Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.
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Boorjian Stephen A, Alemozaffar Mehrdad, Konety Badrinath R, Shore Neal D, Gomella Leonard G, Kamat Ashish M, Bivalacqua Trinity J, Montgomery Jeffrey S, Lerner Seth P, Busby Joseph E, Poch Michael, Crispen Paul L, Steinberg Gary D, Schuckman Anne K, Downs Tracy M, Svatek Robert S, Mashni Joseph, Lane Brian R, Guzzo Thomas J, Bratslavsky Gennady, Karsh Lawrence I, Woods Michael E, Brown Gordon, Canter Daniel, Luchey Adam, Lotan Yair, Krupski Tracey, Inman Brant A, Williams Michael B, Cookson Michael S, Keegan Kirk A, Andriole Gerald L, Sankin Alexander I, Boyd Alan, O'Donnell Michael A, Sawutz David, Philipson Richard, Coll Ruth, Narayan Vikram M, Treasure F Peter, Yla-Herttuala Seppo, Parker Nigel R, Dinney Colin P N
Аннотация
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 × 1011 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.