Nadofaragene Firadenovec Is Effective With Beneficial Dosing Schedule in Real-World for BCG-Unresponsive NMIBC

Mark Tyson II, MD, MPH

The favorable dosing schedule of nadofaragene firadenovec-vncg (Adstiladrin) makes it a suitable option for patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) who have to travel far for care, and patient selection must be done carefully as not to include those who are likely to leak the drug, according to Mark Tyson II, MD, MPH, and Jacob Moyer, BS.

“The most important thing in giving nadofaragene firadenovec, and this may be true for lots of intravesical therapies, [is that] bladder spasms and then subsequent loss of the medication is a real problem,” Tyson said in an interview with OncLive®. “That’s because it’s $60,000 a dose or [in that range]; it’s one thing if you leak gemcitabine at $26 a dose, it’s an entirely different kettle of fish to leak nadofaragene firadenovec at $60,000 a dose.”

Data from a real-world study conducted by Moyer, Tyson, and colleagues at Mayo Clinic locations revealed that, at a median follow-up of 8.2 months, patients who received the intravesical therapy (n = 43) achieved a cystectomy-free survival rate of 95% and all patients were alive at the data cutoff.1

“[In terms of] the real-world findings, even though our numbers appear favorable, it’s too early to say, but it certainly appears that in the real-world setting nadofaragene firadenovec performed no worse than in clinical trials, which is promising,” Moyer, who is first author of the study, added in the interview. “We need extended follow-up and more patients, which I know is coming soon.”

Jacob Moyer, BS

In the interview, Moyer and Tyson detailed findings from the real-world study and considerations when selecting between nadofaragene firadenovec and nogapendekin alfa inbakicept-pmln (Anktiva), which are both FDA approved for patients with BCG-unresponsive NMIBC.2,3 Moyer is a graduate researcher at Mayo Clinic in Scottsdale, Arizona, and Tyson is a urologic oncologist and associate professor of urology at Mayo Clinic Alix School of Medicine in Arizona.

OncLive: What was the rationale for initiating the real-world study and how was it conducted?

Moyer: Since nadofaragene firadenovec received FDA approval in December 2022, there [have not been] any published real-world data. At the 2025 ASCO Genitourinary Cancers Symposium, we presented the first real-world data for patients with FDA-defined BCG-unresponsive NMIBC. We did that through a retrospective review of all the patients treated at 3 Mayo clinic sites in Arizona, Minnesota, and Florida, between when the first dose was given outside of a clinical trial in November 2023 and December 2024 when we collected our last data for this project.

What were key efficacy and safety findings from the study?

Moyer: We had 46 patients who were treated, and of those 46 patients, 3 had pending posttreatment cystoscopy. [Therefore], we had 43 efficacy-evaluable patients, and of those 43 patients, 24 had carcinoma in situ [CIS] with or without papillary disease. At first assessment [which was] 3 months, 79% of the patients with CIS had a complete response [CR], and that was durable [with high-grade recurrence-free survival (RFS) rates of] 74% at 6 months and 60% at 9 months. In the papillary only cohort of 19 patients, the 3-month RFS rate was 68% which was durable [with high-grade RFS rates of] 57% at 6 months and 40% at 9 months. The caveat was that the 6- and 9-month [rates] were Kaplan Meier estimates, whereas the 3-month response rates were simple percentages. The overall survival rate was 100% [as well].

We had 46 patients who we could evaluate safety for, and we mainly saw low-grade transient and local adverse effects [AEs] that were managed in the clinic during treatment. We saw only 9% of patients [experienced] grade 3 AEs which included fatigue, fever, and dizziness. We mostly saw [grade 1 or 2] bladder spasms, some leakage of the medication, and micturition urgency, [and this was] in line with the phase 3 trial findings.

As nadofaragene firadenovec is a newer drug, what is most important for doctors to know about its administration/use?

Tyson: Perhaps one of the most important pieces of this whole equation is to make sure patients are appropriately pretreated with some type of antispasmodic [medication]. We’ve gone through a number of iterations in our practice and have landed on rectal diazepam [Valium]. We give 10 mg of rectal diazepam suppository approximately 15 minutes prior to the instillation, and we have data that will hopefully be published in a couple of months showing that [it] essentially eliminated the loss of the medication. It didn’t quite eliminate it, but [there was a] drastic reduction both in bladder spasms and especially involuntary contraction and loss of the medication around the catheter.

Are there any patients in particular who would be especially good candidates for this drug?

Tyson: The drug’s indication is [for those with] BCG-unresponsive NMIBC with CIS so those are the most appropriate candidates—patients who have refused or are ineligible for radical cystectomy and have disease that’s not responding to conventional intravesical BCG treatments. We have used the drug off label in patients who have BCG-unresponsive papillary only disease, so high-grade Ta [and] there may have even been a couple of patients with T1. In my practice, I’m hesitant to use any of these intravesical therapies for [patients with] BCG-unresponsive T1 disease. Those are not ideal candidates, and those patients should be treated with cystectomy, but for somebody who has a small amount of high-grade papillary Ta disease, it may be reasonable to consider [nadofaragene firadenovec] as opposed to cystectomy.

The once every 90 days administration is ideal for patients who are traveling long distances for their care, and this could be true at an academic center or rural community practice. There are a lot of patients who have to travel long distances, and this would be a reasonable therapy to try in those patients in particular.

Moyer: The forgiving treatment schedule [is key]. We don’t have the power to do pre-baseline characteristic [testing] to see which are good predictors of who will do well on this [therapy], but the forgiving treatment schedule is a factor you have to consider.

Are there any patients you wouldn't use nadofaragene firadenovec in?

Tyson: I generally don’t use it in patients who have very high-risk NMIBC who need a radical cystectomy [such as patients with] high-grade T1 [disease] with concomitant CIS, lymphovascular invasion, [and] perhaps variant histology—[those] patients need to have a radical cystectomy. I also generally don’t use it in patients who have a defunctionalized bladder—poor capacity, poor compliance—[as those are] patients whom I strongly suspect are going to leak the drug around the catheter or who may have worsened bladder function as a result of additional intravesical therapy. I also tend to usher those patients towards cystectomy, and I have not been using it in patients who don’t have strictly defined BCG-unresponsive disease. We follow that closely. If they’re exposed, then I generally put those patients on a clinical trial or more BCG.

For patients who aren't candidates for BCG or are unresponsive, the NCCN guidelines note nadofaragene firadenovec and nogapendekin alfa inbakicept are options for the same patient population and pembrolizumab is also available for select patients. How would you select between the 3 drugs?

Tyson: That’s not a softball question; it’s a tough question. I believe the days of pembrolizumab [Keytruda] monotherapy are coming to an end. When we didn’t have any other option and patients didn’t want cystectomy or further intravesical therapy, pembrolizumab monotherapy was a reasonable option, but now we have intravesical therapies [with] nadofaragene firadenovec and nogapendekin alfa inbakicept that have demonstrated just as good, possibly even slightly better efficacy in clinical trials, and certainly better tolerability. With the 2 intravesical agents, we don’t see any autoimmune-mediated systemic AEs, so I believe the risk/benefit ratio in general favors the 2 intravesical therapies.

How to choose between those 2 drugs is a very difficult task as well. On one hand, nadofaragene firadenovec is given once every 90 days as a monotherapy. On the other hand, nogapendekin alfa inbakicept is given in combination with BCG in the classic induction and maintenance paradigm. If your practice is short on BCG, then you’re not likely going to use nogapendekin alfa inbakicept, but that being said, nogapendekin alfa inbakicept is what I’ve called the leader in the clubhouse. It’s come across the finish line with the highest CR rate at a year in an FDA [studied] population. There are pros and cons to the administration and logistics, and [the data supporting the FDA approvals noted a 51% CR rate for nadofaragene firadenovec and 62% for nogapendekin alfa inbakicept], so there are questions potentially about comparative effectiveness.

I’m not saying that [one agent is] better, we need to do the to do the science to make that determination, but I could see how patients look at that and say, ‘I’d rather have nogapendekin alfa inbakicept.’ Or I could also see how patients look at nadofaragene firadenovec and say, ‘I’d rather have that’. In my practice right now, I can prescribe both—I just got the ability to prescribe nogapendekin alfa inbakicept recently. I have a conversation with the patients, and I lay out the data for them and the risk/benefit ratios, what it takes to go on each of these therapies, and I let them choose.

How do these real-world study findings aid in your selection between the drugs?

Tyson: There are some instances, and maybe it’s true in most instances, where the real-world data don’t measure up to the clinical trial data and that’s because the people we put in clinical trials are heavily vetted, have made it through a litany of inclusion and exclusion criteria, and just don’t reflect the average patient who we see in the clinic. The idea behind this study was how does this drug work for the average patient who’s being seen in the clinic? Even though there’s a large difference between the 79% observed 3-month CR rate in our real-world study and the [53]% [rate] observed in the phase 3 study, I’m hesitant to say that it’s better. Our data don’t show that nadofaragene firadenovec is more effective than we think, it does not appear to be any worse, and that’s very encouraging to see in a real-world study.

References

1. Moyer J, Durant A, Nguyen M, et al. Real-world outcomes of nadofaragene firadenovec in BCG-unresponsive non-muscle invasive bladder cancer. J Clin Oncol. 2025;43(suppl 5):716. doi:10.1200/JCO.2025.43.5_suppl.716
2. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. FDA. January 20, 2023. Accessed March 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-adstiladrin-nadofaragene-firadenovec-vncg-patients-high-risk#:~:text=On%20December%2016%2C%202022%2C%20the,with%20or%20without%20papillary%20tumors
3. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. FDA. April 22, 2024. Accessed March 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer