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

References:

  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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