The FDA has granted approval to nadofaragene firadenovec-vncg (Adstiladrin) as the first gene therapy for adult patients battling high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. This approval marks a significant advancement, providing a novel treatment option for a patient population with limited alternatives.
The approval was based on data from the phase 3 Study CS-003, an open-label, multicenter, single-arm trial (NCT02773849). The intravesical therapy demonstrated a complete response (CR) rate of 51% (n = 50/98; 95% CI, 41%-61%) by 3 months in patients with CIS with or without concomitant high-grade Ta or T1 disease. The median duration of response (DOR) was 9.7 months (range, 3-52+). Notably, 46% (n = 23) of those who achieved an initial CR remained free of high-grade recurrence at 12 months.
Study CS-003 Details
The trial evaluated the safety and efficacy of the non-replicating adenoviral vector-based gene therapy in 103 adults with BCG-unresponsive, high-risk NMIBC with or without papillary tumors after transurtheral resection. Patients had persistent disease, recurrence after an initial tumor-free state, or T1 disease following BCG therapy. All patients underwent transurethral resection of bladder tumor before treatment. Nadofaragene firadenovec-vncg was administered as a 75 mL intravesical instillation once every 3 months for up to 12 months.
The major efficacy outcome measures were CR at any time and DOR, evaluated at 3, 6, 9, and 12 months. The median age of evaluable patients with CIS was 70 years (range, 44-89), with 32% older than 75 years. The majority were White (92%) and male (88%). Patients had received a median of 12 prior BCG instillations (range, 8-12).
Safety Profile
The safety of nadofaragene firadenovec was assessed in 157 patients. Serious toxicities occurred in 11% of patients, including coronary artery disease and hematuria. Adverse reactions led to permanent discontinuation in 1.9% of patients. Dose interruptions were required in 34% of patients, with common toxicities including instillation site discharge, bladder spasm, and micturition urgency. The most common adverse reactions (occurring in >10% of patients) were instillation site discharge (33%), fatigue (24%), chills (16%), pyrexia (15%), bladder spasm (20%), micturition urgency (19%), hematuria (17%), and dysuria (16%). Select laboratory abnormalities included increased glucose, triglycerides, creatinine, decreased phosphate and hemoglobin.
Expert Commentary
According to Steven A. Boorjian, MD, Carl Rosen Professor and chair of the Department of Urology at Mayo Clinic, and lead investigator on the clinical trial, "Patients with BCG-unresponsive NMIBC have historically had limited treatment options other than bladder removal surgery. The approval of [nadofaragene firadenovec] is therefore a significant advance in the current treatment landscape and provides a novel treatment option for patients."
