TYRA-300 shows encouraging safety, efficacy in FGFR3+ metastatic urothelial carcinoma

TYRA-300, an investigational oral FGFR3-selective tyrosine kinase inhibitor, demonstrated initial efficacy while maintaining a favorable tolerability profile in patients with metastatic urothelial carcinoma (mUC), according to interim data from the phase 1/2 SURF301 trial (NCT05544552).¹

Phase 1 of the study remains ongoing.

The data were presented at the 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

"FGFR3 alterations are known to drive tumor biology in a subset of urothelial cancer. While pan-FGFR inhibitors have demonstrated benefit and are approved for use in FGFR3-altered urothelial cancer, they are associated with multiple intolerable on-target toxicities that limit their clinical utility,” said Ben Tran, MD, associate professor at the Peter McCallum Cancer Centre in Melbourne, Australia, in a news release on the data.² “There remains an unmet need to deliver improved precision medicine for urothelial cancer patients that allow patients to not only live longer, but live better.”

In total, 41 patients were included in the preliminary analysis at the time of data cutoff. For the trial, TYRA-300 was evaluated across 6 dose levels, ranging from 10 mg to 120 mg once daily.

In patients with FGFR3-altered mUC, anti-tumor activity was observed across all patients who were treated at the dose levels of 90 mg and higher. In these cohorts, 54.5% of patients (6 of 11) achieved a partial response. This consisted of 5 patients (50%) in the 90 mg cohort and 1 patient (100%) in the 120 mg cohort. Three partial responses were still ongoing at the time of data report.

The disease control rate, consisting of partial response plus stable disease, was 100% among patients with mUC who received TYRA-300 at 90 mg or higher.

According to the authors, the therapy was also generally well-tolerated. There were 4 (10%) serious adverse events (AEs) related to TYRA-300 across all dose levels (10 mg to 120 mg). Of these, 1 was a grade 3 dose-limiting toxicity in the 90 mg cohort, and 2 were grade 3 treatment-related AEs (TRAEs) of increased ALT in the 90 mg cohort, 1 of which led to the discontinuation of treatment.

Overall, AEs of any grade occurred in 78% of patients (n = 32), and AEs of grade 3 or higher occurred in 20% of patients (n = 8). There were no grade 4 or higher TRAEs. No dose-limiting toxicities were reported among patients in the highest dose cohort of 120 mg at the time of data cutoff.

“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,” said Timothy A. Yap, MBBS, PhD, FRCP, from the University of Texas MD Anderson Cancer Center in Houston and co-chair of the EORTC-NCI-AACR Symposium.³ “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.”

Overall, the ongoing SURF301 trial is enrolling participants with mUC and other solid tumors who harbor FGFR3 gene alterations. At the time of data cutoff, 61% of patients (n = 25) in the trial had mUC. Among all patients with FGFR3-altered mUC, 76% had received at least 3 prior lines of therapy.

The median age among all participants was 66 years. Enrollment for the trial is taking place at 21 clinical trial sites across the United States, Europe, and Australia.⁴

For phase 1 of the study, patients will receive TYRA-300 at dose levels ranging from 10 mg – 120 mg once or twice daily. In phase 2, patients will receive TYRA-300 at the recommended phase 2 dose level determined in the first phase.

The primary end points for phase 1 include the incidence of dose-limiting toxicities and adverse events, as well as other safety parameters. Secondary end points include pharmacokinetic parameters, overall response rate, duration of response, duration of complete response, time to response, and progression-free survival.

Phase 1 of the study remains ongoing to determine the maximum tolerated dose.

"The initial results from TYRA-300 are very encouraging. I believe TYRA-300 has the potential to be a next generation targeted therapy, with high selectivity for FGFR3,” Tran concluded in the news release.² “These early data provide support that TYRA-300 can deliver improved anti-tumor activity and tolerability for our FGFR3-altered urothelial cancer patients. TYRA-300 has real potential to improve outcomes, and I look forward to its continued development in all FGFR3-altered cancers."

References

1. Tran B, Zhang A, Hansen A, et al. 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). Presented at: 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics. October 23-25, 2024. Barcelona, Spain. Abstract 500LBA

2. Tyra Biosciences reports interim clinical proof-of-concept data for TYRA-300, an investigational oral FGFR3-selective inhibitor, in phase 1/2 SURF301 study in patients with metastatic urothelial cancer (mUC). News release. Tyra Biosciences, Inc. October 24, 2024. Accessed October 31, 2024. https://ir.tyra.bio/news-releases/news-release-details/tyra-biosciences-reports-interim-clinical-proof-concept-data

3. Patients with advanced bladder cancer with alterations in the FGFR3 gene respond well to investigational drug, TYRA-300. News release. October 25, 2024. Accessed October 31, 2024. https://event.eortc.org/ena2024/2024/10/25/patients-with-advanced-bladder-cancer-with-alterations-in-the-fgfr3-gene/

4. Safety and preliminary anti-tumor activity of TYRA-300 in advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations (SURF301). ClinicalTrials.gov. Updated October 3, 2024. Accessed October 31, 2024. https://clinicaltrials.gov/study/NCT05544552