Akhil Abraham Saji, MD

GU Oncology Now

The National Cancer Institute estimates that more than 82,000 patients will be diagnosed with bladder cancer in 2023.<a href="https://seer.cancer.gov/statfacts/html/urinb.html" target="_blank" rel="noopener">1</a> 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).<a href="https://journals.lww.com/indianjurol/Fulltext/2015/31040/Non_muscle_invasive_bladder_cancer_risk.5.aspx" target="_blank" rel="noopener">2</a> Adjuvant intravesical bacillus Calmette-Gu&eacute;rin (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.<a href="https://link.springer.com/article/10.1007/s11934-016-0625-z" target="_blank" rel="noopener">3</a> 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.<a href="https://www.sciencedirect.com/science/article/abs/pii/S0360301622011932" target="_blank" rel="noopener">4</a> 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.<a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00147-9/fulltext" target="_blank" rel="noopener">5</a> 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 &ldquo;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.&rdquo;<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> The FDA&rsquo;s definition also includes patients with &ldquo;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.&rdquo;<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> 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.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> Unlike prior attempts at intravesical adenovirus therapy, the Adstiladrin compound contains the adenovirus vector bound to Syn3, a &ldquo;polyamide surfactant that enhances viral transduction into urothelium.&rdquo;<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> 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.<a href="https://www.sciencedirect.com/science/article/abs/pii/S0092867423001265" target="_blank" rel="noopener">7</a> Adstiladrin therapy is instilled into patients&rsquo; urinary bladders via catheter at a favorable dosing schedule of once every 3 months.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a>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.<a href="https://ascopubs.org/doi/10.1200/JCO.2017.72.3064" target="_blank" rel="noopener">8</a> 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.<a href="https://ascopubs.org/doi/10.1200/JCO.2017.72.3064" target="_blank" rel="noopener">8</a> 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.<a href="https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin" target="_blank" rel="noopener">9</a> 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.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> 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.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> More than half the patient population had received at least 3 doses of BCG therapy.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a> 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.<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">6</a>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.&nbsp;References<ol>
<li>Cancer Stat Facts: bladder cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed May 15, 2023. <a href="https://seer.cancer.gov/statfacts/html/urinb.html" target="_blank" rel="noopener">https://seer.cancer.gov/statfacts/html/urinb.html</a></li>
<li>Isharwal S, Konety B. Non-muscle invasive bladder cancer risk stratification. Indian J Urol. 2015;31(4):289-296. doi:<a href="https://journals.lww.com/indianjurol/Fulltext/2015/31040/Non_muscle_invasive_bladder_cancer_risk.5.aspx" target="_blank" rel="noopener">10.4103/0970-1591.166445</a></li>
<li>Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-risk non-muscle-invasive bladder cancer&mdash;therapy options during intravesical BCG&nbsp;shortage. Curr Urol Rep. 2016;17(9):68. doi:<a href="https://link.springer.com/article/10.1007/s11934-016-0625-z" target="_blank" rel="noopener">10.1007/s11934-016-0625-z</a></li>
<li>Efstathiou JA, Ballas LK, Niemierko A, et al. Multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle invasive bladder cancer (MIBC). Int J Radiat Oncol Biol Phys. 2022;114(3):S74-S75. doi:<a href="https://www.sciencedirect.com/science/article/abs/pii/S0360301622011932" target="_blank" rel="noopener">10.1016/j.ijrobp.2022.07.472</a></li>
<li>Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:<a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00147-9/fulltext" target="_blank" rel="noopener">10.1016/S1470-2045(21)00147-9</a></li>
<li>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:<a href="https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30540-4.pdf" target="_blank" rel="noopener">10.1016/S1470-2045(20)30540-4</a></li>
<li>Herzog RW, Suzuki M. Adenoviral gene therapy for bladder cancer. Cell. 2023;186(5):893. doi:<a href="https://www.sciencedirect.com/science/article/abs/pii/S0092867423001265" target="_blank" rel="noopener">10.1016/j.cell.2023.02.009</a></li>
<li>Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd&ndash;IFN&alpha;/Syn3 for patients with high-grade, bacillus Calmette-Guerin&ndash;refractory or relapsed non&ndash;muscle-invasive bladder cancer: a phase II randomized study. J Clin Oncol. 2017;35(30):3410-3416. doi: <a href="https://ascopubs.org/doi/10.1200/JCO.2017.72.3064" target="_blank" rel="noopener">10.1200/JCO.2017.72.3064</a></li>
<li>FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Gu&eacute;rin unresponsive non-muscle invasive bladder cancer. FDA. December 19, 2022. Accessed May 15, 2023. <a href="https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin" target="_blank" rel="noopener">https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin</a></li>
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FDA Approval of Adstiladrin Expands Options for Patients With BCG-Unresponsive NMIBC

Non-Muscle Invasive Urothelial Carcinoma

Adstiladrin and its recent approval by the FDA for use in BCG-unresponsive NMIBC expands the armamentarium for treatment of high-risk NMIBC.