AUA 2021: Phase III Trial of Intravesical Nadofaragene Firadenovec in Patients with High-Grade, BCG-Unresponsive, Non-muscle Invasive Bladder Cancer: Two Year Follow-up in the Ta/T1 Cohort

( Most patients newly diagnosed with bladder cancer have non-muscle invasive disease (NMIBC). For patients with intermediate or high-risk NMIBC and those with carcinoma in situ (CIS), adjuvant treatment with BCG is guideline-recommended on the basis of proven benefits in disease recurrence. While BCG is efficacious, many patients eventually develop BCG-unresponsive disease. For many years, there have been very limited options for these patients. Radical cystectomy has remained the gold standard even though numerous approaches including intravesical and systemic therapies have been investigated. Nadofaragene firadenovec is a novel gene-mediated therapy that confers the human IFNα2b gene to bladder urothelium following intravesical instillation and results in prolonged, localized expression of IFNα2b. In a phase III trial, nadofaragene firadenovec treatment was associated with 53.4% of patients with CIS±Ta/T1 achieving a complete response (CR), all within the first 3 months.

In a moderated poster presentation at the American Urologic Association (AUA) Virtual Annual Meeting, Dr. Lotan and colleagues presented 24 month follow-up data among the subset of patients with high-grade (HG) Ta/T1 disease.

This multicenter, open-label Phase 3 trial enrolled two cohorts with BCG-unresponsive NMIBC: carcinoma in situ (CIS±Ta/T1) and HG Ta/T1 alone. In the present analysis, the authors focus on patients with Ta/T1 disease, of whom 48 patients and 50 were included in the efficacy and safety analyses. Patients received nadofaragene (3x1011 vp/mL [75 mL]) intravesically every 3 months for up to 4 doses. The protocol mandated a 5-site (dome, trigone, right and left lateral walls, posterior wall) biopsy at 12 months. Patients who did not have HG disease recurrence at 12 months were offered continued treatment once every 3 months at the investigator’s discretion while those who did not continue treatment were followed.


With a data cutoff of September 2020, 9/48 (18.8%) patients had received a full two years (24 months) of treatment, and 33/48 (68.8%) remained on study with restricted-mean follow-up of 23.5 months (95% CI 22.9-24.1).

Among the 48 patients considered in the efficacy analysis, 35 (72.9%), 21 (43.8%), 16 (33.3%) were HG recurrence-free at 3, 12, and 24 months. Of those who were HG recurrence-free at 3 months, 16/35 (45.7%) remained HG recurrence-free at 24 months and the median duration of HG recurrence-free survival was 19.8 months.


Among the 48 eligible patients, 11 (22.9%) underwent cystectomy in the two years following index. Cystectomy-free survival was 69.8% (95% CI 54.3-80.9) and overall survival was 93.2% (95% CI 80.4–97.8) when estimated via the Kaplan Meier technique at 24 months. Toxicity was in keeping with prior reports with the most common drug-related adverse events (AEs) being instillation site discharge (26%), dysuria (16%), bladder spasm (14%), and micturition urgency (14%). The majority of these were Grades 1 or 2. A single patient (2%) had an AE leading to discontinuation while there was one Grade 4 AE (not related to study drug/procedure).

The authors conclude that, with extended follow-up to 24 months, nadofaragene firadenovec was well tolerated and demonstrates the durability of response in patients with HG Ta/T1, BCG-unresponsive NMIBC.

Presented by: Yair Lotan, MD, Professor of Urology, Chief of Urologic Oncology, and holder of the Helen J. and Robert S. Strauss Professorship in Urology at UT Southwestern Medical Center

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.

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