Each year, nearly 85,000 Americans are diagnosed with bladder cancer, and about 17,500 individuals die from the disease. Urothelial carcinoma is the most frequent type of bladder cancer, constituting over 90% of cases in industrialized nations. Up to two-thirds of advanced urothelial carcinomas are characterized by high expression of the peroxisome proliferator–activated receptor gamma (PPARG).
The results from a phase I clinical trial of FX-909, a first-in-class investigational oral small-molecule inhibitor of PPARG, showed early signs of clinical benefit in patients diagnosed with advanced urothelial carcinoma. According to the study authors, FX-909 is the first small molecule targeting PPARG to show clinical activity in this setting. The study by Gao et al was presented during the AACR-NCI-EORTC International Conference on Molecular Targets.
Study Methodology
The researchers enrolled 46 patients with advanced solid tumors, including 36 with advanced urothelial carcinoma. The patients received FX-909 orally at doses ranging from 30 mg to 100 mg daily in 28-day cycles. The researchers also conducted biomarker analysis to assess tumor PPARG expression, as well as performed skin biopsies to confirm pharmacodynamic changes in response to treatment.
The maximum tolerated dose was determined to be 70 mg; however, lower doses of 30 mg and 50 mg showed improved tolerability while maintaining similar clinical activity. A randomized phase Ib study investigating FX-909 at these lower doses is ongoing in prospectively biomarker-selected patients with PPARG-high advanced urothelial carcinoma in the second line or beyond.
Results
The researchers found that among 31 efficacy-evaluable patients with advanced urothelial carcinoma, 20 had high PPARG expression measured by immunohistochemistry. Of these patients, 14 experienced tumor regression with FX-909, including 4 confirmed partial responses. In addition, one patient with intermediate PPARG expression had a complete response, and another patient with baseline nonmeasurable disease also experienced a complete response.
The most common grade 3 or higher adverse treatment-related side effects included anemia, low platelet counts, and fatigue. Other commonly reported treatment-related side effects included diarrhea and elevated blood sugar levels.
The researchers found that the lower dose of 30 mg was associated with fewer serious side effects, slower onset of side effects, and fewer interruptions or reductions in treatment.
“FX-909 demonstrated a favorable safety profile and is the first small molecule targeting PPARG to show clinical antitumor activity in advanced urothelial carcinoma. A randomized phase Ib study investigating FX-909 (30 mg or 50 mg) is ongoing in prospectively biomarker-selected patients with PPARG-high advanced urothelial carcinoma in the second line or beyond,” concluded the study authors.
Disclosure: Funding for this study was provided by Flare Therapeutics. Dr. Gao is a consultant for 858 Therapeutics, Abeona Therapeutics, ADC Therapeutics, Flare Therapeutics, Janssen, Kanaph Therapeutics, and Lilly. He has received research funding to his institution from Acerand Therapeutics, ALX Oncology, Arvinas, Bayer, and Lilly.
