Nadofaragene firadenovec maintains safety, efficacy in real-world population

In this interview, Mark D. Tyson II, MD, MPH, and Jacob A. Moyer, BS, reflect on key findings from the study, “Real-world outcomes of nadofaragene firadenovec in BCG-unresponsive non-muscle invasive bladder cancer,” which were presented by Moyer at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium in San Francisco, California.

Nadofaragene firadenovec-vncg was approved by the FDA in December 2022.

Nadofaragene firadenovec-vncg (Adstiladrin) was approved by the FDA in December 2022 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.

Tyson is a urologic oncologist at the Mayo Clinic in Arizona, and Moyer is a research intern at Mayo Clinic in Arizona.

This transcript was AI generated and edited by human editors for clarity.

Could you describe the background/rationale for this study?

Moyer: Since nadofaragene firadenovec was approved in December 2022, there hasn't been any published real-world data. Since, of course, real-world outcomes and clinical trial outcomes can vary at times due to screening criteria and differences between a clinical trial population and a real-world population, we conducted a real-world evaluation of patients treated with nadofaragene firadenovec at all 3 Mayo Clinic sites in Arizona, [Minnesota], and Florida. We looked at patients from the first dose given outside of a clinical trial in November 2023 up through December 2024 before we put the data together. All of our patients met the FDA-defined BCG-unresponsive criteria for non–muscle invasive bladder cancer.

What were the key findings?

Moyer: There were 46 patients treated during this time frame. Of those 46 patients, 3 had pending post-treatment cystoscopy. So, although all 46 were evaluated for safety outcomes, 43 were efficacy evaluable. Of those 43 patients, 24 had CIS [carcinoma in situ] with or without papillary disease. At 3 months, those patients had a 79% complete response rate, which was durable in 74% of patients at 6 months and 60% of patients at 9 months. In the papillary only cohort, which had 19 patients, the high-grade recurrence-free survival was 68% at 3 months, which was durable in 57% of patients at 6 months and 40% of patients at 9 months. [Data also showed] 100% overall survival at a median follow-up of about 8 months.

In terms of safety, we saw a lot of low-grade, transient, and local [adverse] effects, usually during treatment, which resolved. Less commonly, we had 9% [of patients] with grade 3 adverse events, which included fatigue, fever, and dizziness. Generally, the safety profile was inline with the clinical trial, which was low-grade and tolerable, although frequent.

Tyson: I would just add that the 3- and 6-month KM estimates are in the intention-to-treat population, and not in the complete response population. So, it wouldn't be 74% of 79% that responded. It would be 74% of the intention-to-treat population who were in complete response at 6 months, and then 60% at 9 months.

Moyer: In fact, within the 79% of CIS patients with complete response at 3 months, 84% of those patients remained in complete response at the end of our 8 months of follow-up.

How do the real-world data compare to the clinical trial data that's been reported with nadofarogene?

Moyer: The approval for nadofaragene was based on a 51% complete response rate in the phase 3 trial. So, our 79% in the CIS population appears higher, but we hesitate to say that with such limited follow-up, different cohorts, [and a] smaller sample size. It’s relieving that it appears no worse than the clinical trial data. Although we don't want to make any sweeping generalizations with this very early real-world data, it is nice to see that it doesn't appear to be worse than the clinical trial data, which is always the concern moving to a real-world population.

Tyson: There are questions about whether the populations that we treat in clinic are equal to the populations that we treat in the setting of the clinical trial, both in terms of the biology of their disease, as well as in terms of their [adverse] effects, comorbidities, etc. Our thought is that we wanted to test nadofaragene and report its effectiveness in a population of patients who may or may not have qualified for the clinical trial in the past. [It's] encouraging to see the results being more or less comparable. If you look at the durability in the intention-to-treat population and in the efficacy evaluable population, it's similar to the durability that we saw in the clinical trial, even if there's a higher topline number at 3 months.

What are some of the implications of these data for clinical decision-making?

Tyson: I don't know that this is a practice-changing study. The practice-changing study was the phase 3 trial; that was the one that led to the approval. I think this is a practice-reassuring study. For those who are already prescribing [nadofaragene] and see value in it, this is going to reassure them that the drug has activity in a real-world population. So, the implication for real-world decision-making is that this drug appears to hold up to what was seen in the trial.

Is there any future work that's planned based on these findings?

Tyson: ABLE-41 is [an ongoing] phase 4, post-marketing study that's being run through Ferring. It's going to accomplish, on a much larger scale, exactly what we've just done in this small, multi-center, retrospective study. The prospective, real-world data will provide even higher quality data to reflect on.

Moyer: The only thing I might add is that in the real-world, we're able to reinduce patients. We reinduced 2 patients, 1 with CIS and 1 with papillary-only disease. In the phase 3 trial, written conservatively, [reinduction] was not part of that. The papillary-only patient is still high-grade recurrence-free at this point, but not the CIS patient who had a recurrence. That's another interesting direction that future trials will definitely report. That's something to keep an eye on as well.

Tyson: I'm glad you brought that up, because we need to talk about the repeat treatment group. There are a couple caveats there. Since it's only 1 dose, you think, "well, maybe if you give more of it, [there’s] more of a chance, and maybe it'll work." But we have to be very careful about this population of patients. The people who were retreated in our group had favorable disease. These aren't people who, [for example,] had a lot of CIS after a single dose. These are patients that had small amount of disease, and the patients were either not healthy enough for surgery or refused it. In that population, I think it's reasonable to consider [retreatment], despite the absence of data showing efficacy.

We did find that 1 of the 2 patients had a response after repeat treatment. This was in the papillary patient, not the CIS patient, so there is a potential role for it. But again, how many treatments we give these patients needs to be cautiously weighed against the risk of this disease progressing and taking somebody's life. That's the last thing that you want to do is miss your window of opportunity. I wouldn't reinduce a T1 patient, for example. [I might] not even treat a T1 patient with this if they're eligible for cystectomy, particularly if they have CIS or [lymphovascular invasion] variant histology and so forth. I want to caution the viewers to not think that we can just treat with numerous doses. In our population, that was a very selective couple of patients, and it was a very forthright conversation that was had with the patient about the risks and benefits.

How do you foresee gene therapy evolving in the treatment paradigm for NMIBC?

Tyson: There are a number of gene therapies in the works. Nadofaragene is the first across the finish line. There's cretostimogene grenadenorepvec which is an oncolytic immunotherapy. Unlike nadofaragene, it's replication competent in [retinoblastoma] pathway-deficient tumor cells. There's detalimogene too, which is a non-viral gene therapy that that is based upon IL-12 and RIG-I, which is a nanoparticle that delivers the plasmid. [There are] at least those 2 in the immediate pipeline, and there may be others in early clinical trial testing. Unlike other diseases where gene therapy wasn't successful, direct application to the bladder seems to be successful. If you're asking me to predict what I think the role of gene therapy is for this disease in the next few years, I would say a quite prominent one.