High-grade non–muscle-invasive bladder cancer that does not respond to intravesical Bacillus Calmette-Guerin (BCG) therapy carries a substantial risk of disease recurrence and progression, and effective salvage intravesical therapies are sorely needed for patients who are unable or unwilling to undergo cystectomy. According to results of a multicenter, open-label phase 3 trial presented in February at the American Society of Clinical Oncology (ASCO) 2020 Genitourinary Cancers Symposium, intravesical nadofaragene firadenovec is effective and well tolerated in patients with high-risk, BCG-unresponsive non–muscle-invasive bladder carcinoma in situ (CIS). In this interview with i3 Health, study author Colin Dinney, MD, discusses his findings regarding this promising treatment and shares his thoughts on upcoming developments in the treatment of non–muscle-invasive bladder cancer.
Can you explain the significance of your findings regarding the safety and efficacy of intravesical nadofaragene firadenovec for high-grade, BCG-unresponsive non–muscle-invasive bladder cancer?
Colin P.N. Dinney, MD: BCG-unresponsive non–muscle-invasive bladder cancer is an inherently resistant disease with limited therapeutic options aside from radical cystectomy. The goal for therapy with nadofaragene firadenovec is to alter the natural history of BCG-unresponsive disease to prevent disease recurrence and progression and provide bladder preservation with acceptable morbidity.
To date, the results with nadofaragene firadenovec have been promising, with 31% of all patients free from high-grade recurrence at 12 months, including 24% of patients with CIS and 43% of those with high-grade papillary tumors. Furthermore, progression occurred in only 5% of patients, and understaging likely played a role in the majority of these cases. Most patients have avoided cystectomy, and the cystectomy-free survival is 65% at 2 years. Only 5 of the 43 patients (12%) who underwent cystectomy at the time of recurrence were upstaged to muscle-invasive or extravesical disease, compared with 44% of those with BCG-unresponsive disease who underwent immediate cystectomy at our institution. Thus, it is possible that nadofaragene firadenovec has altered the biology of these tumors. For those who do not respond favorably, combination therapy with nadofaragene firadenovec as the backbone is a possibility.
Therapy has been well tolerated, and while 70% have reported local or systemic adverse events, these have been of low grade and have been transient for the most part. Only 3 patients (2%) suffered a serious drug- or procedure-related adverse event. There were only 6 grade 3/4 adverse events, reported in 4% of the patients on the trial, and only 3 patients (2%) discontinued therapy due to an adverse event. Fortunately, there were no deaths due to adverse events. Thus, nadofaragene firadenovec provides a favorable risk-benefit profile for patients facing cystectomy.
What further research needs to be done on this topic?
Dr. Dinney: Current efforts focus on approaches to improve the outcomes of patients treated with nadofaragene firadenovec. This can be accomplished by improving patient selection through the identification of biomarkers that predict sensitivity or resistance, by discovering novel vectors that might improve transfection efficiency of interferon-a-2b, and by developing novel combination strategies that take advantage of nadofaragene firadenovec's mechanisms of action. These studies might identify unique patients with earlier-stage disease that are candidates for nadofaragene firadenovec.
What additional research advances are on the horizon in non–muscle-invasive bladder cancer?
Dr. Dinney: The history of drug development for non–muscle-invasive bladder cancer has been bleak, with only four drugs approved by the FDA since 1959 prior to the approval of pembrolizumab earlier this year. In 2012, the Society of Urologic Oncology (SUO), the American Urological Association (AUA), and the FDA launched a collaborative effort to address this deficiency, with an initial focus on defining a pathway for drug development for BCG-unresponsive non–muscle-invasive bladder cancer in order to stimulate activity in this space. This effort was successful, and now the majority of clinical trials for non–muscle-invasive bladder cancer include patients with BCG-unresponsive disease, with ongoing trials investigating chemotherapy, immunotherapy, and gene therapy. Future trials will likely explore novel combination strategies for these patients.
On the other hand, there is a paucity of drug development for BCG-naive and intermediate-risk non–muscle-invasive bladder cancer. This provides a tremendous unmet need for a large population of patients, especially during this time of BCG shortage. Combination chemotherapy provides one option for these patients. Low-grade tumors are characterized by the presence of activating FGFR3 alterations, providing a unique opportunity to evaluate FGFR3 inhibitors in this appropriate patient population.
What advice can you share with community urologists and oncologists treating patients with non–muscle-invasive bladder cancer?
Dr. Dinney: BCG is our most effective therapy for non–muscle-invasive bladder cancer, but over time, most patients eventually experience recurrence, and up to 35% may die of bladder cancer. There is a finite opportunity to deliver alternative therapy to avoid radical cystectomy, but until recently, only valrubicin had been FDA approved for BCG-refractory CIS, with a complete response rate of about 10% at 12 months. Thus, effective second-line therapy for patients facing cystectomy remains an unmet need. Intravesical nadofaragene firadenovec is one alternative, with promising efficacy as well as a manageable safety profile and delivery schedule. As such, it provides a favorable benefit-risk profile for patients with BCG-unresponsive non–muscle-invasive bladder cancer.
About Dr. Dinney
Colin P.N. Dinney, MD, is the W.A. "Tex" & D. Moncrief, Jr. Distinguished Chair in Urology and Professor of Urology at the University of Texas MD Anderson Cancer Center in Houston, Texas. Previously, he served as the Urology Co-Chair of the Genitourinary Steering Committee Bladder Task Force and as President and Director of the Bladder Organ Site Committee of the SUO Clinical Trials Consortium. Dr. Dinney's research has focused on understanding the biology of metastatic bladder cancer and on the development of novel therapeutic strategies for both early and late-stage disease, with a particular emphasis on the role of angiogenesis and on bladder cancer metastasis. A recipient of the SUO Medal, Dr. Dinney has authored more than 400 papers and book chapters on a range of topics related to urologic oncology.
For More Information
Boorjian SA & Dinney CPN (2020). Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): results from a phase III trial. J Clin Oncol (Genitourinary Cancers Symposium Abstracts), 38(suppl_6). Abstract 442. DOI:10.1200/JCO.2020.38.6_suppl.442
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.