Advanced bladder cancer patients with changes in the FGFR3 gene respond well to investigational drug: Clinical study

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

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

He said at the meeting that he and his colleagues have seen positive results regarding the overall response rate (the proportion of patients whose tumors shrink — a partial response — or the proportion of patients who become infected) in metastatic bladder cancer patients with FGFR3 mutations whose cancer has progressed on previous treatments. undetectable vs. complete response to TYRA-300), disease control rate (proportion of patients with partial or complete response to the drug and stable disease), and fewer serious adverse side effects compared with other drugs targeting various forms of FGFR.

Prof. Tran said: “In this first-in-human study, we saw dose-dependent clinical activity in 10 patients, with a 50% overall response rate and 100% disease control rate at a dose of 90 mg given orally once daily. Metastatic bladder cancer harboring FGFR3 mutations.” At doses of 90 mg or more once daily, there were six confirmed partial responses in 11 patients, three of which were ongoing.

“We also found improved tolerability and lower rates of significant adverse side effects, such as increased blood phosphate, skin and eye reactions, and diarrhea, compared to pan-FGFR inhibitors.”

At doses ranging from 10 mg to 120 mg, there were four (10%) treatment-related serious adverse events, including one dose-limiting case of diarrhea at 90 mg and a grade 3 treatment-related elevation in two (5%) cases. 90 mg of a liver enzyme called ALT caused treatment discontinuation in one patient. No treatment-related Grade 4 (life-threatening or disabling) side effects were observed. The 120 mg once daily dose was the highest dose evaluated with no dose-limiting toxicities reported as of August 15, 2024.

The researchers also found that all four patients with FGFR3-mutated bladder cancer for whom blood samples were available and who received the 90 mg dose had reductions in tumor-derived DNA fragments (ctDNA) circulating in the bloodstream. Two of these patients had no evidence of ctDNA suggesting that the cancer had been eliminated.

Prof. Tran said: “Although it is still early in the development of TYRA-300, the initial clinical findings we report here support earlier preclinical findings: We can inhibit FGFR3 overall with limited side effects. As the study progresses, the development of TYRA-300 continues.” “We will explore TYRA-300 in different cancers, hoping to find a way to maximize 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 cancer, 7% have lung cancer, and 22% have other types of cancer. The results available today were for all patients enrolled in the phase I trial with cancers with FGFR3 mutations or fusions.

Approximately 8% of patients with advanced metastatic bladder cancer survive for five years or longer. In healthy, normal cells, Fibroblast Growth Factors (FGFs) bind to their receptors (FGFRs) to regulate cellular proliferation, migration, differentiation and survival.

In cancer cells, the same FGFRs are frequently mutated so that they provide growth and proliferation signals without requiring FGFs to bind to the receptor. This leads to uncontrolled proliferation and tumor growth. For one of these FGFRs, FGFR3, these changes can take the form of small changes, called mutations, or larger changes, in which FGFR3 is fused to another gene, called fusion; both of these can lead to uncontrolled FGFR3 activation and cancer.

Prof. “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, resulting in clinicians not being able to prescribe these medications even though they may be able to do so,” Tran said. Known improvements in response rates TYRA-300 is a next-generation investigational FGFR inhibitor designed to focus solely on the FGFR3 receptor and aims to provide patients with the potential benefits of FGFR inhibition with significantly 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.”

A Phase I clinical trial is ongoing and researchers plan to investigate TYRA-300. metastatic bladder cancernon-muscle-invasive bladder cancer, as well as abnormalities in bone growth known as skeletal dysplasias.

Professor Timothy A. Yap, of the University of Texas MD Anderson Cancer Center in Houston, USA, co-chairs 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 intriguing activity in patients whose cancer has progressed despite prior intensive treatment with other therapies.

“The fact that TYRA-300 can specifically target cancers with FGFR3 mutations or fusions, with fewer side effects than other drugs, gives us hope that patients with difficult-to-treat advanced bladder and other cancers that also have FGFR3 mutations or fusions can be treated.” .” “Once these results are confirmed by further clinical studies, they may benefit from a more gentle and effective treatment.”

Provided by the European Organization for Research and Treatment of Cancer