BCG-Unresponsive NMIBC Responds to Intravesical Adenoviral Gene Therapy


"Intravesical nadofaragene firadenovec [recombinant adenovirus interferon alpha achieved a 53.4% CR rate in patients with BCG-unresponsive carcinoma in situ of the bladder."

A high rate of complete responses (CRs) in patients with bacillus Calmette-Guerin (BCG)–unresponsive non–muscle-invasive bladder cancer (NMIBC) were observed in a phase III trial with the administration of an intravesical recombinant adenovirus gene transfer vector, according to study data presented through the American Urological Association’s (AUA) Virtual Experience for the 2020 AUA Annual Meeting.1

The high-grade recurrence-free survival (RFS) rate at 3 months in patients with papillary disease only (n = 48) was 72.9%, with 43.8% of patients remaining recurrence free at 12 months. Looking at the entire efficacy population (n = 151), rates of high-grade RFS at 3 and 12 months were 59.6% and 30.5%, respectively.

“Intravesical nadofaragene firadenovec [recombinant adenovirus interferon a (rAd–INFa)] achieved a 53.4% CR rate in patients with BCG-unresponsive carcinoma in situ of the bladder,” Stephen A. Boorjian, MD, said during a virtual presentation of the results. “We found that CRs were quite durable, such that 60% of patients with papillary tumors who achieved an initial CR remained high-grade recurrence free at 12 months.”

Durability of response in the patients with papillary disease only was demonstrated, with 60% of patients who achieved a CR at 3 months maintaining therapy response at 12 months. In the group of patients with carcinoma in situ of the bladder, that rate was 45.5%. All patients with carcinoma in situ experiencing a CR (55 of 103) did so within 3 months of receiving their first treatment.

The single-arm, multicenter, open-label trial (NCT02773849) included patients with high-grade BCG-unresponsive NMIBC treated with 3 × 1011 vp/mL intravesical rAd–IFNa/Syn3, with a target dwell time in the bladder of 1 hour. Patients remaining free of high-grade recurrence could have treatment repeated at 3-month intervals.

Evaluation for efficacy consisted of cystoscopy and urine cytology at 3-month intervals with a mandatory biopsy occurring at 12 months after first installation.

The primary end point was the CR rate in patients with carcinoma in situ at any time after first receiving therapy. Secondary outcome measures included durability of CR in patients with carcinoma in situ with or without concomitant high-grade Ta or T1 papillary disease and the rate and durability of high-grade RFS in patients with high-grade Ta and T1 urothelial carcinoma of the bladder, comprising the papillary disease–only cohort.

There were 157 patients enrolled onto the trial who received at least 1 dose of the study drug, with 151 patients qualifying for analysis in the efficacy population. Of those, 48 patients were considered to be in the papillary disease–only group.

Looking at disease progression, only 3 patients (6.3%) progressed to muscle-invasive bladder cancer in the papillary disease–only cohort during the study period, including both clinical progressions detected and transurethral resection and occult progression found at cystectomy. Five patients with carcinoma in situ also progressed to muscle-invasive bladder cancer.

Treatment was well tolerated among all enrolled patients, with adverse events (AEs) of any kind occurring at a rate of 70.1% and serious AEs occurring at a rate of 1.9%, consisting of one case each of sepsis, syncope, and hematuria. Three patients discontinued the study drug due to AEs. No deaths resulting from treatment-related AEs were reported. The most commonly reported treatment-related AE was irritative voiding symptoms.

According to Boorjian, who is vice chair for the department of urology and director of the urologic oncology fellowship at Mayo Clinic in Rochester, Minnesota, the agent rAd–IFNa/Syn3 has previously demonstrated the ability to induce regression of human bladder cancer growing in athymic nude mice in preclinical studies.1 “rAd–INFa is a recombinant adenovirus that has been linked to Syn 3, which is an excipient and functions to enhance adenoviral transduction into bladder cells,” said Boorjian, who is also the Carl Rosen Professor of Urology at Mayo Clinic.

Phase II data published in 2017 in the Journal of Clinical Oncology demonstrated that rAd–IFNa/Syn3 was well tolerated and showed promising efficacy in patients with high-grade BCG-refractory NMIBC who were unwilling or unable to undergo radical cystectomy.2

Of 40 patients randomized to receive 1 of 2 doses of rAd–IFNa/Syn3, 14 (35.0%) remained free from high-grade recurrence at 12 months after initial treatment. Of note, Boorjian said the rate of progression-free survival in the papillary disease–only group was 50% at 12 months. The higher of the 2 doses from this trial was used in the phase III trial.2

“The optimal management for patients with BCG-unresponsive non–muscle-invasive bladder cancer continues to be investigated as many such patients are either medical unfit for or unwilling [to undergo] radical cystectomy,” Boorjian said. “Therefore, the agent represents a promising option for patients with BCG-unresponsive high-grade non–muscle-invasive bladder cancer.”


1. Boorjian S, Diiney C; The Society of Urologic Oncology Clinical Trials Consortium. A phase III study to evaluate the safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive non-muscle invasive bladder cancer: papillary disease cohort results. J Urol. 2020; 203(suppl 4):PD12-07. doi:10.1097/JU.0000000000000846.07

2. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study [published correction appears in J Clin Oncol. 2019;37(24):2187]. J Clin Oncol. 2017;35(30):3410‐3416. doi:10.1200/JCO.2017.72.3064

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