Narayan Details How Nadofaragene Firadenovec Has Broken Ground as the First Gene Therapy for NMIBC


Vikram Narayan, MD, details the mechanism of action of the nadofaragene firadenovec and how the agent is impacting care for patients with BCG-unresponsive non–muscle invasive bladder cancer.

Vikram Narayan, MD

Vikram Narayan, MD

Gene therapies have emerged as a promising option for patients with bladder cancer, and nadofaragene firadenovec-vncg (Adstiladrin) may offer an advantage over pembrolizumab (Keytruda) for the treatment of patients with high-risk BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors, according to Vikram Narayan, MD.

“When we compare this [agent with] pembrolizumab which was also FDA-approved, the big advantage nadofaragene firadenovec offers is that it’s given in the bladder intravesically and dosed once every 3 months [vs once a week for 6 weeks with pembrolizumab],” Narayan said in an interview with OncLive®.

“There was an early release program by the pharmaceutical company earlier this year, which was open to a little less than a dozen sites, so the first patients have been treated with nadofaragene firadenovec commercially,” Narayan added. “In my practice, we just started treating our first patients with it and there’s been a lot of interest in this. There are still unknown questions because there are other similar drugs that are being investigated and may come on the market in the coming months to years. The question of how best to sequence treatments [also] remains, but these are good problems to have because previously these patients had few options outside of the removal of their bladder.”

In the phase 3 trial Study CS-003 (NCT02773849), which supported the December 2022 FDA approval of nadofaragene firadenovec, patients with BCG-unresponsive NMIBC in the CIS cohort (n = 103) achieved a 3-month complete response (CR) rate of 53.4% (95% CI, 43.3%-63.3%). Patients experienced a median duration of CR or high-grade recurrence-free survival of 9.69 months (95% CI, 9.17-not estimable). Additionally, the agent was administered via intravesical instillation at 75 mL of 3 x 1011 viral particles/mL once every 3 months up to 12 months, unacceptable toxicity, or recurrent high-grade NMIBC.

In the interview, Narayan, director of Urological Oncology at Grady Memorial Hospital and an assistant professor in the Department of Urology at Emory University School of Medicine at Winship Cancer Institute in Atlanta, Georgia, detailed how nadofaragene firadenovec has the potential to fill an unmet need for patients with bladder cancer and how gene therapies are impacting the care of these patients.

OncLive: Please describe the mechanism of action of nadofaragene firadenovec.

Narayan: Nadofaragene firadenovec includes a non-replicating adenovirus that delivers the payload of interferon alpha-2b [IFNα-2b]. Interferon is an immune-stimulatory agent and [clinicians] have previously given interferon in the bladder with BCG or by itself but have found limited efficacy. Nadofaragene firadenovec uses an adenoviral vector to deliver interferon directly into urothelial cells to hijack the machinery of urothelial cells to produce the IFNα-2b protein. Then that goes on to have immunomodulatory effects that result in tumor and cell death—you can trigger apoptosis [and] anti-angiogenesis, there are various pathways.

The other component of nadofaragene firadenovec is Syn3 which is a detergent that helps break down the glycosaminoglycan [GAG] layer of the bladder [that] was historically thought to be why giving interferon alone would not work. One of the reasons why we can do every 3-month dosing with nadofaragene firadenovec is because we’re creating a bit of a bioreactor in the bladder of the patient to produce this IFNα-2b protein.

[The] concept of pleiotropic effects of IFNα-2b means that when you have IFNα-2b present, you can trigger a number of immunostimulatory/immunomodulatory effects. We see cell death with TRAIL-mediated apoptosis, anti-angiogenesis, and increased anti-tumor activity of natural killer cells, which preferentially target bladder cancer cells. All those things taken together result in cell death and is what ultimately is thought to be attributable to the CR rates that we saw in the phase 3 study.

The phase 3 study showed a CR rate of approximately 54% at 3 months, and the durability of that [response] was around 25% at 1 year among all patients who received the treatment. There’s still more work to be done, we would like to see those numbers [improve], but one of the hopes that we have is to stimulate interest and discussion in ways that nadofaragene firadenovec can be augmented, combined with other therapies potentially, or maybe even re-dosed to improve that long-term CR rate.

What should clinicians who aren’t familiar with this research take away from it?

The American Urological Association [AUA] guidelines recently included nadofaragene firadenovec as an option for patients with BCG-unresponsive NMIBC. Patients are now coming to us in the clinic asking about this treatment, to know more about it, and to have access to it.

The take-home message is that the drug is a gene therapy drug, but it’s a non-replicating adenoviral vector. It has local effects, meaning that in the trial and preclinical studies, systemic absorption or systemic effects were not noted. Understanding the immune modulating effects of the drug [is important].

What key data supported the approval of the agent?

The Lancet paper that came out several years ago, which was a Society of Urologic Oncology Clinical Trials Consortium run study [was key]. It was a urologist-run trial looking at 2 cohorts of patients, the patients who had BCG-unresponsive disease and CIS without papillary disease, and then patients who had papillary disease without CIS.

These patients received nadofaragene firadenovec dosed once every 3 months assuming they did not have high-grade recurrences, and the treatments were assessed using cystoscopy, urine cytology, as well as for-cause biopsy if a urologist assessed that they had a visual recurrence. In this trial, at 12 months patients underwent a mandatory biopsy to essentially a mapping biopsy, which gave [the data] some additional validity because you can often have false negatives if you rely on visual recurrences alone. That data showed a 53.4% CR rate in the CIS cohort, which was the primary end point, and is ultimately what led to the FDA approval.

What should clinicians know about the safety profile of nadofaragene firadenovec?

Clinicians will likely be very familiar with the handling and other operational pieces [of the drug]. The one thing that clinicians need to know about it is it’s shipped frozen on dry ice [and] needs to be thawed and then used within 24 hours or needs to be stored frozen until it’s used. In terms of handling, it’s very similar to BCG. It’s advisable to bleach the toilet after the patient voids which they typically do at home. The drug is administered and held in the bladder for an hour, which is very similar to other therapies that we use, and it’s given through a catheter, which all urologists and urology nurses are familiar with.

What unmet needs does nadofaragene firadenovec help to fill and what unmet needs remain?

The biggest unmet need is having a treatment for [patients with] BCG-unresponsive NMIBC. The concern that patients have [occurs] when we tell them they [did not respond to] BCG and all the other treatments we have are not as efficacious or they involve life-altering surgery in the form of removal of the bladder.

In terms of AEs, [nadofaragene firadenovec] was very well tolerated in the phase 3 trial—very few patients discontinued the drug due to adverse effects [AEs] and there were no deaths due to AEs. The most common AEs were [instillation site discharge, fatigue, bladder spasm, hematuria] dysuria, and micturition urgency. These are AEs that patients are familiar with because they’re similar to [those with] BCG.

We do believe that this drug fills the unmet need of previously not having a good intravesical alternative for patients who have BCG-unresponsive NMIBC, but it’s not a panacea by any means. It’s not a magic bullet in the sense that although 53.4% of patients have a CR at 3 months, approximately half of patients don’t have a CR and those patients still face the need for some alternative therapy for which we need to do more work and research to figure out.

What are the future directions for this agent and research with it?

It would be nice to be able to identify biomarkers that might be able to predict who may be more [or less] likely to respond to the therapy, so we can switch [the latter population of] patients to other treatment options. In terms of biomarkers, those include things like urinary biomarkers as well as adenoviral antibody levels. It’s worthwhile to [consider combination therapies], and there is a study that’s underway to look at combination therapies [with] nadofaragene firadenovec plus other agents that may augment responses.

The question of whether re-dosing nadofaragene firadenovec [is ideal remains]. In the original trial, if patients failed or had recurrence of high-grade disease, they would not get additional treatments; they would be switched to an alternative therapy because when we were designing [the CS-003] trial the interest was to make sure that patients were safe and not given treatments that wouldn’t work. Now that we have data on efficacy, it’s reasonable to see whether a second treatment does offer benefit if a patient recurs initially. There’s justification for that [because] patients will often get repeat induction BCG, and some of the other drugs that are being developed in this space also have re-dosing regimens if they have failures.

What role do gene therapies have in the bladder cancer treatment paradigm? How could these agents impact outcomes going forward?

A number of gene therapy agents are now being investigated besides nadofaragene firadenovec. Gene therapy is emerging as a [potential] significant option for patients who have BCG-unresponsive disease and bladder cancer in general. We’re likely going to see more of [these therapies] and we may even look at different payloads [of nadofaragene firadenovec in particular], but the bladder is a natural cavity for safe gene therapy treatment options because it’s easily accessible via catheter, you can provide contact-based delivery of the drugs that you’re using, and we know from preclinical data that for many agents the absorption systemically is very low assuming there isn’t a raw surface or something along those lines or active hematuria. For that reason, [in] bladder cancer at least in the anti-tumor space, there’s a lot of interest in gene therapy. With the approval of nadofaragene firadenovec we’ll likely see other agents emerge as well in this space.


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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