TYRA-300 Shows Promise in Treating Metastatic Bladder Cancer with FGFR3 Alterations
核心洞察
TYRA-300, a selective FGFR3 (搜索) inhibitor, demonstrates promising antitumor activity in patients with metastatic urothelial cancer (搜索) harboring FGFR3 alterations, with a 54.5% partial response rate at doses of 90 mg or higher.
The SURF301 trial's early results indicate that TYRA-300 is well-tolerated, with fewer of the adverse effects commonly associated with pan-FGFR inhibitors, offering a potentially improved safety profile.
Pharmacokinetic analysis suggests that a dose of 90 mg daily provides adequate FGFR3 (搜索) target coverage, supporting its selection as the optimal dose for achieving the desired therapeutic effect in this patient population.
An investigational drug, TYRA-300, is showing promise in treating patients with metastatic bladder cancer (搜索) that has spread to other parts of the body and harbor Fibroblast Growth Factor Receptor 3 (FGFR3 (搜索)) alterations. The early results come from the phase 1/2 SURF301 trial and were presented at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.
The first-in-human study included 41 patients and showed dose-dependent clinical activity, with a 50% overall response rate and a 100% disease control rate at a dose of 90mg given orally once a day in heavily pre-treated patients with metastatic bladder cancer (搜索) harboring FGFR3 (搜索) mutations. At doses of 90mg or more, once a day, there were six confirmed partial responses in 11 patients, and three of these responses are still ongoing.
Improved Tolerability
TYRA-300 also demonstrated improved tolerability compared to pan-FGFR inhibitors, with lower rates of significant adverse side effects, such as increased phosphate in the blood, skin and eye reactions, and diarrhea. In doses ranging from 10mg to 120mg, there were four (10%) treatment-related serious adverse side effects, including one dose-limiting case of diarrhoea at 90mg, and two (5%) cases of grade 3 treatment-related increases in a liver enzyme called ALT at 90mg, which led to treatment discontinuation in one patient. There were no Grade 4 (life threatening or disabling) treatment-related side effects. The 120mg once daily dose was the highest dose evaluated with no dose-limiting toxicities reported by August 15, 2024.
Impact on ctDNA
Researchers also found that in all four patients with bladder cancer (搜索) with FGFR3 (搜索) mutations receiving the 90mg dose for whom blood samples were available, there were decreases in tumor-derived fragments of DNA (ctDNA) circulating in the blood stream. There was no sign of ctDNA in two of these patients, suggesting the cancer had been eradicated.
Expert Commentary
"While pan-FGFR inhibitors are available and approved for use in metastatic urothelial cancer (搜索), the known side effects of these drugs can seriously affect the quality of life of patients and, as a result, clinicians may not prescribe them despite the known improvements in response rates," said Dr. Ben Tran, a medical oncologist at Peter McCallum Cancer Centre (搜索) in Melbourne, Australia. "TYRA-300 is a next generation investigational FGFR inhibitor, that is designed to focus solely on the FGFR3 (搜索) receptor, aiming to provide the potential benefits of FGFR inhibition to patients with much fewer side effects."
Professor Timothy A Yap from the University of Texas MD Anderson Cancer Center, Houston, USA, who is co-chair of the EORTC-NCI-AACR Symposium, commented, "These first results from the phase 1 clinical trial of TYRA-300 show compelling activity in patients whose cancer has progressed despite being heavily treated with other therapies previously. The fact that TYRA-300 seems able to specifically target cancers with FGFR3 (搜索) mutations or fusions, with fewer side effects than other drugs, gives us hope that patients with hard-to-treat advanced bladder and other cancers that also have FGFR3 mutations or fusions, may be able to benefit from a kinder and more effective therapy once these results have been validated in further clinical trials."
About the SURF301 Trial
The SURF301 trial is a single-arm, multipart study evaluating TYRA-300 across various solid tumors with FGFR3 (搜索) alterations. The phase 1 component includes patients with advanced solid tumors who have exhausted standard-of-care options. In phase 1 part B, patients are required to have advanced solid tumors with FGFR3 mutations.
Phase 2 of the study is focused on patients with FGFR3 (搜索)-altered urothelial carcinoma who have either developed resistance to a prior FGFR inhibitor or have not yet received one, as well as other patients with solid tumors harboring FGFR3 mutations.