Gene Therapy Nadofaragene Firadenovec Shows Promise in High-Grade Non-Muscle Invasive Bladder Cancer

Nadofaragene firadenovec, a non-replicating recombinant type five adenovirus vector-based gene therapy, is associated with a sustained durability of response when given once every three months in patients with high-grade, bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), according to study presented by Anne Schuckman, MD, of Keck Medicine of the University of Southern California, at the 2021 American Urological Association Annual Meeting.

Patients with BCG-unresponsive NMIBC are at a significantly increased risk of disease recurrence and progression, despite the use of optimal therapy. Nadofaragene firadenovec, which delivers a copy of the human IFNα2b gene to patients, represents a promising gene therapy for the disease.

Dr. Schuckman and colleagues noted that a previous phase 3 study found nadofaragene firadenovec met its primary endpoint in a total of 157 patients with high-grade, BCG-unresponsive NMIBC, with approximately 53.4% of patients with CIS±Ta/T1 achieving a complete response (CR) by three-month follow-up.

To examine the long-term follow-up of these patients, Dr. Schuckman and researchers enrolled 107 of the BCG-unresponsive, CIS±Ta/T1 (CIS with/without HG Ta or T1) patients into an open-label phase III trial. A total of 103 patients were included in the efficacy analysis. The gene therapy nadofaragene 3×1011 vp/mL was given once every three months for a maximum of 4 doses. At 12 months, a five-site biopsy was performed. Patients who lacked high-grade recurrence at the 12-month follow-up were allowed to continue treatment once every three months, while patients who did not receive additional treatment were followed for outcomes assessment.

The data cutoff occurred in September 2020. At the cutoff, 62.1% (n=64) of the efficacy cohort remained on the study treatment. The mean follow-up period was 23.5 months, and up to 17.5% (n=18) of patients received 24 months’ worth of treatment.

At a 24-month follow-up, 19.4% (n=20) of patients remained free of high-grade recurrence. Approximately 36% of the 55 CIS±Ta/T1 patients who experienced a CR after treatment were also free of high-grade recurrence at the 24-month follow-up. The median duration of high-grade relapse-free survival in these patients was 12.2 months.

Around 32% (n=33) of patients at 24 months had undergone cystectomy. The KM cystectomy-free survival rate in these patients was 64.6%, while overall survival was 94.4%.

Overall, treatment with nadofaragene firadenovec was generally well tolerated. There was one grade 4 non-treatment-related adverse event (AE), but no grade 5 AEs were reported. Common drug-related AEs included instillation site discharge (24.3%), fatigue (23.4%), bladder spasm (17.8%), and micturition urgency (16.8%). Most of the common AEs were grades 1 and 2. Only two (1.9%) patients discontinued the study drug due to treatment-related AEs, including instillation site discharge (n=1) and bladder spasm (n=1).