Introduction:

Patients with bacillus Calmette-Guérin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) are at significant risk for recurrence and progression. Although cystectomy is a recommended definitive treatment, it is associated with morbidity and mortality. Nadofaragene firadenovec-vncg is a nonreplicating recombinant adenovirus vector-based gene therapy that delivers human interferon alpha-2b cDNA into the bladder epithelium. In a phase 3 study (NCT02773849), 55/103 participants (53.4%) with carcinoma in situ (CIS) with or without papillary tumors (± Ta/T1) achieved a complete response (CR) by 3 months. Here, cystectomy-free survival (CFS) and pathologic outcomes at cystectomy were evaluated among participants with BCG-unresponsive NMIBC with CIS ± Ta/T1 treated with nadofaragene firadenovec, stratified by CR status at 3 months. The objective of this analysis was to test the hypothesis that nadofaragene firadenovec would enable many participants to avoid cystectomy without compromising the window of cure for those who did not achieve or maintain a CR.

Methods:

An open-label, multicenter, phase 3 study enrolled participants with BCG-unresponsive NMIBC to receive a single dose of nadofaragene firadenovec, with repeat dosing every 3 months in the absence of high-grade recurrence. Incidence of cystectomy and CFS (calculated from the first dose of nadofaragene firadenovec to the first date of cystectomy or death due to any cause) were assessed through 5 years of follow-up. Cystectomy pathology reports were assessed through the 36-month data cutoff (the 36-month visit of the last enrolled participant) to evaluate stage and progression. Results are presented for the overall CIS ± Ta/T1 population and stratified by CR status at 3 months.  

Results:

Median follow-up time was 48.9 months among all treated participants with CIS ± Ta/T1 (N=107). Among participants included in efficacy analyses (N=103), 44 (42.7%) underwent cystectomy, including 15 (14.6%) who achieved a CR at 3 months and 29 (28.2%) who did not. Of the 37 participants who underwent cystectomy with pathology data available, 6 had MIBC at cystectomy, of whom 3 had MIBC at transurethral resection before cystectomy and 3 underwent cystectomy for clinical NMIBC. Three participants were pT0 at cystectomy. The Kaplan–Meier (KM) estimated median duration of CFS was 47.9 months, 63.9 months, and 11.3 months in all participants with CIS ± Ta/T1, participants with a CR, and participants without a CR, respectively (Table). The KM probability of CFS for at least 60 months was 43.2%, 65.5%, and 16.0% in all participants with CIS ± Ta/T1, participants with a CR, and participants without a CR, respectively.

Conclusion:

Nadofaragene firadenovec treatment resulted in clinically meaningful CFS for participants with BCG-unresponsive NMIBC with CIS ± Ta/T1, particularly among those who achieved an initial CR at 3 months. The rate of upstaging at the time of cystectomy was consistent with historical reports on immediate cystectomy for NMIBC, indicating nadofaragene firadenovec is a safe bladder-sparing option that does not sacrifice the window of cure for patients with BCG-unresponsive NMIBC.

Funding: Ferring Pharmaceuticals, Inc.