Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 11 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.
Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3–4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.
Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state.
Funding: FKD Therapies Oy.
Authors: Prof Stephen A Boorjian, MD, Mehrdad Alemozaffar, MD, Prof Badrinath R Konety, MD, Neal D Shore, MD, Prof Leonard G Gomella, MD, Prof Ashish M Kamat, M, Prof Trinity J Bivalacqua, MD, Prof Jeffrey S Montgomery, MD, Prof Seth P Lerner, MD, Joseph E Busby, MD, Michael Poch, MD Paul L Crispen, MD, Prof Gary D Steinberg, MD, Anne K Schuckman, MD, Prof Tracy M Downs, MD, Prof Robert S Svatek, MD, Joseph Mashni Jr, MD, Brian R Lane, MD, Prof Thomas J Guzzo, MD Prof Gennady Bratslavsky, MD, Lawrence I Karsh, MD, Michael E Woods, MD, Gordon Brown, DO, Daniel Canter, MD, Adam Luchey, MD, Prof Yair Lotan, MD, Tracey Krupski, MD, Brant A Inman, MD, Michael B Williams, MD, Prof Michael S Cookson, MD, Kirk A Keegan, MD, Prof Gerald L Andriole Jr, MD, Alexander I Sankin, MD, Prof Alan Boyd, MD, Prof Michael A O'Donnell, MD, David Sawutz, PhD, Richard Philipson, MD, Ruth Coll, BSc, Vikram M Narayan, MD, F Peter Treasure, PhD, Prof Seppo Yla-Herttuala, MD Nigel R Parker, PhD, Prof Colin P N Dinney, MD
Boorjian S.A, Alemozaffar M, Konety B, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. The Lancet Oncology. Nov 27, 2020, Online First
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ASCO GU 2020: Safety and Efficacy of Intravesical Nadofaragene Firadenovec for patients with High-Grade, BCG Unresponsive Nonmuscle Invasive Bladder Cancer - Phase 3 Trial Results
BCANTT 2020: Phase 3 Trial of Nadofaragene Firadenovec for High-Risk, BCG Unresponsive, Non-Muscle Invasive Bladder Cancer
Read an Expert Commentary by Bishoy Faltas, MD