New drug TYRA-300 shows effectiveness in treating metastatic bladder cancer

Patients with advanced bladder cancer that had spread to other parts of the body (metastasized) responded well in a Phase I clinical trial of an investigational drug, TYRA-300. The drug targets changes in the FGFR3 gene, which drive tumor growth in about 10-20% of these patients.

Associate Professor Ben Tran, a medical oncologist at the Peter McCallum Cancer Center in Melbourne, Australia, presented the initial August 15, 2024 results from 41 patients enrolled in the SURF301 trial in a recent oral presentation at the 36th EORTC-NCI Meeting. AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, ​​Spain.

He told the meeting that he and his colleagues had reported positive results in overall response rate (the proportion of patients whose tumors are or are shrinking – a partial response) in patients with metastatic bladder cancer with FGFR3 mutations whose cancer had progressed with previous treatments. saw undetectable – a complete response) to TYRA-300, the disease control rate (the proportion of patients who respond partially or completely to the drug and stabilize the disease), and fewer serious side effects compared to other drugs targeting multiple forms of FGFR aim.

In this first-in-human study, we observed dose-dependent clinical activity in ten patients with an overall response rate of 50% and a disease control rate of 100% at an oral dose of 90 mg once daily in heavily pretreated metastatic bladder cancer with FGFR3 mutations. At doses of 90 mg or more once daily, there were six confirmed partial reactions in 11 patients, and three of these reactions are ongoing.

In addition, we noted improved tolerability compared to pan-FGFR inhibitors, with lower rates of significant adverse events, such as: B. increased phosphate levels in the blood, skin and eye reactions and diarrhea.”

Ben Tran, medical oncologist at the Peter McCallum Cancer Center in Melbourne, Australia

At doses between 10 mg and 120 mg, there were four (10%) treatment-related serious adverse reactions, including one dose-limiting case of diarrhea at 90 mg and two (5%) cases of treatment-related increase in a liver enzyme called ALT at a dose of 90 mg, which led to discontinuation of treatment in one patient. There were no grade 4 (life-threatening or disabling) treatment-related adverse events. The once-daily dose of 120 mg was the highest dose evaluated with no dose-limiting toxicities reported through August 15, 2024.

Researchers also found that all four bladder cancer patients with FGFR3 mutations who received the 90 mg dose and for whom blood samples were available had a decrease in tumor DNA fragments (ctDNA) circulating in the bloodstream . In two of these patients there was no evidence of ctDNA, suggesting the cancer had been eradicated.

Prof Tran said: “Although the development of TYRA-300 is still in its early stages, the initial clinical results we have reported here support the previous preclinical results: that we can inhibit FGFR3 with generally limited side effects. As the study progresses, and as the development of TYRA-300 progresses, we will evaluate TYRA-300 in various cancer types in the hope of finding a way to maximize the potential benefit of FGFR3 inhibition for our patients.”

In this Phase I study, as of August 15, 2024, 61% of enrolled patients have bladder cancer (urothelial cancer), 10% have head and neck cancer, 7% have lung cancer, and 22% have other cancers. The results published today include all patients in the Phase I trial who had cancers with FGFR3 mutations or fusions.

About 8% of patients with advanced metastatic bladder cancer survive five years or longer. In healthy, normal cells, fibroblast growth factors (FGFs) bind to their receptors (FGFRs) to regulate cell proliferation, migration, differentiation, and survival. In cancer cells, the same FGFRs are often mutated so that they provide growth and proliferation signals without the need for FGFs to bind to the receptor. This leads to uncontrolled proliferation and tumor growth. For one of these FGFRs, FGFR3, these changes can occur in the form of small changes called mutations, or larger changes in which FGFR3 is fused to another gene, called fusions. Both can lead to uncontrolled FGFR3 activation and cancer.

Prof Tran said: “Although pan-FGFR inhibitors are available and approved for use in metastatic urothelial cancer, the known side effects of these drugs can seriously impact patients' quality of life and doctors may therefore not prescribe them.” The known improvements in response rates are a next-generation FGFR inhibitor that focuses exclusively on the FGFR3 receptor and aims to provide the potential benefits of FGFR inhibition to patients I have been involved in the development of FGFR for many years. inhibitors and when I first saw the data for TYRA-300 I was very excited and knew I wanted to be involved in bringing TYRA-300 to our patients.”

The Phase I clinical trial continues and researchers plan to study TYRA-300 in metastatic bladder cancer, non-muscle invasive bladder cancer, and bone growth abnormalities called skeletal dysplasias.

Professor Timothy A Yap, MD Anderson Cancer Center, University of Texas, Houston, USA, is co-chair of the EORTC-NCI-AACR Symposium and was not involved in the research. He said: “These initial results from the Phase 1 clinical trial of TYRA-300 demonstrate compelling efficacy in patients whose cancer has progressed despite prior intensive treatment with other therapies. The fact that TYRA-300 appears to be able to specifically target cancers with FGFR3 mutations or fusions that have fewer side effects than other drugs gives us hope that patients with difficult-to-treat advanced bladder and other cancers, who also have FGFR3 mutations or fusions may benefit from gentler and more effective therapy once these results are available and have been validated in further clinical studies.”