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Gene-mediated therapy for high-grade NMIBC delivers positive results in trial

Urology Times JournalVol 48 No 7
Volume 48
Issue 07

72.9% of patients with papillary disease achieved high-grade recurrence-free survival at 3 months after initial treatment.

Intravesical nadofaragene firadenovec (recombinant adenovirus interferon alfa with Syn3 [rAD-IFNα/Syn3], FerGene) is a promising therapeutic option for patients who have bacillus Calmette-Guérin (BCG)-unresponsive high-grade non–muscle invasive bladder cancer (NMIBC), said Stephen A. Boorjian, MD, at the 2020 American Urological Association Virtual Experience.1

He reported results from a subgroup analysis of a multicenter, phase 3, open-label trial, demonstrating that the novel intravesical gene-mediated therapy was well tolerated, safe, and efficacious, specifically highlighting the findings from the cohort of patients with papillary disease.

Stephen A. Boorjian, MD

Stephen A. Boorjian, MD

“The optimal management for patients with BCG-unresponsive NMIBC continues to be investigated because many of these patients are either medically unfit for or unwilling to undergo radical cystectomy,” said Boorjian, Carl Rosen Professor of Urology at the Mayo Clinic in Rochester, Minnesota.

“In this phase 3 study, nadofaregene firadenovec demonstrated a clinically meaningful benefit in a patient population for whom nonsurgical treatment options have been limited.”

Nadofaragene firadenovec combines a recombinant adenovirus vector encoding the human IFNα2b gene with the excipient Syn3, which enhances transduction of the adenovirus vector into bladder cells. A phase 2 study completed several years ago investigated 2 doses of nadofaragene firadenovec (1.1 or 3 x 1011 vp/mL) in 40 patients with BCG-unresponsive high-grade NMIBC. Its results showed that at 12 months after the first instillation, 14 patients (35%) were free fromhigh-grade recurrence.

“Of particular interest in the phase 2 study, the 12-month, high-grade, recurrence-free survival rate among patients with papillary-only tumors was 50%,” Boorjian said.

The phase 3 study investigated nadofaragene firadenovec 3 x 1011 vp/mL in patients with high-grade NMIBC who met the FDA definition for BCG-unresponsive disease. A total of 157 patients were enrolled, received at least 1 treatment, and were included in the safety population. Six patients who did not met the definition of BCG unresponsiveness were excluded from the efficacy population, leaving an evaluable cohort of 103 patients with carcinoma in situ (CIS) and 48 patients with papillary disease.

The investigational gene-mediated therapy was instilled into the bladder with a targeted dwell time of 1 hour. Efficacy was evaluated based on findings from cystoscopy and urine cytology performed every 3 months, with biopsy if indicated, and a mandatory biopsy performed at 12 months after first instillation. Repeat treatments could be given every 3 months to patients who remained free from high-grade recurrence.

“The quarterly delivery schedule for this agent was favorable to both patients and providers,” Boorjian said.

The primary end point analysis showed that a complete response was achieved by 55 of 103 patients with CIS (53.4%), which occurred by 3 months after the first instillation. Among the 48 patients with papillary disease, 35 patients (72.9%) achieved high-grade recurrence-free survival at 3 months after their initial treatment.

Analyses of data collected at 12 months showed that, among patients who achieved a complete response, 21 (60%) of those with papillary disease and 25 (45.5%) of those with CIS remained free from high-grade recurrence.

Only 3 patients (6.3%) from the papillary disease cohort experienced progression to muscle invasive disease during the available follow-up. Within the CIS cohort, 5 patients (4.9%) progressed to muscle invasive disease.

The safety analysis for the phase 3 trial included all 157 enrolled patients who received at least 1 dose of nadofaragene firadenovec. It showed that the most common study drug–related adverse events (AEs) were irritative lower urinary tract symptoms, which were transient.

Three patients (1.9%) experienced a serious study drug– or procedure-related AE. Those AEs included single episodes each of sepsis, syncope, and hematuria. In addition, 3 patients (1.9%) discontinued the study drug because of a treatment-emergent AE. There were no deaths in the study.

Disclosure: Dr Boorjian is a consultant for Ferring, Sanofi, ArTara Therapeutics, and FerGene.


1. Boorjian S, Dinney C, The Society of Urologic Oncology Clinical Trials Consortium. A phase 3 study to evaluate the safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive non-muscleinvasive bladder cancer: papillary disease cohort results. Presented at: 2020 AUA Virtual Experience. Abstract PD12-07.

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