Background: Alterations to FGFR3 are the most common somatic mutations in non-muscle invasive bladder cancer (NMIBC), present in 40-60% of high-grade Ta and > 80% of recurrent low grade Ta tumors. FGFR3 mutations are also known to be associated with a “cold” tumor microenvironment (TME) that may mediate BCG resistance. Erdafitinib, a targeted inhibitor of FGFR 1-4, is the first FDA approved targeted therapy for locally advanced/metastatic bladder cancer. As FGFR3 mutations are present 3-5x more commonly in NMIBC than metastatic disease, erdafitinib is a logical therapeutic candidate for FGFR3-altered NMIBC. Through this ongoing phase II trial, we seek to determine the safety and efficacy of erdafitinib for the treatment of intermediate and high risk FGFR3-altered NMIBC after prior intravesical therapy. Methods: To address the need for expanded targeted therapeutics for NMIBC,_, we launched an investigator-initiated phase II window of opportunity (WOO) trial of erdafitinib (NCT04917809, PI Pietzak). We are currently enrolling patients with intermediate or high risk NMIBC with history of ≥1 or more induction courses of BCG and/or intravesical chemotherapy who present with a clinically staged Ta papillary recurrence on office cystoscopy. Patients are also required to have an oncogenic FGFR3 mutation or fusion, as confirmed by OncoKB on MSK-IMPACT, to be included in the trial. Trial patients are treated with 6 mg oral erdafitinib daily for 28 days during the “window of opportunity” time period between office cystoscopy and transurethral resection of the recurrent bladder tumor (TURBT). The primary outcome is the rate of objective response, defined as complete (no visible tumor) or partial ( > 50% reduction of measured diameter by Response Evaluation Criteria for Tumors of the Bladder [RECIT-Bladder]) as compared to cystoscopy at TURBT. We are employing an optimal Simon two-stage binomial design, assuming an objective response of > 15% would and < 2% would not be worthy of further study. We plan to enroll 16 patients in the first stage and 9 in the second (87% power). Secondary outcomes include safety (CTAE 5.0), patient reported outcomes, and recurrence-free survival. Correlative studies will be conducted with urine, blood, and tumor tissue samples. Urine and blood are collected before (day 1), during (day 14) and after treatment (day 28) and will undergo immune and molecular studies to understand shifts in the microenvironment in the setting of response and resistance. This trial is being conducted in parallel with a co-clinical trial of patient derived organoid/xenograft models (MSK 19-015, PI Pietzak) to further refine the understanding of FGFR3 mutational resistance to standard treatment and the effects of targeted immunotherapy on tumor clinicogenomics. Clinical trial information: NCT04917809.