TYRA-300 Is Safe, Generates Preliminary Antitumor Activity in FGFR3+ Metastatic Urothelial Cancer

Treatment with the potential first-in-class, investigational, oral, selective FGFR3 inhibitor TYRA-300 was safe and produced preliminary antitumor activity in patients with metastatic urothelial cancer harboring FGFR3 alterations, according to data from the phase 1/2 SURF301 trial (NCT05544552).¹

Findings showed that patients with FGFR3-altered metastatic urothelial cancer treated with TYRA-300 at a dose of at least 90 mg per day (n = 11) achieved a partial response (PR) rate of 54.5%, and 3 of the 6 responses were ongoing at data cutoff. The disease control rate was 100%.

Ten of these patients received the agent at 90 mg per day, and the PR rate in this group was 50%. The lone evaluable patient treated at 120 mg per day also experienced a PR

The agent was well tolerated, and toxicities associated with FGFR1 and FGFR2 were uncommon. Ten percent of patients treated at doses of TYRA-300 ranging from 10 mg per day to 120 mg per day experienced serious treatment-related adverse effects (TRAEs). One dose-limiting toxicity of grade 3 diarrhea was reported at the 90-mg dose level. One patient treated at 90 mg per day experienced a grade 3 TRAE of increased alanine aminotransferase levels, which led to treatment discontinuation.

“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. 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,” Ben Tran, MD, an associate professor at Peter McCallum Cancer Centre in Melbourne, Australia, stated in a news release. “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 antitumor activity and tolerability for our [patients with] FGFR3-altered urothelial cancer. TYRA-300 has real potential to improve outcomes, and I look forward to its continued development in all FGFR3-altered cancers.”

SURF301 is a single-arm, multi-part, ongoing trial evaluating TYRA-300 in patients with FGFR3-altered advanced solid tumors.² The phase 1 portion includes patients at least 18 years of age with histologically confirmed advanced solid tumors who have exhausted standard-of-care treatment options. Patients are required to have an ECOG performance status of 0 or 1. In part A of phase 1, patients must have evaluable disease per RECIST 1.1 criteria; measurable disease per RECIST 1.1 criteria is required for part B. Notably, histologically confirmed advanced solid tumors harboring eligible FGFR3 mutations or fusions are only necessary for inclusion in part B.

Phase 2 comprises patients at least 18 years of age with FGFR3-altered urothelial carcinoma who progressed on a prior FGFR inhibitor and harbor a resistance mutation or other kinase domain mutation; patients with FGFR3-altered urothelial carcinoma who have not received a prior FGFR inhibitor; and patients with any solid tumor harboring an eligible FGFR3 gene mutation or rearrangement.

Key exclusion criteria consist of any ocular condition likely to increase the risk of eye toxicity, a history of or current uncontrolled cardiovascular disease, and active, symptomatic, or untreated brain metastases.

Part A of phase 1 was the dose-escalation portion of the study, in which TYRA-300 was evaluated at doses ranging from 10 mg to 120 mg once per day. This portion of the study has concluded.¹ Part B of phase 1 serves as the dose expansion portion of the study, and phase 2 will further evaluate TYRA-300 at doses determined in phase 1.²

The study’s primary end points are determination of the maximum tolerated dose in phase 1, part A; determination of the recommended phase 2 dose in phase 1, part B; and overall response rate in phase 2.

Forty-one patients have been enrolled onto the phase 1 portion as of the data cutoff date of August 15, 2024. Among these patients, 44% received at least 3 prior lines of therapy. Seventy-six percent of patients with FGFR3-altered metastatic urothelial cancer received at least 3 prior lines of therapy.¹

Pharmacokinetic and pharmacodynamic data from 41 evaluable patients showed that the plasma concentrations of TYRA-300 indicated adequate target coverage at doses of at least 90 mg per day.

"The preliminary data are what we were expecting to see with TYRA-300, being generally well-tolerated with fewer toxicities, and anti-tumor activity in [patients with] FGRF3-altered metastatic urothelial cancer," said Doug Warner, MD, chief medical officer of TYRA Biosciences, stated in a news release. “The emerging profile of TYRA-300 supports further development in metastatic urothelial cancer, where an attractive opportunity exists for a more tolerable option in the second line.”

References

1. 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. October 24, 2024. Accessed October 25, 2024. https://www.prnewswire.com/news-releases/tyra-biosciences-reports-interim-clinical-proof-of-concept-data-for-tyra-300-an-investigational-oral-fgfr3-selective-inhibitor-in-phase-12-surf301-study-in-patients-with-metastatic-urothelial-cancer-muc-302286685.html
2. 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 25, 2024. https://clinicaltrials.gov/study/NCT05544552