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Neal Shore: Well, hi, everybody. I'm Neal Shore. I'm the Medical Director of the Carolina Urologic Research Center. It's a great pleasure for me to have on the program today to get his expertise in non-muscle invasive bladder cancer, particularly in this burgeoning area of approvals for BCG unresponsive patients, particularly BCG unresponsive with carcinoma in situ. Mark Tyson is an associate professor of uro-oncology at Mayo Clinic in Arizona. Mark, great to have you here.

Mark Tyson: Thank you, Dr. Shore. Thanks for having me.

Neal Shore: Absolute pleasure. So, you know, for decades, we really didn't make a lot of advances in bladder cancer. Now, it's been explosive, in muscle invasive, particularly frontline, second, third-line treatments, but we want to focus today on non-muscle invasive bladder cancer treatments, particularly the BCG unresponsive space. And I know you've been following the approval and some of the more recent data that's been presented, some long-term follow-up on nadofaragene firadenovec, this viral gene intravesical delivery system. So maybe you can review with our listeners some of that top-line information.

Mark Tyson: Yeah, absolutely. I'm happy to. And like I said, thank you for having me. I'm delighted to be here with you and with UroToday. Yourself and Steve Boorjian and a number of others were the authors of the phase three that was published a few years ago now, studying Adstiladrin in the phase three setting. It was mostly BCG unresponsive CIS, though there was a papillary cohort. And these patients conformed, as you said, to the typical standard FDA definition of BCG unresponsive, which I think might be helpful to pause and just remind our viewers that this is any patient who's had induction with stage progression to T1. So they've had five of six induction courses with T1 following immediately after, or they have persistent disease, persistent papillary disease, within six months of adequate BCG with the FDA describes as five plus two. So five of six induction, plus either two of six of a second induction, or two of three of a maintenance course, or CIS within 12 months of adequate BCG.

So if they fit one of those three definitions, then they're eligible for the trial that you and Steve Boorjian published. And that trial was very impressive because it was essentially the first intravesical agent that had made real headway in this disease in a long time. And so, it was exciting to see that come out. As you summarized, nadofaragene firadenovec is a recombinant adenovirus that delivers the human interferon alpha gene to the bladder epithelium and it induces an inflammatory response. And that's how we think it works. It is convenient for patients. In the trial that we spoke about, it was once every 90 days. So that tends to be liked by patients. It's intravesical, instilled for about an hour. The main findings from that trial were about 50% of patients, 53% of patients had a complete response at any time point.

And about 25% of those were durable to three years, which was just updated at the SUO this last fall/winter. So that was really exciting to see. So of the 107 patients, 14 of them had a durable long-term disease-free response. And that doesn't sound like a lot, but if you're one of those 14 patients, then you're quite happy. But also, what we found was about half of the patients were able to avoid cystectomy. So even if they did have a disease recurrence, they didn't have a recurrence in such a way that the investigator felt like they needed to remove the bladder. So I think this is serious progress in the field. Of course, more work is needed, but that all led to the licensing and approval of nadofaragene for commercial use, which I think is what we were going to talk about today.

Neal Shore: Yeah, no, that's a great summary, and thanks for doing that in such a concise way. Yeah, we saw the FDA approve the drug, and I think it was in about November, December of 2022. And now, the company has given guidance that they've really optimized their production. And so, it's been approved now for a little over a year. There's optimization on production, which means there should be full accessibility in the United States. And I think, as we would all agree, 95 plus percent of patients who have BCG unresponsive disease, high-grade TaG3 CIS, even T1, when offered radical cystectomy, they're always like, "Well, are there other options?" We have the approval of pembrolizumab for BCG unresponsive CIS from KEYNOTE-057. There's the much older approval of valrubicin back in the day, but I don't really think most folks are using that drug. The efficacy outcome on that is not tremendous.

There are certainly better results and better trial data looking at Merck 057 and the phase two and the phase three on nadofaragene firadenovec, which commercially goes by Adstiladrin. One thing, as you mentioned, SUO, kudos to Colin Dinney and the SUO Clinical Trials Consortium, that is really one of the most important studies that that organization did. Great collaboration, getting this across the finish line, very rapid accrual, community sites, tremendous academic leadership, your colleague at Mayo, Steve Boorjian, and other really great people on the study. So now that we have this approval, Mark, so I'm just wondering, what are some of the important implementation issues for folks to be aware of, if you want to do it? You mentioned the dosing schedule, which is incredibly attractive, I think, right? It's intravesical once every 90 days. That's very appealing.

Mark Tyson: I agree, and it's certainly an easy sell from that standpoint, especially if patients are traveling for care. They come in, they get their cystoscopy, it's negative, they get their Adstiladrin dose and leave. So I think the dosing schedule is a really important aspect of this, and it is convenient. But there are other, I think, important aspects of it. You mentioned KEYNOTE-057. With Adstiladrin, we don't see any of the systemic adverse events that are autoimmune mediated, and it is intravesical. So most of the side effects are local side effects in the bladder. So that's another key piece that, as patients weigh their options between pembro, valrubicin, gem/doce, and nadofaragene or clinical trial, nadofaragene has side effects that are mostly limited to the bladder.

But I will say, just on that topic, the side effects in the bladder can be impressive at times. There are some patients who really have a hard time holding this in. My nurses estimate probably about two out of every three patients, they have some pain and discomfort during instillation. I think most of that is remedied with a Valium. You give them a Valium a couple of hours before, and most of them do fine with that. But overall, well tolerated. Intravesical therapy holds off cystectomy for a few more years, hopefully holds off recurrences potentially for another couple years. I think it's a really important development in the non-muscle invasive space.

Neal Shore: Yeah, very good points. Yeah, it's intravesical. It's easy to administer. Yeah, we see a spectrum of patients with all intravesical therapies. Some tolerate it like it's essentially saline or water, and some that do get some irritated symptoms. But my experience, both in the clinical trials and now post-approval, is, overall, really good tolerability. Kudos to Colin Dinney, who did some of the really pioneering work looking at urinary levels. And you see these marked increases of interferon in the bladder. So the viral gene recombinant DNA, it sort of creates, for lack of a better term, like a bit of a bioreactor, and you don't get systemic detection, unlike giving any parenteral or systemic therapy. I think that was your point, and I think it was a very good one. So I think this is very much within the comfort level, the wheelhouse for urologic clinics, whether you're in an academic tertiary center or a community center. Are there any other interesting unique things about getting it going in the Mayo Clinic in Arizona?

Mark Tyson: Yeah, there were some learning curves associated with this product, some new things for us, for sure. My nurses estimate that the whole process takes about 90 minutes. So I think if you are starting to operationalize an Adstiladrin program, I would try to save a space for about 90 minutes, the catheterization going in, the instillation, and watching them, taking the catheter out.

Obviously, that's important for the first dose. If they tolerate it well, then additional doses, you may not need to keep them around for that amount of time. But that first dose, I think it's important. The other aspect too, to remember, is that it takes three to four hours to thaw this drug. It comes, I think, in a minus 80 container, and it sits in a minus 80 freezer until it's time to treat the patient. So for us, that meant bringing the patient on campus a couple of hours ahead of their appointment, just so that we knew that they were here.

It's a very expensive medication if you were to thaw it, and then, the patient were to get into a car accident or miss a flight, then you were kind of on the hook for that. Although I did hear, through the grapevine, there might be an insurance program through Ferring for that, but I can't speak to that personally. I haven't used it. But we generally require patients to come a little early so that we can thaw it and ensure that they're here. There's also another sort of nuance of ordering it. I think it can only be ordered Monday through Wednesday. At least that's what my pharmacist tells me. And maybe that's a vestige of it being sent from Finland, I think, is where it's sent in from at the moment.

So that's another thing to kind of keep in mind. You may have to schedule your patients around that ordering timeframe. But overall, I think it was well worth it. We've dosed, I think, 15 or 20 patients or so so far. It's gone very well. I don't have anything major to describe in terms of downsides. It just takes a little bit of operational expertise to get the patients to come in when they're supposed to be here and deliver the drug in the way it's supposed to be delivered.

Neal Shore: Yeah, those are great insights, tips, and tricks. 15 to 20, that's very impressive. Yeah, you're right, it has to be thawed. Like any new approved therapy, these are not inexpensive. So many other examples of that. And so, very important to make sure the patient is in the clinic and didn't have a motor vehicle accident or overslept. And I think those things are not overly challenging. I know I've been on some recent advisory boards, and I've heard the company, they're really very diligent in working through, making sure that the process is as smooth as possible. Of course, reimbursement. There's the wild west of the United States and our different Medicare carriers and commercial payers. And any new therapy always has that sort of time lapse before people are saying, "Okay, we put in an EOB, and it got taken care of." Not a unique process for nadofaragene, but certainly, something that everyone wants to make sure is taken care of.

But at the end of the day, the clinical efficacy is pretty strong and the tolerability and the dosing schedule and the ease of administration. So I think it's been a really tremendous advance. Kudos to the folks who really did all this work. Really the SUO CTC, the Clinical Trials Consortium, a really great job. And of course, Colin Dinney and the folks from Kuopio, Finland, as you mentioned. I'm pretty sure that the Ferring bladder cancer team is working very diligently on a manufacturing facility in the US, in New Jersey. So I think that'll be forthcoming very, very soon. Any other comments on the space and your experience?

Mark Tyson: Yeah, it's a really interesting development because you run a lot of clinical trials too, obviously. And so, this is the first time, I think, an agent has come in and it's competed with the clinical trials. KEYTRUDA has always competed with the clinical trials, but patients could readily decline that if they didn't want to take the small but real risk of an autoimmune-mediated side effect. This drug doesn't really have a huge downside in terms of side effects, and it has a one in four chance of working, so at a year, so for BCG unresponsive CIS. So I think that's a different calculus now facing clinical trialists, like you and I and others in academic centers, where we have these portfolio of clinical trials for unresponsive patients, that now have a commercially viable option. So what I've noticed is that it's more or less relegated most of the clinical trials to that next line of therapy. I'm, for the most part, putting most of my BCG unresponsive CIS patients on Adstiladrin before putting them on clinical trials. I'd be interested in hearing about how you're handling that.

Neal Shore: Well, yeah, and we still love doing clinical trials, especially in this space. There are a lot of other exciting novel mechanisms of action out there. But I'm kind of concomitantly looking at patients for trial enrollment. I love clinical trials because that's how you change clinical practice. But at the same time, now that we have an extremely well-tolerated, very patient-friendly, and clinic-friendly dosing schedule, with clear efficacy, we're doing a concomitant pre-authorization for Adstiladrin or nadofaragene firadenovec. And then, we have that full-throated shared decision-making conversation with patients. But with that, Mark, I just want to thank you so much for your insights and your experience. It's really helpful for our colleagues out there to hear it. Any closing comment?

Mark Tyson: No, thank you for having me. I'm delighted to be here with you today, and I appreciate the opportunity to chat with you. It's always fun, and I always learn a lot. So thank you.

Neal Shore: All right, my pleasure. Thanks very much.