FDA Approval Summary: Nadofaragene firadenovec-vncg for bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer

Abstract

On December 16, 2022, the FDA approved the adenoviral vector-based gene therapy nadofaragene firadenovec-vncg (brand name Adstiladrin) 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). The product represents the first approved adenoviral vector-based gene therapy and the first approved gene therapy for bladder cancer. Determination of efficacy was based on results from Study rAd-IFN-CS-003 (Study CS-003), a single-arm trial in 98 evaluable patients with BCG-unresponsive NMIBC with CIS who received intravesical instillations of the gene therapy product (75 mL of nadofaragene firadenovec at 3 × 10¹¹ viral particles per mL) once every 3 months. The major efficacy outcome measures were complete response (CR) at any time and duration of response (DoR). Fifty subjects experienced CR 3 months after initial treatment (CR=51%; 95% CI: 40.7; 61.3%), of whom 46% remained in response for ≥12 months. The median DoR was 9.7 months (range: 3 to 52+). Common adverse reactions included instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, pyrexia, and dysuria. The approval of nadofaragene firadenovec provides a new therapy option for patients with BCG-unresponsive NMIBC with CIS who are ineligible for cystectomy.

Introduction

On December 16, 2022, FDA approved nadofaragene firadenovec (brand name Adstiladrin), the first gene therapy for the treatment of bladder cancer. Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy indicated for adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.

For decades, standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) has consisted of transurethral resection of the bladder tumor followed by immunotherapy with intravesical bacillus Calmette-Guérin (BCG). BCG is administered in an induction phase and in a maintenance phase for up to 3 years of therapy in total. Treatment with BCG results in initial complete response (CR) in approximately 70% of patients, but 5-year rates of tumor recurrence are approximately 40% (1,2). BCG-unresponsive NMIBC with carcinoma in situ (CIS) is defined as persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy, where adequate BCG is defined as either 5 of 6 doses of an initial induction course with at least 2 of 3 doses of maintenance therapy, or at least 5 of 6 doses of an initial induction course with at least 2 of 6 doses of a second induction course (3). Standard treatment for patients with BCG-unresponsive NMIBC is radical cystectomy, which carries substantial morbidity and mortality; the incidence of complications is 35% to 40% and the 90-day mortality rate is 4.7% (4). At the time of approval of nadofaragene firadenovec, non-surgical treatments approved for patients with BCG-unresponsive NMIBC included intravesical chemotherapy with valrubicin, which has limited efficacy (5), and systemic immunotherapy with pembrolizumab. Other intravesical chemotherapies commonly used off-label include gemcitabine, mitomycin C, and the doublet of gemcitabine and docetaxel. Approval of pembrolizumab was based on KEYNOTE-057, a single arm study in patients with BCG-unresponsive NMIBC, which demonstrated a CR rate of 41% and median duration of response (DoR) of 16.2 months in the context of associated systemic immune-related adverse reactions that may limit adoption in this disease setting (6).

Subsequent to the approval of nadofaragene firadenovec, nogapendekin alfa inbakicept-pmln, an interleukin-15 (IL-15) receptor agonist administered intravesically in combination with BCG, was approved in April 2024 based on the single-arm study QUILT-3.032, which demonstrated a CR rate of 62% in patients with BCG-unresponsive CIS. Fifty-eight percent of patients with CR had a DoR ≥12 months and 40% had a DoR ≥24 months (7).

Nadofaragene firadenovec is an adenovirus vector-based gene therapy designed to deliver to the bladder urothelium a copy of a gene encoding human interferon-alfa 2b (IFNα2b). The IFNα2b has pleiotropic anti-tumor effects, which include angiogenesis inhibition, anti-proliferation and apoptosis, and stimulation of innate and adaptive immune responses. This report summarizes the FDA’s clinical review of nadofaragene firadenovec, with a focus on regulatory considerations leading to the decision to approve the product.

Clinical Trial Design

Study CS-003 was a single-arm trial evaluating the safety and efficacy of nadofaragene firadenovec in adults with high-grade, BCG-unresponsive NMIBC. Patients were enrolled at 33 centers in the United States. Patients with CIS with or without concomitant Ta/T1 disease had relapsed disease diagnosed within 12 months of their last BCG intravesical treatment and had previously received at least two courses of BCG within a 12-month period. Patients received a single dose of nadofaragene firadenovec (3 × 10¹¹ viral particles/mL) administered in 75 mL instillations repeated every 3 months in the absence of recurrent high-grade disease. Response assessments were conducted at 3, 6, and 9 months and included urine cytology, cystoscopy, and biopsy if indicated. At Month 12, patients underwent urine cytology, cystoscopy, and mandatory bladder biopsies. Per study protocol, at least five biopsies were required (dome, trigone, right and left lateral wall, posterior wall). Biopsy of the prostatic urethra was performed in men with positive cytology and prior prostatic disease.

The primary efficacy outcome measure was the rate of CR at any time after the first instillation of nadofaragene firadenovec in patients with CIS. The FDA defined CR as negative cytology with either of the following: negative cystoscopy (with transurethral resection of bladder tumor/biopsy as appropriate) or positive cystoscopy with biopsy-proven benign or low-grade NMIBC. CR could also be determined in the setting of a positive cytology if bladder biopsies were negative and an alternative site of malignancy (upper tract or prostatic urethra) was confirmed. Patients with screening cystoscopy based on a potentially more sensitive modality than white light (e.g., blue light), but without confirmed CR on the same or similar modality, were not considered evaluable. The key secondary outcome measure was the durability of CR in patients with CIS who showed CR at any time after the first instillation (8).

Results

Efficacy

Of 107 patients enrolled in Study CS-003, 103 had sufficient prior BCG therapy (median number of instillations: 12; range: 8 to 18) to be considered BCG-unresponsive. However, five of these patients were considered unevaluable for response due to unknown cystoscopy imaging modality at screening (n=2) or positive cytology at CR determination without adequate evaluation of the upper and lower urinary tracts (n=3) and were therefore excluded from the efficacy population. Of 98 evaluable patients, 88% were male and 92% were White, with a median age of 70 years (32% were >75 years of age; range: 44 to 89). Tumor pattern at study entry was CIS with T1 (5%), CIS with high-grade Ta (19%), and CIS (76%).

Fifty patients had a CR at the first disease assessment (3 months after treatment start), for a CR rate of 51% (95% CI: 40.7, 61.3%). No patients subsequently experienced a CR. The median DoR was 9.7 months (range: 3 to 52+). Nine patients had recurrent disease upon mandatory biopsy at Month 12 (Figure 1).

Figure 1.

Duration of response among patients who received intravesical instillations of nadofaragene firadenovec once every 3 months, Study rAd-IFN-CS-003. Source: FDA analysis of data from Study rAd-IFN-CS-003.

Of 44 treated patients who underwent subsequent radical cystectomy and for whom pathologic data were available, 14% (n=6) had muscle-invasive (T2 or greater) disease at cystectomy. Two patients who did not undergo cystectomy experienced progression to muscle-invasive disease during the 12-month treatment period.

Safety

The safety of nadofaragene firadenovec was evaluated in 157 patients with high-risk BCG-unresponsive NMIBC (107 patients with CIS with or without concomitant papillary disease, and 50 patients with papillary-only disease) who received at least one dose of nadofaragene firadenovec.

The most common adverse reactions (occurring in at least 10% of patients) were instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, pyrexia, and dysuria (Table 1). Twenty percent of patients experienced Grade 3 or 4 adverse reactions, of which hypertension was the most common (2.5%). Administration of nadofaragene firadenovec was discontinued in 1.9% of patients due to bladder spasm, instillation site discharge, or benign neoplasm of bladder. No patient died within 4 months of the last dose. With a minimum follow-up of 7 months and a median follow-up of 24 months, 2 patients (1.9%) with CIS experienced progression to muscle-invasive or extra-vesical disease prior to cystectomy.

Table 1:

Adverse Reactions Occurring in at Least 10% of Patients with Non-Muscle Invasive Bladder Cancer, Study rAd-IFN-CS-003

Adverse Reaction	Nadofaragene firadenovec (N=157) Grades 1 or 2a (%)
General disorders and administration site conditions	-
Instillation site discharge	33
Fatigue	24
Chills	16
Pyrexia	15
Renal and urinary disorders	-
Bladder spasm	20
Micturition urgency	19
Hematuria	17
Dysuria	16

^a.Graded per NCI CTCAE v4.03; there were no Grade 3 or 4 reactions.

Abbreviation: NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events.

Source: FDA analysis of data from Study rAd-IFN-CS-003.

Regulatory Insights and Discussion

Nadofaragene firadenovec is the first gene therapy approved for the treatment of bladder cancer. Results from Study CS-003 supported the FDA’s favorable benefit-risk assessment of nadofaragene firadenovec for the treatment of patients with BCG-unresponsive NMIBC with CIS (Table 2). As an intravesically administered therapy, nadofaragene firadenovec offers patients an alternative to cystectomy and is associated with a low risk of systemic toxicity. Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy. Low levels of replication-competent adenovirus may be generated during manufacturing. The theoretical risks from generation of replication-competent adenovirus include the potential for disseminated infection. Therefore, persons who are immunocompromised or immunodeficient should avoid exposure to this product.

Table 2:

FDA Benefit/Risk Analysis, Nadofaragene Firadenovec for Bacillus Calmette-Guérin-Unresponsive Non-Muscle Invasive Bladder Cancer with Carcinoma In Situ

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	Following intravesical BCG therapy, patients with recurrence or persistence of high-risk NMIBC with CIS are at high risk of progression to muscle-invasive or metastatic bladder cancer	Patients with NMIBC are at high risk for recurrence and progression to advanced and metastatic disease despite treatment with currently available treatment modalities.
Treatment Options at the Time of FDA Review	-Valrubicin; 18% CR rate, 13.5 month median duration or response. -Radical cystectomy; Nearly 5% 90-day post-operative mortality rate. Rate of cure poorly defined in the BCG-unresponsive patient population due to heterogeneity of population and prior BCG exposure. -Pembrolizumab; 41% CR rate, 16.2 month median duration of response, however associated with systemic immune-related toxicities	-Cystectomy is potentially curative but associated with significant morbidity and mortality. -FDA-approved treatment options at the time of review included valrubicin and pembrolizumab.
Benefit	-In the CIS cohort with or without associated high-grade papillary disease, the demonstrated CR rate at 3 months post treatment was 51% with the median durability of CR of 9.69 months. -23% of all treated patients remained in CR at least one year following response.	The observed CR rate and duration of CR are clinically meaningful; approximately 1 in 4 patients treated did not need radical cystectomy for at least one year.
Risk and Risk Management	-The most common (incidence >10%) adverse reactions in rAd-IFN-CS-003 included instillation site discharge, fatigue, bladder spasm, micturition urgency, hematuria, chills, dysuria, and pyrexia. -19% of patients experienced a Grade 3–4 AE, of which hypertension (2.5%) was the most common. -Two (1.9%) with CIS experienced disease progression on study prior to cystectomy. In the subset of patients with CIS who underwent subsequent cystectomy for whom pathologic data were available (n=43), the incidence of pathologic upstaging to muscle-invasive disease (T2) was not higher than expected (6/43; 14%).	-Serious toxicity associated with nadofaragene firadenovec was infrequent. Adverse reactions were typically local in nature and low grade. -Although interpretation of a single-arm trial is limited, the risk of progression during nadofaragene firadenovec therapy was comparable to that of radical cystectomy. However, the duration of follow-up at the time of approval was insufficient to fully characterize this risk.

Abbreviation: AE, adverse event.

Source: FDA analysis of data from Study rAd-IFN-CS-003.

There are limited treatment options for patients with BCG-unresponsive NMIBC with CIS. Due to the challenges of randomizing patients to either placebo or a therapy perceived as unacceptable, FDA has accepted single-arm trials evaluating durable CR rate for regulatory approval. In January 2020, FDA approved pembrolizumab for BCG-unresponsive NMIBC based a CR rate and DoR evaluated in a single-arm trial. Accordingly, results from the single-arm Study CS-003 with CR rate and DoR as primary and key secondary endpoints, respectively, were considered sufficient evidence of effectiveness to support approval. Study CS-003 demonstrated a clinically meaningful CR rate supported by adequate evidence of DoR and a risk for upstaging and progression that did not appear higher than expected. The robustness of the assessment of durability was enhanced by mandatory bladder biopsies at Month 12. While mandatory biopsies are not typically performed in clinical practice, their use in single-arm clinical trials may reduce the potential risk of investigator response assessment bias.

Although single-arm trials may be appropriate in clinical settings where a randomized controlled trial (RCT) is either unethical or infeasible to conduct, the lack of comparator arms can be challenging. For patients with BCG-unresponsive CIS, randomized trials may better control for disease and patient heterogeneity as well as variability with investigator determination of CR, which may be highly operator dependent. Additionally, since time-to-event endpoints, such as recurrence-free survival, cannot be interpreted in the context of a single-arm trial, a RCT is required for evaluation in papillary-only NMIBC, in which visible disease should have been fully resected (9).

Future Directions

The approval of nadofaragene firadenovec provides a new intravesical therapy option for patients with BCG-unresponsive NMIBC with CIS who are ineligible for or refuse cystectomy with its attendant morbidities. However, there remains an unmet need for new therapies to improve response rates, DoR, and risk of progression in this population. There are now several FDA-approved treatments for patients with BCG-unresponsive NMIBC, and RCTs are becoming increasingly feasible given these effective control arm options. Randomized comparisons for future trials can provide better comparative safety assessment as well as take advantage of time to event endpoints to evaluate papillary-only disease. Sponsors of clinical trials are encouraged to meet with the FDA to discuss details of their trial designs.

Abbreviations List:

BCG

bacillus Calmette-Guérin

CIS

carcinoma in situ

CR

complete response

DoR

duration of response

IFNα2b

human interferon-alfa 2b

IL-15

interleukin-15

NMIBC

non-muscle invasive bladder cancer

RCT

randomized controlled trial