TPS579 Background: The standard of care for high-risk non-muscle invasive bladder cancer (NMIBC) after exposure to induction only BCG or relapse >12 months after “adequate” BCG is retreatment with BCG. However, ~50% of patients will relapse within 6 months. Thus, there is a critical need to develop novel combination therapies to improve BCG immunotherapy efficacy. Combination BCG with immune checkpoint inhibition is associated with a ~12-18% risk of serious treatment-related adverse events and BCG combined with Mitomycin C (MMC) has unacceptable urinary toxicity. Intravesical Gemcitabine (GEM) is a common treatment for NMIBC, is well tolerated, has better efficacy after BCG than MMC, and, based on preclinical data, may synergistically enhance the efficacy of BCG by augmenting the immune tumor microenvironment. We completed a prospective Phase I trial of chemoimmunotherapy with gemcitabine and BCG in BCG-relapsed/BCG-exposed NMIBC that was well-tolerated (no treatment related grade ≥3 adverse events) with promising early efficacy (95% [19/20] 6-month complete response rate). No dose limiting toxicities were seen. The maximum tolerated dose (MTD) was 2000 mg gemcitabine and 50 mg TICE BCG. Methods: To address the need for more effective and less toxic bladder preserving treatment options by enhancing the effectiveness of BCG, we launched an investigator-initiated phase I/II trial of combination intravesical gemcitabine with BCG in patients with BCG-exposed NMIBC (NCT04179162). The Phase II portion is currently enrolling patients with BCG-exposed carcinoma in-situ (CIS ±Ta/T1) that recurred within 24 months of last BCG (BCG-exposed/BCG-relapsing NMIBC). Patients with BCG-unresponsive disease, contraindication to BCG, or prostatic/ureteral urothelial disease are excluded. Induction intravesical GEM (2000mg, twice weekly) is given weeks 1, 4, 7, and 10 and intravesical BCG (40mg, Tice strain, weekly) is given weeks 2, 3, 5, 6, 8, and 9. Responders receive SWOG maintenance BCG. The primary endpoint is clinical complete response (CR) at 6 months (absence of high-grade disease on cystoscopy/TURBT and negative cytology) using a Simon’s optimal 2-stage design testing the null hypothesis of a true CR of 55% at 6 months (based on historical outcomes of BCG alone) against a 1-sided alternative. In the first stage, the study would stop if ≤ 9/15 patients had a CR. In the second stage, the null hypothesis will be rejected if ≥ 29 CRs are observed in 43 total patients (type I error rate 5% and power of 80% if the true CR rate is 75%). Phase I patients treated at the MTD (14/25) are included in Phase II. Secondary outcomes include recurrence-free, progression-free, and cystectomy-free survival. Correlative studies explore immune and molecular predictors of response and resistance to chemoimmunotherapy in tumor tissue, urine, and blood. Clinical trial information: NCT04179162 .

TPS4614 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 .