Tyra Biosciences' TYRA-300, a potential first-in-class FGFR3-selective tyrosine kinase inhibitor, has shown encouraging early data in patients with metastatic urothelial carcinoma (mUC). The interim results from the Phase I/II SURF301 trial, presented at the 36th EORTC-NCI-AACR Symposium, indicate promising anti-tumor activity and a favorable safety profile in heavily pretreated patients.
The SURF301 trial is designed to assess the anti-cancer efficacy of TYRA-300 and determine the recommended Phase II dose. The data cutoff included 41 patients, with 25 having metastatic urothelial carcinoma. TYRA-300 was evaluated across six dose levels, ranging from 10 mg to 120 mg once daily.
Efficacy and Safety Results
Interim results showed that all FGFR3-positive patients who received at least 90 mg of TYRA-300 experienced anti-tumor activity. Specifically, 54.5% of patients (n = 6) with mUC achieved a partial response. This included 5 patients (50%) in the 90 mg cohort and the single patient (100%) in the 120 mg cohort. Three partial responses were still ongoing at the time of data report. The disease control rate, defined as partial response plus stable disease, was 100% among patients who received TYRA-300 at 90 mg or higher.
The therapy was generally well-tolerated. Across all dose levels (10 mg to 120 mg), 10% of patients experienced serious adverse events (AEs) related to TYRA-300. One patient in the 90 mg cohort experienced a grade 3 dose-limiting toxicity. Two patients in the 90 mg cohort experienced grade 3 treatment-related AEs (TRAEs) of increased ALT, one of which led to treatment discontinuation. Overall, AEs of any grade occurred in 78% of patients, and AEs of grade 3 or higher occurred in 20% of patients. Notably, there were no grade 4 or higher TRAEs, and no dose-limiting toxicities were reported in the 120 mg cohort.
Addressing Unmet Needs in Urothelial Carcinoma
Urothelial carcinoma, particularly when metastatic, presents a significant challenge. FGFR3 alterations are known to drive tumor biology in a subset of these cancers. While pan-FGFR inhibitors like Balversa (erdafitinib) have shown 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. TYRA-300 aims to overcome these limitations by selectively targeting FGFR3, potentially leading to improved tolerability and patient outcomes.
Expert Commentary
"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. "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."
Ben Tran, MD, associate professor at the Peter McCallum Cancer Centre in Melbourne, Australia, added, "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. 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."
Trial Design and Future Directions
The ongoing SURF301 trial is enrolling participants with mUC and other solid tumors who harbor FGFR3 gene alterations across 21 clinical trial sites in the United States, Europe, and Australia. Phase 1 of the study continues to determine the maximum tolerated dose. Phase 2 will evaluate TYRA-300 at the recommended Phase 2 dose level determined in Phase 1. The primary endpoints for Phase 1 include the incidence of dose-limiting toxicities and adverse events, while secondary endpoints include pharmacokinetic parameters, overall response rate, and progression-free survival.
Tyra Biosciences plans to explore larger opportunities with Phase II studies in metastatic urothelial cancer, non-muscle invasive bladder cancer, and achondroplasia.
