In a phase I clinical trial (SURF301) investigating the fibroblast growth factor receptor 3 (FGFR3) oral inhibitor TYRA-300 in patients with advanced bladder cancer, the drug showed early antitumor activity and produced lower rates of significant adverse events compared with pan-FGFR inhibitors. The study is ongoing to determine the optimal dose of the agent and will explore the activity of FGFR3 in other solid tumor cancers. The data were presented at the 36th European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics (Abstract 500LBA).

Previous studies have shown that in the United States, bladder cancer is the fourth most common malignancy in men and that alterations in FGFR3 occur in about 20% of muscle-invasive bladder cancers and metastatic urothelial carcinomas.

Study Methodology

As of August 15, 2024, the researchers had enrolled 41 patients with advanced cancers with or without FGFR3 alterations in a phase I clinical trial investigating TYRA-300. Of these patients, 61% have bladder cancer, 10% have head and neck cancers, 7% have lung cancers, and 22% have other types of solid tumors. The median number of prior treatments was three. Patients received daily doses of TYRA-300 ranging from 10 mg to 120 mg. The researchers assessed drug safety, preliminary antitumor activity, pharmacokinetics, and circulating tumor DNA (ctDNA).

Key Results

Among the 41 patients, 4 (10%) had serious treatment-related adverse side effects, including one dose-limiting case of diarrhea at 90 mg, and 2 (5%) had grade 3 treatment-related increases in alanine aminotransferase at 90 mg, which led to one patient discontinuing treatment. There were no grade 4 treatment-related side effects. The 120-mg once-daily dose was the highest dose evaluated, with no dose-limiting toxicities reported. The maximum tolerated dose has not been reached.

The pharmacokinetic assessment demonstrated greater than dose-proportional drug exposures with doses higher than 60 mg. Antitumor activity was observed in 11 patients with FGFR3-positive metastatic urothelial carcinomas at doses of 90 mg or more, 3 of whom responded, with the median duration of response not yet reached. Among 10 patients with FGFR3-positive disease receiving TYRA-300 at 90 mg/d, 5 had a confirmed partial response and a disease control rate of 100%.

Decreases in ctDNA were seen in four patients receiving the 90-mg dose for whom blood samples were available. There was no sign of ctDNA in two of these patients, suggesting the cancer had been eradicated, the investigators noted.

“Early antitumor activity and safety data support the continuing development of TYRA-300 for [metastatic urothelial carcinoma] and other solid tumors. The phase I portion [of this study] is still ongoing, with the optimal dose not yet determined,” concluded the study authors.

Clinical Significance

“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,” said Ben Tran, MBBS, FRACP, first author of this study and a medical oncologist at Peter MacCallum Cancer Centre in Melbourne. “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; 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.”

Disclosure: This study was funded by Tyra Biosciences, Inc. For full disclosures of the study authors, visit www.aacr.org.