On May 06, 2024 Ferring Pharmaceuticals reported the final 60-month follow-up data from the Phase 3 study of ADSTILADRIN (nadofaragene firadenovec-vncg) were presented at the American Urological Association (AUA) 2024 Annual Meeting (Press release, Ferring Pharmaceuticals, MAY 6, 2024, View Source [SID1234642710]). The study demonstrated an 80% overall survival rate and 49% cystectomy-free survival rate at Month 60 in adult patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1), and in patients with high-grade Ta/T1 without CIS. These data, which are the longest follow-up of efficacy and safety data reported for a novel agent for BCG-unresponsive NMIBC, were simultaneously published ahead of print and will be included in the July issue of The Journal of Urology.
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ADSTILADRIN is the first and only intravesical non-replicating adenoviral vector-based gene therapy approved by the U.S. Food and Drug Administration (FDA) in patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. The mechanism of action of ADSTILADRIN is designed to deliver the human interferon-alfa 2b gene (IFNα2b) directly into the bladder to enable secretion of interferon alfa-2b protein with a single treatment every three months.
"ADSTILADRIN represents a novel treatment option for BCG-unresponsive NMIBC with a convenient quarterly dosing pattern for patients," said Vikram M. Narayan, Assistant Professor at Emory University Department of Urology, Director of Urologic Oncology at Grady Memorial Hospital, who presented the five-year results at AUA. "Oftentimes, disease recurrence and progression can lead to bladder removal surgery, so it is important that ADSTILADRIN allowed bladder preservation in nearly half of the patients in the CIS cohort and two-thirds of those in the Ta/T1 cohort after five years."
About the Phase 3 ADSTILADRIN Data and Final Five-Year Analysis in BCG-Unresponsive NMIBC
These new data are part of the final five-year follow-up analysis from the Phase 3 study which included two cohorts: patients with CIS ± Ta/T1 (CIS cohort) and patients with high-grade Ta/T1 without CIS (papillary disease [PD cohort]). Patients with NMIBC who fully met the criteria of being BCG-unresponsive, as defined by the 2018 FDA Guidance for Industry, were enrolled in the study.
Patients with NMIBC CIS±Ta/T1 and high-grade Ta/T1 papillary disease (without CIS) received ADSTILADRIN 75 mL intravesical instillation (3×1011 viral particles) once every three months for up to 12 months (quarterly dosing), or until unacceptable toxicity or recurrent high-grade (HG) NMIBC. Retreatment in patients who did not achieve a complete response at three months after a single dose was not allowed, per the protocol. Three clinical trials in the existing multi-year ADSTILADRIN studies program that were previously announced include retreatment.
At 12 months after initial treatment, patients had a biopsy of five sites (dome, trigone, right and left lateral wall, and posterior wall) in the bladder. Patients with no evidence of high-grade recurrence continued receiving ADSTILADRIN once every three months at the discretion of their treating physician, entering an additional four-year treatment and monitoring phase.
Data Show ADSTILADRIN is a Well-Tolerated and Novel Treatment Option for BCG-unresponsive NMIBC
Median follow-up was 50.8 months (IQR 39.1-60.0), with 26.8% receiving five instillations and 7.6% receiving treatment for 57 months. Among patients who were high-grade recurrence free (HGRF) at Month 3, 13 patients were followed and remained HGRF at month 57. The Kaplan-Meier (KM)-estimated probability of remaining HGRF for at least 57 months was 13.2% and 32.7% in the CIS and PD cohorts, respectively.
The overall survival at 60 months was 76.3% in the CIS cohort and 85.9% in the PD cohort. The cystectomy-free survival rate at Month 60 was 43.2.% and 58.7% in the CIS and PD cohorts, respectively. Clinical progression to muscle invasion was rare in the trial population and seen in only 3.3% of all patients (four with CIS and one with Ta/T1) over the five-year follow-up period.
Most treatment emergent adverse events (TEAEs) experienced by patients were transient Grade 1 or 2 (66% of all patients studied), and <4% of patients experienced Grade 3 TEAEs with the most common being discharge around the catheter during instillation, fatigue, bladder spasm, urgency to urinate, chills, dysuria, pyrexia, and urinary incontinence. There were no Grade 4 or 5 TEAEs, no treatment-related deaths, and no new safety signals reported with long-term follow-up.
"These positive five-year follow-up data from our Phase 3 trial continue to demonstrate the efficacy and safety of ADSTILADRIN for NMIBC patients who no longer respond to BCG therapy," said Pierre-Yves Berclaz, M.D., Ph.D., Executive Vice President and Chief Science and Medical Officer, Ferring Pharmaceuticals. "This first-of-its-kind study adds to the body of evidence from our 24-month and 36-month data results and makes ADSTILADRIN the only novel agent with five-year data. With ADSTILADRIN, Ferring has pioneered gene therapy for NMIBC, representing a critical advancement that offers patients renewed hope for more time without disease progression and radical treatment. We look forward to enlarging the body of evidence for ADSTILADRIN with our expanded clinical trial program, which we announced earlier this year."
If you are a healthcare provider interested in the ADSTILADRIN clinical trial program, please visit www.abletrials.com.
About ADSTILADRIN
ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical non-replicating gene-therapy for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered locally as a monotherapy by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high and transient local expression of interferon alfa-2b protein, a naturally-occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer.
ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-grade, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).1
About Non-Muscle Invasive Bladder Cancer (NMIBC)
NMIBC is a form of bladder cancer that is present in the superficial layer of the bladder and has not invaded deeper into the bladder or spread to other parts of the body.2 In the United States, bladder cancer is the seventh most common cancer, fourth among men,3-4 and it is estimated that there will be approximately 83,190 new cases of bladder cancer in the U.S. in 2024.5 Historically, 75% of bladder cancer presents as NMIBC.6 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care. However, more than 50% of patients who receive initial treatment with BCG will experience disease recurrence and progression within one year, with many developing BCG-unresponsive disease.5 Current treatment options for BCG-unresponsive patients are very limited, and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder).7
INDICATION
ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.
WARNINGS AND PRECAUTIONS:
Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.
USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.
ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).
You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.
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