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Zachary Klaassen: Hi, my name is Zach Klaassen, a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today for a discussion about the AUA South Central Section meeting, some interesting data presented by Dr. Yair Lotan, who's joining us from UT Southwestern. Today we're going to be discussing the efficacy of intravesical nadofaragene for patients with BCG-unresponsive cancer, specifically talking about 36-month follow-up for this trial. Yair, thanks so much for joining us today.

Yair Lotan: Sure, absolutely. Thank you so much for talking with me about this. So I'm pleased to speak about this trial. This is a multi-center trial and was led by Dr. Boorjian at Mayo Clinic, and represents a three-year follow-up for looking at the efficacy of intravesical nadofaragene for patients with BCG-unresponsive non-muscle-invasive bladder cancer. I think one of the unique aspects of this trial is that most of the trials for the newer agents do not have follow-up or have not published long-term follow-up, and nadofaragene is one of the newer approved agents. So it's important to see how well it works over time in order to discuss this type of information with patients who often want to know what the long-term efficacy will be.

Here are my disclosures. So the phase 3 trial was a single-arm trial looking at nadofaragene, which is an intravesical non-replicating adenovirus vector that stimulates the production of interferon in the bladder. You give one instillation every three months. And the way the trial was designed was that you received a dose every three months as long as the therapy was working. And it's important to distinguish this from some of the other trials which allow retreatment in case of persistent or recurrent disease, because in this trial, you could not receive a re-induction if you had persistent carcinoma in situ.

There were two arms. One was carcinoma in situ with or without papillary disease, and the second arm had papillary-only disease with either high-grade Ta or T1. The pivotal trial, though, was based on the carcinoma in situ, which is consistent with FDA guidance for how these drugs are being evaluated. And it had 107 patients, and there were 50 patients in the papillary-only arm. When you looked at the primary endpoint—we'll talk about it a little bit more in another slide—but for carcinoma in situ, there was a 53% response for participants at three months, and it was higher for the papillary group at around 73%. Very safe drug. Most of the side effects were consistent with local instillation issues such as leakage of fluid when you were injecting, or bladder spasms or urgency, but no grade 4 or 5 drug-related adverse events.

In this figure, you can see the 36-month efficacy for nadofaragene. On the left side, you can see the carcinoma in situ with or without papillary disease. Again, 53% CR rate at three months. By a year, it was around 24%. And I should note that this study had mandatory biopsies at a year for patients, even if they had normal white light cystoscopy and normal cytology, and a few patients were found to have recurrences at that time point. By two years, you can see that only five patients less had efficacy, from 25 to 20 patients. And by three years, 14 patients still were disease-free. In terms of durable response, we start off with 100% of those patients who were responding at three months. And you can see that at a year it was about 45%. And by three years, about 25% remained high-grade recurrence-free.

In the papillary-only cohort, around 73% were disease-free at three months, about 43% at a year, about a third at two years, and about 23% at three years. Durable response was obviously based on initial full responders; 60% of those stayed disease-free at one year and about 31% at three years.

These are Kaplan-Meier estimates for durable response. I think the key here is to note that the median duration of complete response was about 10 months, and by three years about a third of patients who initially responded maintained that complete response.

In terms of cystectomy-free survival, which is obviously one of the important endpoints for patients with non-invasive disease, about half the patients were cystectomy-free in the CIS arm and about 64% in the high-grade Ta arm. Overall survival was very high in the entire cohort, over 90%. There were no new safety signals during the 36-month follow-up period. A few patients stopped due to non-serious AEs such as bladder spasms, but there were no other treatment-related events of significance and no deaths.

So the key takeaway is that half the patients with CIS achieved a CR rate at three months. Again, there was no re-induction allowed for non-responders. About a quarter of the participants who had initial CR remained disease-free at three years. About 31% of papillary patients also remained disease-free at three years, and more than half the patients were able to keep their bladders and remain cystectomy-free. No new safety signals, mostly with local adverse events. In conclusion, this is a well-tolerated, safe therapy for patients who are unwilling or unable to undergo cystectomy.

Zachary Klaassen: Yeah, thanks so much for that update. That's great data. Certainly, as we look at—this is such a hot disease space as you know—how do these 36-month results for nadofaragene stack up against some of the other agents that we have in that BCG-unresponsive disease space?

Yair Lotan: I think because this is an area where a lot of trials and drugs are being developed, we actually have an absence of good data down the road for most of these drugs. Other than Keytruda, Adstiladrin or nadofaragene was the next approved agent, we really just have retrospective data on gemcitabine-docetaxel, N-803 or ANKTIVA just got approved in May. And trials like SunRISe-1 looking at TAR-200 and BOND-003 are still trying to get their 12-month data. So it's going to be quite a few years before we actually have any way to assess long-term effectiveness for all the other agents that are coming in and hopefully will be commercially available.

I think the good news is that there are patients who maintained complete responses. I think, though, the fact that two-thirds of the patients or more had recurrences suggests not only that we need new drugs, but also close vigilance and surveillance for these patients, because they're rare cure rates. We still know cystectomy is the best chance of cure. It obviously has lifelong quality of life implications and morbidity, and patients would like to avoid those. So it's good to have more options, but long-term data is something that we're still lacking for most of the available drugs.

Zachary Klaassen: Yeah, well said. I think you kind of led into my next question in terms of counseling these patients, even just today, talking to patients who are on pembro, they've been through gem-doce, now thinking about Adstiladrin.

I think I like the cystectomy-free data there because that's 36 months now. And really, that's what these patients are trying to avoid within reason of not having their cancer progress. So how does this, in your clinic, tertiary center, seeing a lot of these patients at 36-month data now, how does that change your counseling when you're talking to them about this option?

Yair Lotan: I think it's another piece of information. I don't know that it really changes my counseling. In many ways, the way I view high-risk bladder cancer is, it's a three-month interval.

Zachary Klaassen: Yeah.

Yair Lotan: But what can we do to get you to the next three months and hopefully the next clean cystoscopy? Yes, it's nice to be able to tell them, "Look, there are long-term responders, and if you have a good response at three months, there's a decent chance you're going to maintain a good response." The exact number of three years is less relevant. I'm obviously encouraged by the fact that half the patients at three years were cystectomy-free. But the caveat there is that we know that half the patients had persistent disease at three months, and it was really a shared decision not to remove the bladder at that point. It wasn't because necessarily the drug was working well for them. It was just because they either went on another clinical trial or attempted another drug.

What we really need as clinicians is to have an ability to predict which patient is going to progress. Because if you knew you're always going to have carcinoma in situ until the day you died of something else, you would just say, "This is perfect. Never take out the bladder."

Zachary Klaassen: Right.

Yair Lotan: It's those patients who progress or potentially metastasize that may be missing an opportunity to get cured by cystectomy alone. Figuring out can they have one, two, or three different drugs as you face with your patient is really the critical question. And unfortunately, we still don't have perfect tools for that, nor do we have perfect biomarkers to tell us, "Look, nadofaragene is going to be a great drug for you, or maybe one of the other drugs is going to be a better drug for you." And it would be nice to have a more precise way to counsel patients about which treatment they should undergo.

Zachary Klaassen: Yeah, absolutely. Great discussion. Maybe just a couple of take-home messages for our listeners today.

Yair Lotan: Well, I think the take-home lesson is that you do have options other than removing the bladder. It's a careful discussion of the pros and cons with your clinician because we still know that cystectomy has a role in these patients. The drug was quite safe, and the good news is there were no long-term side effects that showed up down the road. The other good news is it did work for some patients for the duration. So when we start you on this drug, if it's a good choice for you, we hope that you have a long-term response.

Zachary Klaassen: Absolutely. Yair, thanks so much for taking time out of your busy schedule and for sharing this new data on UroToday.

Yair Lotan: Thank you so much.