Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial

Abstract

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

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.

Conflict of interest statement

Declaration of interests

SAB reports consulting fees and personal fees from Ferring, FerGene, Sanofi, and ArTara. MA reports personal fees from Ferring. BRK reports clinical trial funds from FKD; clinical trial support from BMS, Merck, and Photocure; and consulting fees and personal fees from Ferring, Convergent Genomics, Boston Scientific, and Francis Medical. NDS has participated in research and consulting for Amgen, Astellas, AstraZeneca, Bayer, Dendreon, Ferring, Janssen, Merck, Pfizer, Sanofi-Genzyme, Tolmar, BMS, Myovant, and Nymox. LGG reports personal fees from Ferring (advisory board) and a grant from the NRG Radiation Therapy Oncology Group. LGG also reports pending patents to Thomas Jefferson University for shed tumour cells detection. AMK reports advisory board work, consulting work, or personal fees from Merck, BMS, Eisai, Arquer, MDx Health, Photocure, AstraZeneca, IBCG, TMC Innovation, Theralase, BioClin Therapeutics, FKD, Cepheid, Medac, Asieris, Pfizer, Abbott Molecular, US Biotest, Ferring, Imagin, Cold Genesys, Roviant, Sessen Bio, CEC Oncology, and Nucleix, and has a joint pending patent to University of Texas/MD Anderson Cancer Center for a CyPRIT-Cytokine Panel for Response to Intravesical Immunotherapy. TJB reports personal fees and consulting work from Ferring and Photocure. SPL has received grant funding from FKD, Vaxiion, UroGen, Endo, and Vivential; consulting fees and personal fees from UroGen, Vaxiion, Merck, Pfizer, FerGene, Verity, QED, mIR Scientific, Genentech, UroToday, Dava Oncology, and Nucleix; compensation for his editorial work from the Bladder Cancer Research Journal and UpToDate; and has a patent pending for TCGA Expression Subtype Single Patient Classifier. GDS reports personal fees in his role as scientific adviser for FKD, Merck, CG Oncology, Ferring, BMS, Janssen, Photocure, Urogen, Seattle Genetics, Aduro, Pfizer, Engene Bio, and AbbVie. AKS reports consulting work for Photocure, Merck, and FerGene, and personal fees from FKD. RSS reports personal fees from and consulting work for FKD, Ferring, Merck, and MDx Health. LIK reports personal fees from and consulting work for Urogen, AstraZeneca, Ferring, Vaxiion, and Merck, and clinical trials support for Exact Sciences, FKD, GenomeDx, Janssen, Merck, QED, Urogen, Vaxiion, Nucleix, Genetech/Roche, and Ferring. GBro reports consulting, lecturing, and adviser fees from Astellas, Janssen, Bayer, and UroGPO. YL reports grants from FKD, Anchiano, Storz, Abbott, Pacific Edge, Cepheid, MDxHealth, and Decipher, and personal fees from FerGene, Merck, Ferring Research, AbbVie, Photocure, Urogen, Synergo, CAPs Medical, and Vessi. BAI reports receiving clinical trial grants from FKD, Genentech, Dendreon, Taris Biomedical, Urogen, Combat Medical, Anchiano, Nucleix, and Abbott; and personal fees from Combat Medical, Nucleix, and Ferring. MBW reports consulting work for Pacific Edge Diagnostics, Ferring, Olympus, Pfizer, and Astellas; and research for FKD, Astellas, Janssen, Merck, Anchiano, Astra Zeneca, and Dendreon. MSC reports grants and personal fees from MDX Health; personal fees from Williams, Hall & Latherow, Myovant Sciences, Bayer, Sturgill, Turner, Barker & Mahoney, Boehl Stopher & Graves, Merck, Astellas, Janssen, and La Cava & Jacobson; and grants from Bayer and Janssen Biotech. GLA reports a research grant from FKD. AIS reports personal fees from Photocure and Genentech. MAO reports grant support from Abbott Molecular, consulting work for Fidia, Theralese, Urogen, and Vaxiion, and is an investigator for Medical Enterprises and Photocure. FPT reports consulting work for 4D, Acacia, Algipharma, Altimmune, Ascension, AstraZeneca, Ateria, Athersys, Biocompatibles, Camallergy, Canbex, CellAct, Chimerix, Clinigen, Diagnostics in the Real World, Diurnal, FKD Therapies Oy, Genexine, Gensight, Hubro, Imcyse, Invex, Italfarmaco, Mallinckrodt, Medicinova, MeiraGTX, Mundipharma, Mylan, Opsona, Optibio, Origin Sciences, Orphazyme, Phoenix, ReViral, Therakind, Trizell, and Vaxxas. RC is an employee of Trizell, which received fees from FKD. AB and SY-H received personal fees from FKD. NRP received personal fees from FKD and Trizell. CPND acknowledges using shared resources covered by the Cancer Center Support Grant funding from the National Institutes for Health/ational Cancer Institute (award number P30CA016672) at MD Anderson Cancer Center, has received grant and personal fees from FKD, and is a creator of intellectual property owned by UT/MDACC related to the use of genetic alterations as a predictive biomarker for response to nadofaragene firadenovec. All other authors declare no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

HGRF=high-grade recurrence-free. *Post-enrolment review of medical records. †Defined in the final Statistical Analysis Plan. Five patients in the carcinoma in situ Ta or T1 cohort and three patients in the high-grade Ta or T1 cohort progressed to detrusor muscle invasion (≥pT2) by data cutoff.

Figure 2:. High-grade recurrence-free survival in patients with non-muscle-invasive bladder cancer given nadofaragene firadenovec, in patients who had a complete response at 3 months

(A) Patients with carcinoma in situ, with or without Ta or T1. (B) Patients with high-grade Ta or T1.