FDA Approval of Adstiladrin Expands Options for Patients With BCG-Unresponsive NMIBC

The National Cancer Institute estimates that more than 82,000 patients will be diagnosed with bladder cancer in 2023.¹ Of those patients, an estimated 70% will be diagnosed with non-muscle-invasive bladder cancer (NMIBC), and approximately 10% of that patient population will have carcinoma in-situ (CIS).² Adjuvant intravesical bacillus Calmette-Guérin (BCG) therapy is typically administered to patients with intermediate- or high-risk NMIBC based on American Urological Association risk stratification. Patients in the high-risk category are particularly difficult for urologists to manage, as nearly 80% of patients experience recurrence and 50% will experience progression at 5 years.³ The gold standard of management for such patients is radical cystectomy with urinary diversion; however, with an estimated overall complication rate of nearly 60%, cystectomy is not without its downsides.⁴ In terms of bladder-sparing therapy, options such as intravesical valrubicin and pembrolizumab exist for patients with CIS, but overall response rates are generally very low.⁵ Therefore, the research and continued development of more intravesical agents remains of paramount importance to give patients seeking bladder-sparing therapy more options.

The US Food and Drug Administration (FDA) defines BCG-unresponsive bladder cancer as “at least 5 of the 6 induction doses and 2 of the 3 maintenance treatments of BCG or at least 2 of 6 instillations of a second induction course in which maintenance BCG is not given.”⁶ The FDA’s definition also includes patients with “recurrences of high grade Ta or T1 non-muscle-invasive bladder cancer within 6 months, or CIS within 12 months of disease-free state after BCG.”⁶ These definitions were referred to as BCG-refractory and BCG-relapsed disease, respectively.

Adstiladrin (nadofaragene firadenovec gene therapy) is an intravesical agent produced by Ferring Pharmaceuticals. The mechanism of action involves a nonreplicating adenovirus gene therapy that stimulates an antitumor response by infecting bladder cells and producing cytokine interferon alfa-2b.⁶ Unlike prior attempts at intravesical adenovirus therapy, the Adstiladrin compound contains the adenovirus vector bound to Syn3, a “polyamide surfactant that enhances viral transduction into urothelium.”⁶ Stimulating production of interferon alfa-2b results in increased interferon alpha receptor binding on bladder cancer cells, which can ultimately restrict bladder cancer cell growth.⁷ Adstiladrin therapy is instilled into patients’ urinary bladders via catheter at a favorable dosing schedule of once every 3 months.⁶

Several clinical trials were conducted to evaluate the efficacy and safety of Adstiladrin in patients with NMIBC. Prior to the trial that led to FDA approval, phase 2 data provided by Shore et al demonstrated both safety and potential efficacy. Patients with high-grade (HG) BCG-refractory or BCG-relapsed disease were given Adstiladrin randomized 1:1 at a lower and higher dose based on data from the original phase 1 study.⁸ Overall, the phase 2 trial demonstrated that Adstiladrin was very well tolerated and safe. No grade 4 or 5 adverse events (AEs) were noted, and the most common AEs were organ localized (eg, dysuria, urgency). Furthermore, the primary end point of the trial, HG recurrence-free survival (RFS), was comparable at 33.3% in the low-dose group and 36.8% in the high-dose group at the 12-month mark.⁸ These data, along with the fact that the response was noted to be durable (patients remained disease-free for up to 24 months), suggested that Adstiladrin was a viable therapy for further study.

In December 2022, the FDA approved Adstiladrin for use in high-risk BCG-unresponsive bladder cancer with CIS, with or without papillary tumors present in the bladder.⁹ This landmark approval was based on the CS-003 trial and marked the first time that an adenovirus-based gene therapy was approved for the treatment of bladder cancer. CS-003, a phase 3, single-arm clinical trial, was run by Stephen Boorjian, MD, at the Mayo Clinic to evaluate the efficacy and safety of intravesical Adstiladrin in a larger series of patients.⁶ Enrollment took place at 33 hospitals and health systems across the United States, thereby ensuring a large and diverse pool of potential patients.

The authors enrolled a total of 157 patients between September 19, 2016, and May 24, 2019, from a pool of 198 patients.⁶ More than half the patient population had received at least 3 doses of BCG therapy.⁶ Unlike other intravesical agents such as pembrolizumab, which have only been approved for BCG-unresponsive CIS, CS-003 enrolled patients with isolated, high-grade Ta and T1 disease (32%), as well as those with CIS. The primary outcomes of interest were complete response rate and freedom from HG recurrence. Of the 48 patients enrolled in the HG Ta/T1 cohort, 43.8% of patients were HG recurrence-free at the 12-month mark. In the CIS cohort, 24.3% of patients were HG recurrence-free at 12 months. Adstiladrin was found to be overall very safe (consistent with phase 2 data), with no grade 4 or 5 AEs reported. More than half of patients (66%) reported transient treatment-related AEs such as peri-catheter discharge, fatigue, and lower urinary tract symptoms, which were all classified as grade 1 or 2.

Adstiladrin and its recent approval by the FDA for use in BCG-unresponsive NMIBC expands the armamentarium for treatment of high-risk NMIBC, the authors concluded. The inclusion of patients with isolated HG Ta/T1 tumors is unique and ensures that a wider range of patients will have access to this bladder-sparing therapy. The authors noted that future studies will focus on identifying mechanisms of nonresponse.⁶

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.

References

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6. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
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8. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd–IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin–refractory or relapsed non–muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol. 2017;35(30):3410-3416. doi: 10.1200/JCO.2017.72.3064
9. FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. FDA. December 19, 2022. Accessed May 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin