Patients with advanced bladder cancer with alterations in the FGFR3 gene respond well to investigational drug, TYRA-300

(Press-News.org) Barcelona, Spain: Patients with advanced bladder cancer that had spread to other parts of the body (metastasised) have responded well in a phase I clinical trial of an investigational drug, TYRA-300. The drug targets changes in the FGFR3 gene that drive tumour growth in about 10%-20% of these patients.

 

Associate Professor, Ben Tran, a medical oncologist at Peter McCallum Cancer Centre in Melbourne, Australia, presented the first results as of 15 August 2024 from 41 patients enrolled in the SURF301 study in a late-breaking oral presentation at the 36th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

 

He told the meeting that in patients with metastatic bladder cancer with FGFR3 mutations, whose cancer had progressed on previous treatments, he and his colleagues saw positive results regarding the overall response rate (the proportion of patients whose tumours shrink – a partial response – or becomes undetectable – a complete response) to TYRA-300, the disease control rate (the proportion of patients who have a partial or complete response to the drug and stable disease) and fewer serious adverse side effects compared to other drugs that target several forms of FGFR.

 

Prof. Tran said: “In this first-in-human study, we saw dose dependent clinical activity in ten patients, 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 harbouring FGFR3 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.

 

“In addition, we saw 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 diarrhoea.”

 

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 15 August 2024.

 

The researchers also found that in all four patients with bladder cancer with FGFR3 mutations receiving the 90mg dose for whom blood samples were available, there were decreases in tumour-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.

 

Prof. Tran said: “While it remains early in the development of TYRA-300, the initial clinical findings we have reported here, support the earlier pre-clinical findings: that we can inhibit FGFR3 with generally limited side effects. As the study progresses and as the development of TYRA-300 continues, we will explore TYRA-300 in different cancers, hoping to find a way to maximise the potential benefit of FGFR3 inhibition for our patients.”

 

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

 

Around 8% of patients with advanced metastatic bladder cancer survive for five years or more [2]. In healthy, normal cells, Fibroblast Growth Factors (FGFs) bind to their receptors (FGFRs) to regulate cellular proliferation, migration, differentiation and survival. In cancer cells, these same FGFRs are frequently mutated so that they provide growth and proliferation signals without FGFs having to bind to the receptor. This leads to uncontrolled proliferation and tumour growth. For one of these FGFRs, FGFR3, these alterations can take the form of small changes, called mutations, or larger changes where FGFR3 is fused to another gene, called fusions, both of which can lead to uncontrolled FGFR3 activation and cancer.

 

Prof. Tran said: “While pan-FGFR inhibitors are available and approved for use in metastatic urothelial cancer, 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. TYRA-300 is a next generation investigational FGFR inhibitor, that is designed to focus solely on the FGFR3 receptor, aiming to provide the potential benefits of FGFR inhibition to patients with much fewer side effects. I have been involved in the development of FGFR inhibitors for many years 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 the researchers plan to investigate TYRA-300 in metastatic bladder cancer, non-muscle invasive bladder cancer, as well as abnormalities in bone growth known as skeletal dysplasias.

 

Professor Timothy A Yap from the University of Texas MD Anderson Cancer Center, Houston, USA, is co-chair of the EORTC-NCI-AACR Symposium and was not involved in the research. He said: “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 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.”

 

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Abstract no: 500LBA, “Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301)”, by Ben Tran, presented in plenary session 7 ‘Late breaking abstracts and proffered papers: novel discoveries in drug development’, 15:00-16:50 hrs CEST, Friday 25 October, Room 111-112.

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research]. The Symposium takes place in Barcelona from 23-25 October 2024.

[2] https://www.cancer.gov/types/bladder/survival.

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