On April 8, 2024 Ferring Pharmaceuticals reported the presentation of three-year follow-up data from the Phase 3 study1 at the 39th Annual European Association of Urology (EAU) Congress demonstrating a sustained durable response of ADSTILADRIN (nadofaragene firadenovec-vncg) in two cohorts of adult patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) (Press release, Ferring Pharmaceuticals, APR 8, 2024, View Source [SID1234641917]). Follow-up data from the high-grade Ta/T1 papillary disease cohort were presented for the first time at the EAU meeting and interim data from the cohort of patients with carcinoma in situ (CIS) with or without papillary tumors were reported in November 2023. Results from both patient cohorts are available at clinicaltrials.gov/study/NCT02773849.
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ADSTILADRIN is the first and only intravesical non-replicating gene therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.
"While radical cystectomy provides excellent cancer control for NMIBC patients who no longer respond to standard therapy, most are elderly with significant comorbidities or are unwilling to undergo a life-altering procedure," said Colin P.N. Dinney, M.D., Chairman of the Department of Urology, Division of Surgery, at the University of Texas MD Anderson Cancer Center, Houston, and a lead investigator of the Phase 3 study. "Intravesical gene therapy represents an important innovative treatment option for these patients. In this follow-up analysis of the Phase 3 study, we demonstrated a sustained response to ADSTILADRIN treatment over three years, allowing more than half of the patients in the study to remain cystectomy free for at least 36 months."
Ongoing Follow-up of Patients in Phase 3 Study
The follow-up analysis is part of a Phase 3 study in which patients received ADSTILADRIN 75 mL intravesical instillation (3×1011 viral particles/mL) once every three months for up to 12 months (four doses) or until signs of toxicity or recurrent high-grade (HG) NMIBC. The trial enrolled 157 patients with BCG-unresponsive NMIBC and included two cohorts: 107 patients with CIS ±Ta/T1 (CIS cohort) and 50 patients with high-grade Ta/T1 without CIS (papillary disease [PD]). The efficacy analysis included 103 and 48 patients in the CIS and PD cohorts, respectively, who met the protocol definition of BCG-unresponsive NMIBC.
Patients who were high-grade recurrence free (HGRF) at Month 12 were allowed to continue ADSTILADRIN treatment every three months as part of an ongoing follow-up analysis. In total, 12.1% (13/107) and 20.0% (10/50) of patients in the CIS and PD cohorts, respectively, received ADSTILADRIN at three years.
Follow-up Analysis Shows Durable Response
In the CIS cohort, about 53% achieved a complete response (CR) at Month 3 in the primary analysis. By 36 months, more than 25% of these patients (14/55) remained HGRF. In the high-grade PD cohort in a secondary analysis, nearly 73% were HGRF at Month 3 and of these patients, about 31% (11/35) remained HGRF through three years.
The median duration of CR in both cohorts was nearly 10 months (9.2 – 24.0), with an approximately 34% (21.6% – 47.1%) Kaplan-Meier (KM)-estimated probability of duration of CR for at least three years. The estimated median (95% CI) duration of HGRF survival was six months (3.4 – 8.3) in the CIS cohort and about 12 months (6.7 – 20.3) in the PD cohort. The KM-estimated cystectomy-free survival (95% CI) at three years was nearly 54% (43.3 – 63.1) in the CIS cohort and nearly 64% (48.0 – 75.6) in the PD cohort, and the three-year overall survival was about 90% (82.3 – 94.9) and about 91% (78.5 – 96.7) in the CIS and PD cohorts, respectively.
"ADSTILADRIN is a novel therapy that has demonstrated its value as an effective and well-tolerated standard-of-care treatment for high-risk NMIBC patients with CIS ± Ta/T1 who have BCG-unresponsive disease," said Pierre-Yves Berclaz, M.D., PhD., Executive Vice President and Chief Science and Medical Officer, Ferring Pharmaceuticals. "This 3-year analysis provides further evidence for the durable efficacy and long-term safety of ADSTILADRIN in this on-label patient population, as well as additional data showing its therapeutic potential in a separate population of NMIBC patients with papillary disease. We look forward to continuing patient follow up as we work to redefine the treatment of NMIBC."
The treatment was well-tolerated and no new safety signals were observed during this three-year long-term follow-up analysis. Over the course of three years, only three patients discontinued treatment due to an adverse event (AE), including two in the CIS cohort because of Grade 3 bladder spasm (n=1) and Grade 2 instillation site discharge (n=1), and one in the PD cohort due to Grade 2 benign neoplasm of the bladder. No events leading to discontinuation were considered serious AEs.
About ADSTILADRIN
ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical 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 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 quantities 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 which 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 men3-4, 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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