases, reported molecular real-world data (RWD) demonstrating that high PPARG expression in patients with MIUC is associated with an immunosuppressive tumor microenvironment (TME) and shorter real-world progression-free survival to anti-PD1 treatment (Press release, Flare Therapeutics, NOV 3, 2023, View Source [SID1234636927]). The translational data were shared at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 38th Annual Meeting (SITC) (Free SITC Whitepaper) 2023 taking place November 1-5, 2023 in San Diego, California.
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"While immunotherapy approvals have changed the treatment landscape for MIUC, approximately 70% of patients will still succumb to refractory or acquired resistance," said Michaela Bowden, Ph.D., Chief Development Officer at Flare Therapeutics. "These results offer a unique opportunity to further investigate an immune-mediated mechanism of action for FX-909 with potential to combine with an anti-PD1 agent."
In the poster presentation titled, "PPARG amplification is associated with lack of response to anti-PD1 in Muscle-Invasive Urothelial Cancer," molecular RWD, comprising 1,393 genomic and/or transcriptomic profiles from MIUC patients were utilized to evaluate baseline PPARG expression and amplification associated with anti-PD1 response in MIUC patients. Additional key takeaways are as follows:
Higher PPARG expression and PPARG amplification are negatively correlated with PD-L1 expression in MIUC.
Tumors with elevated PPARG levels and PPARG amplification exhibited a suppressive immune phenotype, typified by an inverse association with CD8+ T cell infiltration.
PPARG amplification is significantly associated with shorter real-world Progression Free Survival to anti-PD1.
FX-909, a first-in-class covalent PPARG inhibitor, entered the clinic this year and is currently being evaluated in a Phase 1 study. The data presented today suggest that FX-909 in combination with ICI agents could potentially provide a new therapeutic strategy that helps MIUC patients with high PPARG expression overcome resistance to immunotherapy.
About FX-909
Flare Therapeutics’ lead investigational compound, FX-909, is a first-in-class novel, highly potent and selective small molecule that inhibits the transcription factor peroxisome proliferator-activated receptor gamma (PPARG) to treat patients with the luminal subtype of advanced urothelial carcinoma (UC) and potentially other solid tumors. Preclinical data for FX-909 has demonstrated robust anti-tumor activity, excellent PK/PD correlation, durable efficacy, and a favorable safety profile in mouse models of UC (PPARG-amp and RXRA-mut) at very low oral doses.
About the FX-909 Phase 1 Study
The ongoing phase 1 study is a first-in-human, dose-escalation and -expansion study of FX-909 in patients with advanced solid malignancies, including advanced urothelial carcinoma. The study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of FX-909. FX-909 will be given initially in a dose-escalation phase (Part A) to determine the recommended phase 2 dose. FX-909 will be given initially orally once daily in 28-day cycles. Part B will be a monotherapy expansion phase to further evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of FX-909 in patients with locally advanced (unresectable) or metastatic urothelial carcinoma. Additional information on this clinical trial can be found on www.clinicaltrials.gov (NCT05929235).
About Advanced Urothelial Carcinoma (UC)
In 2020, there were an estimated 725,549 people living with bladder cancer in the United States alone, making it the sixth most common cancer overall, and fourth most common among men (SEER – 2020). Each year, there are more than 83,000 new cases diagnosed among men and women, and about 25% of those cases are classified as muscle-invasive UC (DRG 2020). Advanced UC has high rates of recurrence, where treatment outcomes have remained poor with typical five-year survival rates of 8% in advanced metastatic disease (SEER – 2020). The transcription factor peroxisome proliferator-activated receptor gamma (PPARG) is associated with the luminal lineage subtype reflecting approximately 65% of all advanced UC cases (Robertson, Cell 2017). Recurrent genetic alterations in PPARG are characteristic of this molecular subtype.