Nadofaragene Firadenovec Gets Go-Ahead in High-Risk Non–Muscle Invasive Bladder Cancer


The FDA has approved nadofaragene firadenovec-vncg for patients with high-risk non-muscle invasive bladder cancer.

Nadofaragene firadenovec-vncg(Adstiladrin), a gene therapy, has been approved to treat adults with high-risk Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.1

The regulatory decision was based on data from the open-label, multicenter, single-arm phase 3 Study CS-003 (NCT02773849), in which the intravesical therapy elicited a complete response (CR) rate of 51% (n = 50/98; 95% CI, 41%-61%) by 3 months in those with CIS with or without concomitant high-grade Ta or T1 disease.2 The median duration of response (DOR) was 9.7 months (range, 3-52+). Of those who achieved an initial CR, 46% (n = 23) continued to be free of high-grade recurrence at 12 months.

“This approval provides healthcare professionals with an innovative treatment option for patients with high-risk non-muscle invasive bladder cancer that is unresponsive to BCG therapy,” Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research, FDA, stated in press release. “Today’s action addresses an area of critical need. The FDA remains committed to facilitating the development and approval of safe and effective cancer treatments.”

Study CS-003 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.

These patients had persistent disease after acceptable BCG therapy, disease recurrence after an initial tumor-free state after acceptable BCG therapy, or T1 disease after a single induction course of BCG. Ninety-eight of these patients were evaluable for response. Patients received acceptable BCG if they had at least 5 or 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course.

Before treatment with the gene therapy, all patients underwent transurethral resection of bladder tumor to eliminate all resectable disease. Those with residual CIS not amenable to complete resection were permitted. However, those with extra-vesical, muscle invasive, or metastatic urothelial carcinoma were excluded.

Patients received nadofaragene firadenovec-vncg 75 mL intravesical instillation once every 3 months for up to 12 months or until intolerable toxicity or recurrent high-grade disease. Those without evidence of high-grade recurrence were permitted to continue the therapy every 3 months.

CR at any time and DOR served as the major efficacy outcome measures of the trial. CR was evaluated at 3, 6, 9, and 12 months.

In those with CIS who were evaluable for response, the median age was 70 years (range, 44-89); 32% of patients were older than 75 years. Moreover, 92% of patients were White and 88% were male. At study entry, 5% of patients had CIS with T1, 19% had CIS with high-grade Ta, and 76% had CIS. Patients received a median of 12 instillations of prior BCG (range, 8-12).

The safety of nadofaragene firadenovec was evaluated in 157 patients enrolled to CS-003. Eleven percent of patients experienced serious toxicities; those that occurred in more than 1% of patients were coronary artery disease and hematuria. Adverse reactions resulted in permanent discontinuation of the therapy in 1.9% of patients; these effects included bladder spasm instillation site discharge and benign neoplasm of the bladder.

Thirty-four percent of patients required dose interruptions of nadofaragene firadenovec. Toxicities that resulted in dose interruption in more than 10% of patients included instillation site discharge, bladder spasm, and micturition urgency.

The most common adverse reactions reported in more than 10% of patients who received the therapy 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 that worsened from baseline in more than 15% of patients who received nadofaragene firadenovec were increased glucose (all grade, 38%; grade 3 or 4, 6%), increased triglycerides (30%; 1.9%), increased creatinine (17%; 0%), decreased phosphate (16%; 1.4%), and decreased hemoglobin (16%; 0.6%).

"Patients with BCG-unresponsive NMIBC have historically had limited treatment options other than bladder removal surgery," Steven A. Boorjian, MD, Carl Rosen Professor and chair of the Department of Urology at Mayo Clinic, and lead investigator on a recent clinical trial of the therapy, added in another press release.3 "The approval of [nadofaragene firadenovec] is therefore a significant advance in the current treatment landscape and provides a novel treatment option for patients."


  1. FDA approves first gene therapy for the treatment of high-risk, non-muscle-invasive bladder cancer. News release. FDA. December 16, 2022. Accessed December 16, 2022.
  2. Nadofaragene firadenovec-vncg (Adstiladrin). Prescribing information; Ferring Pharmaceuticals; 2022. Accessed December 16, 2022.
  3. Ferring receives approval from US FDA for Adstiladrin for high-risk, BCG-unresponsive non-muscle invasive bladder cancer. News release. Ferring Pharmaceuticals. December 16, 2022. Accessed December 16, 2022.

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