On December 16, 2022, nadofaragene firadenovec-vncg, an adenoviral vector–based gene therapy, was approved for patients with high-risk bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors.¹

Supporting Efficacy Data

Approval was based on findings in the U.S. multicenter Study CS-003 (ClinicalTrials.gov identifier NCT02773849), in which 98 evaluable patients received nadofaragene firadenovec as a 75 mL intravesical instillation (3 × 10¹¹ viral particles [vp]/mL) every 3 months for up to 12 months or until unacceptable toxicity or recurrent high-grade non–muscle-invasive bladder cancer; patients without high-grade recurrence could continue to receive nadofaragene firadenovec every 3 months beyond 12 months.

A complete response (defined as negative cystoscopy with applicable transurethral resection of bladder tumor and biopsies and urine cytology) was achieved in 50 patients (51%, 95% confidence interval [CI] = 41%–61%). The median response duration was 9.7 months (range = 3 to 52+ months), with 46% of responses lasting at least 1 year.

How It Is Used

The recommended dose is 75 mL at a concentration of 3 × 10¹¹ vp/mL, instilled once every 3 months into the bladder via a urinary catheter. Premedication with an anticholinergic is recommended prior to each instillation.

Safety Profile

Among 157 patients with high-risk BCG-unresponsive non–muscle-invasive bladder cancer receiving nadofaragene firadenovec in Study CS-003, the most common adverse events of any grade were instillation-site discharge (33%), fatigue (24%), bladder spasm (20%), urinary urgency (19%), hematuria (17%), chills (16%), dysuria (16%), and pyrexia (15%). No grade 3 or 4 adverse events were observed. The most common grade 3 or 4 laboratory abnormalities included increased glucose (6%; 38% any grade), increased triglycerides (1.9%; 30% any grade), and decreased phosphate (1.4%; 16% any grade). Other common laboratory abnormalities of any grade were increased creatinine (17%) and decreased hemoglobin (16%).

Serious adverse events occurred in 11% of patients, most commonly (> 1%) coronary artery disease and hematuria. Adverse events led to discontinuation of treatment in three patients (1.9%).

Nadofaragene firadenovec has warnings/precautions for delaying cystectomy, which could lead to the development of muscle-invasive or metastatic bladder cancer, and risk of disseminated adenovirus infection. The product should be avoided in immunocompromised or immunodeficient patients, who may be at risk of disseminated infection because of low levels of replication-competent adenovirus. The product is contraindicated in patients with hypersensitivity to interferon alfa or any component of the product. 

REFERENCE

1. Adstiladrin (nadofaragene firadenovec-vncg) suspension, for intravesical use, prescribing information, Ferring Pharmaceuticals, December 2022. Available at https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin. Accessed January 4, 2023.