Nadofaragene Firadenovec, a Novel Gene Therapy-Based Treatment for BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer - Expert Commentary

A few bladder-sparing treatment options are available for BCG-unresponsive patients, including valrubicin and the recently FDA-approved pembrolizumab. However, additional treatment options that achieve a durable response are needed. A recent phase III open-label clinical trial by Boorjian et al., published in Lancet Oncology, investigated the efficacy of a novel strategy for intravesical interferon alfa gene delivery. The authors used nadofaragene firadenovec (rAd-IFNα/Syn3), a non-replicating recombinant adenovirus vector-based gene therapy that delivers a copy of the human interferon alfa-2b gene to urothelial cells. An earlier phase 2 study in 40 patients achieved a 12-month recurrence-free survival of 35%.

The study enrolled patients with BCG-unresponsive disease, which included those with persistent carcinoma in situ (CIS), or high-grade Ta/T1 tumors at six months despite receiving adequate BCG therapy, patients who have recurrences of high-grade Ta/T1 NMIBC within six months, carcinoma in situ within 12 months of disease-free state after BCG.  All patients received 75 mL nadofaragene firadenovec by intravesical administration through a urinary catheter. Repeat administration at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was a 12-month complete response rate defined by negative urine cytology and cystoscopy as assessed by the treating physician.

After excluding patients who did not meet the BCG-unresponsive definition, a total of 151 patients were included in the efficacy analyses with a median age of 71 years. 103 patients had CIS with or without Ta/T1, and 48 patients had high-grade Ta/T1 disease.

In the per-protocol efficacy analysis cohort of CIS  patients (with or without a high-grade Ta or T1 tumor) cohort, 55/103 (53.4%) patients achieved a complete response at three months which was significantly higher than the prespecified null hypothesis rate of no more than 27% (p<0·0001). The median duration of response was approximately ten months. 25/103 (24.3%) remained recurrence-free at 12 months. The most common adverse effects were micturition urgency, and there were no treatment-related deaths.

A head-to-head comparison between nadofaragene firadenovec and pembrolizumab or other second-line chemotherapy combinations such gemcitabine-docetaxel is lacking. The cost-effectiveness of these approaches also needs to be considered.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York


  1. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–17. PMID: 33253641
  2. Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Bajorin DF, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. J Clin Oncol. 2020 May 20;38(15_suppl):5041–5041.
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