In December 2022, the Food and Drug Administration (FDA) approved Adstiladrin (nadofaragene firadenovec-vncg), a nonreplicating, adenoviral, vector-based 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 was the first gene therapy approved by the FDA for high-risk NMIBC.
GU Oncology Now spoke with Colin Dinney, MD, of the Department of Urology at The University of Texas MD Anderson Cancer Center, regarding the data that led to this approval, the growing body of research in NMIBC, and how Adstiladrin figures to impact the current treatment paradigm.
What is the current standard of care for treating BCG-unresponsive NMIBC?
Dr. Dinney: Prior to the approval of Adstiladrin, there were only 2 drugs approved for BCG-unresponsive NMIBC— valrubicin and pembrolizumab—neither of which have been widely embraced by the urology community. Thus, in addition to Adstiladrin, there are other alternatives to cystectomy under development, including various chemotherapeutic agents, toxins, and immunotherapies. Adstiladrin, a gene therapy, is one of the first of these to receive approval—and after many years of investigation.
What have the early data, as well as the latest phase 3 study data, shown us about Adstiladrin?
Dr. Dinney: The phase 1 study demonstrated biosafety, as no dose-limiting toxicity was observed. We noted encouraging efficacy at the highest doses tested in patients with highly resistant tumors, which countered our initial skepticism.
The phase 2 trial—run exclusively by the Society of Urologic Oncology Clinical Trials Consortium (SUO-CTC)—similarly provided encouraging efficacy with no dose-limiting toxicity. We reported a 30% complete response rate for CIS and a 50% recurrence-free survival rate for high-grade Ta/T1 disease at 12 months.
All of this led to the phase 3 trial, again run by the SUO-CTC. We were one of the first new trials in this space following the FDA guidance document released in 2018. As a result, our trial design was conservative in order to minimize risk for our patients and to avoid overstating our results. Patients were taken off study if they had persistent disease at 3 months, and an end-of-study biopsy was mandated at 12 months to limit investigator bias when defining an end-of-study complete response. Results were consistent with the early trials. We observed a 53% complete response rate for patients with CIS and a 73% high-grade recurrence-free survival for high-grade Ta/T1 disease at 3 months. This was important since almost 50% of these patients maintained that status at 12 months. Subsequently, we identified that the induction of antiadenovirus antibody titers predicted the probability of a durable response in those patients free from disease at 3 months (Mitra et al).
Adverse events were manageable, and the treatment was well tolerated. While 70% of patients reported a study drug- or catheterization-related adverse event, most of these were self-limiting and not serious. Only 3 patients (2%) had a serious adverse event and stopped treatment. One was syncope (which was attributed to the study drug), another patient reported hematuria related to the procedure, and the third patient developed sepsis that was attributed to the procedure.
One important benefit of Adstiladrin that distinguishes it from other drugs in its class is the favorable schedule. Adstiladrin is administered intravesically once every 3 months, which is appreciated by patients and physicians alike.
How does the approval of Adstiladrin figure to impact the treatment paradigm in this population? Do you view it as an immediate standard-of-care treatment option, or is there still long-term data analysis to do before it fundamentally alters care for these patients?
Dr. Dinney: Of the options currently available, Adstiladrin has the most appeal because of its tolerability, efficacy, favorable treatment schedule, and the accessible distribution to urologists. Adstiladrin will be shipped directly to the prescribing urologist’s office as a ready-to-use formulation. This means that community urologists can offer Adstiladrin to their patients without the need for pharmacy support and without the need for a medical oncologist to assist in the management of the patient.
Do you believe this approval will open the floodgates for other gene therapy approvals in high-risk NMIBC? How does this approval figure to impact future study design?
Dr. Dinney: The landscape for drug development for high-risk NMIBC changed dramatically in 2012. At that point, the FDA had approved only 4 drugs for NMIBC since 1959. The FDA recognized that NMIBC represents an unmet need, and a collaboration between the SUO, the American Urological Association, and the FDA was launched to address this deficiency. The initial focus was to define a pathway for drug registration for what’s now known as “BCG-unresponsive disease.” At the request of the FDA, the patient population was clearly defined, and a single-arm trial was approved, leading to the explosion in drug development for BCG-unresponsive NMIBC. The success of these efforts is apparent in clinical trials; most trials for patients with NMIBC include patients with BCG-unresponsive disease.
While we are pleased with the development of Adstiladrin to date, we continue our efforts to improve the impact of Adstiladrin for our patients. Current research is focused on improving the selection of patients by identifying biomarkers that predict response or resistance. In parallel, potential mechanisms of drug resistance are being identified so that novel combination strategies targeting resistance mechanisms can be developed for those patients predicted to be resistant.
What would you say to individuals who are wary of the safety of Adstiladrin and gene therapies altogether?
Dr. Dinney: Patients and physicians share concerns about the safety of adenoviral-mediated gene therapy, especially since we have all faced the dread of transmitted viral disease over the past 3 years. The death of a patient from an overwhelming inflammatory response—secondary to the systemic administration of a non-recommended, extremely high dosage of an adenovirus early in the genesis of human gene therapy—temporarily paralyzed the field until it became clear that when administered correctly, adenoviral gene therapy is safe.
The adenoviral backbone of Adstiladrin has been modified to make it distinct from the adenoviruses that cause human diseases. Its replication sequence has been removed, rendering it replication deficient. This limits the risk for serious illnesses in patients under treatment and the transmission to other close contacts. Another theoretical, unwanted consequence of viral gene therapy that has been minimized is the risk for viral gene insertional mutagenesis and the development of a secondary malignancy. Finally, Adstiladrin is delivered directly into the bladder, and no measurable adenoviral-interferon-α DNA has been detected in the circulation, indicating that there is limited transmission of the interferon gene outside the bladder.
A final concern is the risk for an immune reaction or an unpredictable off-target effect. Patients who have a cold or flu might have natural antibodies in their circulation that could neutralize the adenovirus, rendering this viral gene therapy less effective. This concern has not been confirmed by clinical experience, since the induction of systemic antiadenoviral antibodies did not limit the production of interferon in the urine of patients who were re-dosed, and actually predicted a favorable clinical response.
Thus, patients should be informed that Adstiladrin has a favorable safety profile with no patient deaths secondary to an adverse event ever reported. When you combine this with the promising efficacy data and a favorable treatment schedule, it is apparent that Adstiladrin provides a positive benefit-risk profile for patients with BCG-unresponsive NMIBC facing cystectomy.