TYRA-300 Begins Phase 2 Trial in FGFR3-Altered NMIBC
A groundbreaking trial for TYRA-300, an oral FGFR3 inhibitor, aims to transform treatment for patients with low-grade intermediate-risk bladder cancer.
Bladder cancer stages: © pikovit - stock.adobe.com
The first patient has been dosed in the phase 2 SURF302 trial (NCT06995677) of TYRA-300, a highly selective oral FGFR3 inhibitor, for the treatment of patients with low-grade, intermediate-risk non–muscle-invasive bladder cancer (NMIBC).1
Bladder cancer remains one of the most common malignancies of the urinary tract, with NMIBC accounting for approximately 75% of newly diagnosed cases. Within this group, intermediate-risk disease poses a unique challenge, particularly when characterized by FGFR3 genetic alterations. FGFR3 is one of the most frequently mutated genes in low-grade NMIBC, present in approximately 70% of cases. These mutations are associated with tumorigenesis and recurrence, making FGFR3 an attractive therapeutic target.
TYRA-300 is a potential first-in-class, investigational oral selective FGFR3 inhibitor developed using Tyra’s proprietary SNÅP (Structure-based Novel Architecture Platform) technology. It is designed to spare FGFR1, FGFR2, and FGFR4 to minimize off-target toxicities often associated with pan-FGFR inhibition, while also maintaining activity against FGFR3 gatekeeper mutations that confer resistance to some existing therapies.
The candidate previously demonstrated promising interim proof-of-concept data in patients with metastatic urothelial carcinoma (mUC), establishing a rationale for further exploration in earlier stages of bladder cancer, particularly those with defined FGFR3 alterations.
"Our goal is to develop TYRA-300 as the first once-daily oral treatment designed to reduce disease recurrence, as well as surgical procedural intervention and intravesical therapy, for people living with [intermediate-risk] NMIBC," said Erik Goluboff, MD, senior vice president of clinical development at Tyra Biosciences, in a press release. "We believe we are well positioned to contribute meaningful advancements to the field of bladder cancer with SURF302, and we anticipate that the clinical data will offer valuable insights with the potential to enhance patient outcomes."
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SURF302: Trial Design and Objectives
SURF302 is a multicenter, open-label, phase 2 study evaluating the safety and efficacy of TYRA-300 in patients with FGFR3-altered low-grade intermediate-risk NMIBC.2 The trial will enroll up to 90 patients across various US sites. Eligible patients must have histologically confirmed low-grade NMIBC with a residual visible marker lesion and documented FGFR3 mutation or fusion.
Participants are randomized into 2 parallel dose cohorts:
- Cohort A: TYRA-300 at 60 mg once daily
- Cohort B: TYRA-300 at 50 mg once daily
A third cohort (C) may be opened to evaluate alternative dosing, contingent upon safety and efficacy outcomes from the initial 2 groups.
The dual-cohort structure allows simultaneous evaluation of 2 dosing regimens to rapidly assess optimal therapeutic index. This is particularly important in NMIBC, where tolerability is crucial given the chronic nature of the disease and patient preference for bladder-preserving strategies. The inclusion of a flexible third cohort ensures adaptability based on emerging safety and efficacy data, reinforcing the trial’s design as both rigorous and responsive.
Eligibility is restricted to patients with intermediate-risk, low-grade NMIBC, as defined by AUA 2024 guidelines. This includes those with low-grade Ta with recurrence within 1 year, solitary low-grade Ta tumors >3 cm, multifocal low-grade Ta lesions, or low-grade T1 tumors. All patients must have residual visible tumor (3 mm to 12 mm) postdiagnostic biopsy or transurethral resection of bladder tumor and documented FGFR3 activation. Prior Bacillus Calmette-Guérin (BCG) therapy within 1 year and intravesical chemotherapy within 8 weeks are exclusionary. Standard hematologic, hepatic, and renal function benchmarks apply, along with the ability to swallow oral tablets and adhere to effective contraception measures.
The trial also will include patients with well-controlled HIV or viral hepatitis, reflecting a broader effort toward accessibility while ensuring safety through predefined management protocols.
The primary end point is the complete response rate at 3 months posttreatment. Secondary end points include recurrence-free survival, progression-free survival, median duration of response, time to recurrence, and safety/tolerability profiles.1
Beyond NMIBC, TYRA-300 is being evaluated in 2 additional phase 2 trials:
- SURF301 (NCT05544552): Targeting mUC
- BEACH301 (NCT06842355): Investigating TYRA-300 in pediatric patients with achondroplasia
The BEACH301 trial has also opened for enrollment, with first pediatric dosing anticipated in the second half of 2025.
If successful, TYRA-300 could represent a paradigm shift in the management of intermediate-risk NMIBC, a population for whom treatment options are currently limited to surveillance, intravesical chemotherapy, or BCG (with limited efficacy and high recurrence rates). A targeted oral therapy could offer patients a bladder-sparing, mutation-driven treatment that is both convenient and personalized.
"I am excited that the phase 2 trial evaluating oral TYRA-300 in [intermediate-risk] NMIBC is now underway," said Tom Jayram, MD, director of the Advanced Therapeutics Center at Urology Associates in Nashville, TN, in a press release. "[Intermediate-risk] NMIBC is a challenging disease for urologists and patients alike, with the potential for recurrence, progression, and the morbidity of multiple procedures for disease surveillance. Selective FGFR inhibitors are an exciting new option in this disease space that can allow a personalized approach to bladder cancer. TYRA-300 is an investigational, daily oral tablet that has shown encouraging preliminary safety and efficacy in an early phase trial and has the potential to be a paradigm shift in how urologists can treat bladder cancer."
