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Clinical Trial
. 2024 Jul;212(1):74-86.
doi: 10.1097/JU.0000000000004020. Epub 2024 May 5.

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial

Vikram M Narayan  1 , Stephen A Boorjian  2 , Mehrdad Alemozaffar  3 , Badrinath R Konety  4 , Neal D Shore  5 , Leonard G Gomella  6 , Ashish M Kamat  7 , Trinity J Bivalacqua  8 , Jeffrey S Montgomery  9 , Seth P Lerner  10 , Joseph E Busby  11 , Michael Poch  12 , Paul L Crispen  13 , Gary D Steinberg  14 , Anne K Schuckman  15 , Tracy M Downs  16 , Joseph Mashni Jr  17 , Brian R Lane  18 , Thomas J Guzzo  8 , Gennady Bratslavsky  19 , Lawrence I Karsh  20 , Michael E Woods  21 , Gordon Brown  22 , Daniel Canter  23 , Adam Luchey  24 , Yair Lotan  25 , Brant A Inman  26 , Michael B Williams  27 , Michael S Cookson  28 , Sam S Chang  29 , Alexander I Sankin  30 , Michael A O'Donnell  31 , David Sawutz  32 , Richard Philipson  33 , Nigel R Parker  34 , Seppo Yla-Herttuala  34 , Dorte Rehm  35 , Jørn S Jakobsen  35 , Kristian Juul  35 , Colin P N Dinney  7
Affiliations
Clinical Trial

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial

Vikram M Narayan et al. J Urol. 2024 Jul.

Abstract

Purpose: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up.

Materials and methods: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF).

Results: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease.

Conclusions: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Keywords: BCG-unresponsive bladder cancer; bladder cancer; gene therapy; intravesical instillation; nonmuscle invasive bladder cancer.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Narayan reported serving as a consultant for and receiving funding from Ferring Pharmaceuticals Inc and Ciox Health. Dr Boorjian reported serving as a consultant for and receiving funding from Ferring Pharmaceuticals Inc, FerGene, ArTara, and Prokarium. Dr Konety reported serving as a consultant/advisor for and receiving funding from Photocure, Asieris Inc, Ferring Pharmaceuticals Inc, Illumina Inc, and Abbott Inc, and reported ownership/investment interest in Astrin Biosciences and Styx Biotechnology. Dr Shore reported serving as a consultant for and receiving funding from Astellas, Dendreon, Janssen, Bayer, Myriad, MDxHealth, Tolmar, Myovant, Pfizer, EMD Serono Inc, AstraZeneca, Merck, Urogen, Guardant, Abbvie, Amgen, Bristol Myers Squibb, Boston Scientific, Clovis Oncology, Exact Imaging, FerGene, Foundation Medicine, CG Oncology, Invitae, Nymox, Propella, Sanofi, Sesen Bio, Exact Science, Pacific Edge, Cold Genes, Genesis Care, Alessa, Akido, Amgen, Arquer, Asieris, Clarity, Genentech, Guardant, Ferring Pharmaceuticals Inc, ImmunityB, Incyte, Lantheus, Lilly, Minomic, NGM, Nanogen, Novartis, Photocure, PlatformQ, Profound, Promaxo, Protara, Speciality Networks, Telix, Vaxiion, Vessi, FIZE Medical, Accord, ANTEV, BioProtect, Aura Biosciences, Palette Life, and Preview, and reported receiving funding from a leadership role in GenesisCare, Alessa, and Photocure, and funding related to a scientific study from Genentech. Dr Gomella reported receiving consultancy and advisory board fees from Astellas, Abbvie, AstraZeneca, Bayer, Clovis, Merck, and MDx Health. Dr Kamat reported serving as a consultant/advisor for and receiving scientific funding from Photocure, Theralase, Merck, BMS, TMC Innovation, Arquer, Medac, Asieris, US Biotest, Imagin, Eisai, Cold Genesys, Sessen Bio, Biological Dynamics, Seattle Genomics, ProTara, Janssen Pharmaceuticals, Incyte DSMB, Urogen, Engene, Roche, FerGene, Imvax, CG Oncology, Nonagen, Cystotech, Pfizer, Astellas Pharmaceuticals, and Vivet Therapeutics. Dr Kamat reported receiving funds for health publishing from European Urology Oncology, The Journal of Urology®, and UroToday, and reported receiving funds for intellectual property interest from CyPRIT, receiving funds for being in a leadership position from IBCG and IBCN, and receiving funds for scientific study or trial involvement from FKD, Adolor, Heat Biologics, FerGene, Seattle Genomics, Janssen + Taris, AIBCCR, PCORI, SWOG, SPORE, and NIH. Dr Bivalacqua reported serving as a consultant for and receiving funding from Ferring Pharmaceuticals Inc, CG Oncology, and Urogen. Dr Lerner reported serving as a consultant/advisor for Vaxiion, Verity, Pfizer, Surge Therapeutics, C2i Genomics, BMS, Incyte, Protara, AstraZeneca, Gilead, Urogen, and Ferring; participating in a scientific study or trial for FKD, Viventia, Roche/Genetech, Vaxiion, QED Therapeutics, Aura Biosciences, and Surge Therapeutics; holding a role in health publishing for UpToDate and Bladder Cancer Journal; and serving as a meeting participant or lecturer for grand rounds urology, UroToday, Dava Oncology; he also has a patent for TCGA classifier. Dr Steinberg reported membership in Clinical Trial Protocol Committees for Merck, BMS, Janssen, CG Oncology, Pfizer, PhotoCure, Fidia, Seagen, and Protara; being a past or present scientific advisor/consultant within the past 36 months for CG Oncology, PhotoCure, Merck, Taris Biomedical (Now Janssen), Fidia Pharma, Urogen, Ferring Pharmaceuticals Inc, FerGene, Bristol Myers Squibb, AstraZeneca, Pfizer, Janssen, Epivax Therapeutics, EnGene Bio, Astellas, SeaGen, Verity Pharmaceuticals, Protara, xCures, Nonagen, Nanology, Imvax, Asieris, UroViu, and Aura Biosciences; and owning equity stock/options in Epivax Therapeutics, CG Oncology, and Engene Bio. Dr Schuckman reported serving on an advisory board and receiving funding from Pacific Edge. Dr Karsh reported receiving funding related to scientific study, consultancy, and speaker roles from AbbVie, AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Dendreon, FKD Therapies Oy, Ferring Pharmaceuticals, Janssen, Merck, Pfizer, and Sanofi; and research funding to institution from AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Cleveland Dx, Epizyme, FKD Therapies Oy, Ferring Pharmaceuticals, Janssen, OncoCell mDx, Merck, Pfizer, and Sumitomo Pharma. Dr Brown reported serving as a consultant/lecturer for and receiving funding from Astellas, Janssen, Bayer, AstraZeneca, and Merck. Dr Lotan reported serving as a consultant/advisor for and receiving funding from Pacific Edge, Photocure, AstraZeneca, Vessi Medical, Nucleix, Merck, Engene, CAPS Medical, C2i Genomics, FerGene, Abbvie, Ambu, Seattle Genetics, Verity Pharmaceuticals, Urogen, Stimit, Nanorobot, Convergent Genomics, Aura Biosciences, Nonagen, Valar Lab, Pfizer, Phinomics, CG Oncology, Virtuoso Surgical, XCures, Uroviu, On Target Lab, Promis Diagnostics, and Uroessentials. Dr Lotan reported receiving funds for involvement with data monitoring and safety committee from Urogen, and disclosed nonfinancial scientific study or trial involvement with FKD, MDxHealth, and GenomeDx Biosciences Inc. Dr Inman reported receiving research funding from Profound Medical, Medtronic, Combat Medical, FKD Therapies, Genentech Roche, CG Oncology, Janssen, and Seattle Genetics, as well as funding as an advisor for Johnson & Johnson and Combat Medical. Dr Williams reported serving as a consultant/advisor for and receiving funding from Pacific Edge Diagnostics, Ferring Pharmaceuticals Inc, Olympus, Pfizer, and Astellas. Dr Williams reported receiving funds as a meeting participant or lecturer from UroGPO and for scientific study or trial involvement from Astellas, and disclosed nonfinancial scientific study or trial involvement with Janssen, Merck, Anchiano Therapeutics, AstraZeneca, Dendreon Pharmaceuticals, FKD Therapies, Genomic Health, and Pfizer. Dr Cookson reported serving as a consultant/advisor for and received funding from Sigatera, Bayer, Propella Consulting, Pfizer, Lantheus, Nanogen Bioscience Inc, MJH Life Sciences, Pacific Edge Diagnostics, Janssen Pharmaceuticals, Janssen Scientific Affairs, and Myovant Sciences. Dr Cookson reported receiving funds from LyndxDx as a meeting participant and Remedica Medical Education & Publishing for health publishing, and discloses nonfinancial involvement with clinical trial agreements with Ferring Pharmaceuticals Inc and MDX. Dr Chang reported serving as a consultant/advisor for and receiving funding from Nonagen, Tu Therapeutics, AstraZeneca, and Lantheus. Dr Sankin reported serving as an advisor for and received funding from Ambu. Dr O’Donnell reported serving as a consultant for and receiving funding from Fidia, Merck, Photocure, Theralase, Urogen, and Vaxiion. Dr Parker reported receiving funding from FKD and Trizell. Dr Dinney reported serving as a consultant for and receiving funding from AstraZeneca and CG Oncology, and receiving research funding from NCI. No other disclosures were reported.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Patient disposition (CONSORT [Consolidated Standards of Reporting Trials] diagram). BCG indicates bacillus Calmette-Guérin; CIS, carcinoma in situ; CR, complete response; HGRF, high-grade recurrence–free; NMIBC, nonmuscle-invasive bladder cancer. aPostenrollment review of medical records. bAs defined in the final statistical analysis plan. cThis patient did not have any posttreatment response assessment. dThis patient was later recorded as having recurrence of high-grade disease at month 18. eOf the 3 patients who discontinued for other reasons, all 3 received last treatment at month 9. fOne patient was subsequently reported to have high-grade recurrence at month 63.
Figure 2.
Figure 2.
A, Kaplan-Meier estimates of durability of complete response in patients with carcinoma in situ, among patients who achieved complete response. B, Kaplan-Meier estimates of durability of high-grade recurrence–free survival in patients with carcinoma in situ, all patients. C, Time to complete response and duration of complete response in patients with carcinoma in situ. NMIBC indicates nonmuscle-invasive bladder cancer.
Figure 3.
Figure 3.
A, Kaplan-Meier estimates of durability of high-grade recurrence–free survival in patients with high-grade Ta/T1 disease. B, Duration of high-grade recurrence–free survival in patients with high-grade Ta/T1 disease. NMIBC indicates nonmuscle-invasive bladder cancer.
Figure 4.
Figure 4.
A, Kaplan-Meier estimates of cystectomy-free survival in patients with carcinoma in situ. B, Kaplan-Meier estimates of cystectomy-free survival in patients with high-grade Ta/T1 disease.
Figure 5.
Figure 5.
A, Kaplan-Meier estimates of overall survival in patients with carcinoma in situ. B, Kaplan-Meier estimates of overall survival in patients with high-grade Ta/T1 disease.
See this image and copyright information in PMC

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