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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And joining us today is Professor Dan Canter who heads the advanced therapeutics at Georgia Urology Associates.

Dr. Canter, thank you for taking the time to spend with us today. We're going to touch upon a little bit of the data and the buzz around nadofaragene now finally being available for our patients, and get some of your insights into how we could use this in the real world and how people should bring this into their clinic.

So first off, you are very familiar with nadofaragene of course, but if you could highlight for our audience what are some of the key data points from the trials and the reports that brought it to your attention as to yes, this is something good for our patients.

Daniel Canter: Yeah. Well, first of all, thank you for having me and inviting me to discuss this new and exciting therapy.

So as you know, well, we both participated in the Phase 1, 2, and the Phase 3 trials. So I was fortunate in that I had real-world or hands-on experience with the medicine during the clinical trials.

And the first thing was how well-tolerated it was. That was what I remarked or noticed during the clinical trials. I think I keep telling everyone in the sense that in terms of administration, in terms of tolerability, it's very much like BCG, and maybe better than BCG just because the administration schedule is every three months rather than every week for six weeks.

But I think one of the things when you look at the clinical efficacy or the response rates, I think what you see is that number one, it was one of the first medicines that was at least studied in a clinical trial, and obviously, it was open label and it wasn't randomized, but it was one of the first medicines that have modern data that systematically looked at response rates and defined patient populations that were eligible.

So I think that was really exciting. And then when you look at complete response rates at three months and complete response rates at 12 months, you see at three months we were looking at a 53% response rate with CIS and then a 73% response rate with high-grade TaT1 disease. And then at 12 months, you had a 24% complete response rate in the CIS cohort, and then what they termed high-grade disease-free survival was 44% at one year.

So one year data is all we have right now, and obviously, we'll have more, but it's still very exciting because I think historically the numbers we would have are probably not as good, and we now have at least this systematic and clinical trial data to use as a benchmark not only for this therapy but other therapies that could be developed in the future.

Ashish Kamat: That's a very good point that you sort of highlight, right? Because it's the data, but it's also important to recognize that the FDA guidance document, which was in discussions with several groups in 2016 and then finalized in 2018, was followed by the nadofaragene trial, and the SUO-CTC led the charge. It was a truly collegial collaborative effort with multiple institutions all part of the SUO participating.

And the data that came out was fairly robust if it followed strict conclusion criteria, the patients were selected appropriately, and of course, like you said, even though it's a single-arm study, it was done in a rigorous enough manner that we can use that data in some ways to sort of mentally at least have a benchmark of this is what it should be.

Now, we talked about the 12-month data, which I think is very important because patients don't really, I mean, they're interested in what happens at three months, but most patients are like, "Hey, if at three months I have a 100% response rate, but then later on it's zero. How does it matter to me, right? I've just gone through this intense therapy and then it doesn't work."

So what you mentioned about the 12-month data is very important. What's your sense? Because you've been in bladder cancer for several years, you have a sense as to what works, what doesn't work. How do you counsel your patients on the data that you mentioned, 25, 23% at 12 months? How do you discuss that with your patients and how should people discuss this?

Daniel Canter: Well, it's a great question and I think it's a nuanced question because, as you know, and you've been taking care of bladder cancer patients longer than I have and have much more experience than I have, but as you know, these are patients who are not young and not really particularly healthy.

And so I think that the way I try to counsel patients is that I think we're starting to be in a period of a bounty for non-high-grade, people who are specifically BCG refractory non-muscle-invasive bladder cancer. Keytruda got accelerated approval, and then now we have nadofaragene, and then there are other therapies that should be coming hopefully online this year and next year.

And so I think what it really does is it gives patients options to really at the bottom line I think for a lot of these patients, and not just the patients, but providers, I think we're delaying or we're delaying safely or maybe pushing off or avoiding in the future a radical cystectomy.

And I think that's really, as we know, the radical cystectomy can be curative from an oncologic standpoint, but it can come with a lot of risks and actually not just morbidity, but a not insignificant mortality rate for patients.

So I think the way I try to counsel it now is to say, "Listen, this is just helping, this is an effective therapy, it's not 100% curative, but it's like a lot of things in oncology, we can use this. Hopefully, you'll be in that percentage of patients who have a complete response at a year, maybe longer. And if you then fail, then there may be another option, and there may be another option that comes on the market after that."

So it's really trying to do our best to push almost the mandatory need for a cystectomy as far out into the future as we can. And hopefully, the goal would be for some of these patients to have their bladder cancer in a sort of steady state and maybe something else will be the disease that ends their life.

Ashish Kamat: Yeah. And again, it's something that we as a community have recognized over the years that there is a window, and the window of the ability to save the bladder is appropriately narrow, but at the same time, it's not so rigid that we can't offer patients these options. So the points that you made are really on target.

Daniel Canter: If I may add, I think what's really exciting with some of these therapies is that they're somewhat similar in some respects, I think especially with intravesical. I mean, I think they seem to be immunostimulatory, immunomodulatory, maybe not totally specific, but again, when we look at things like Keytruda, that acts through a different mechanism of action.

So I think that the nice thing is that we are hopefully going to have different mechanisms of action to attack or treat non-muscle-invasive bladder cancer. So to your point about bladder salvageability, not just from a cancer standpoint but from a functional standpoint, maybe that window will widen so that we can, again, keep patients with not only oncologically safe but also with a functional bladder that does not significantly impede their quality of life.

Ashish Kamat: Yeah, no, absolutely. And then switching gears a little bit to a more practical issue, because there was a period where nadofaragene was just not available due to manufacturing issues. Now it's available. It's not freely available, but it's getting there.

Daniel Canter: Yeah.

Ashish Kamat: Some pearls that you could share with our listeners and audience that want to try and get nadofaragene at their center as to how you've gone about it and how you've gotten it onto your formulary?

Daniel Canter: Well, so we've been fortunate in that we've been part of their Early Experience Program because I was an investigator in the clinical trials. And I think we're also fortunate, or I'm fortunate, that being in a large urology group, we don't have to go through a hospital system to go through the P&T and all the other committees needed.

And so we just needed to get comfortable. So I think that reduced the logistics in terms of getting on board and getting comfortable with, I think currently, it's a somewhat expensive therapy that obviously has to go through the typical insurance approvals and so on and so forth.

Ashish Kamat: We often hear from people that there's this reluctance in the community or in non-academic centers about it being a viral gene therapy and, "Oh my God, how are we going to actually get this into our system?" Any thoughts there?

Daniel Canter: Yeah. Well, I mean, again, I think the thing that's nice about the community is that at a practice like ours, the decision-making can be much quicker and less ponderous. And fortunately, since I had experience with the therapy and it's a gene therapy, I could explain to everyone how safe it was, and it's an adenovirus that's attenuated, so it's not going to cause some sort of devastating pandemic and allay those fears. Obviously, post-COVID, I think there's always that fear anytime you hear "virus."

But I think we're fortunate where I'm fortunate where people kind of trust our team that's involved in bringing new therapies on that they understood that we had experience with it, there's all this data, there's the correlates data that Dr. Dinney and others published, and I know you were on that paper as well, looking at those types of levels and stuff.

So I think, again, it was easier just because the decision-making process was a much smaller group, which fortunately I was able to be a part of and able to steer that discussion without getting distracted by these things that sometimes can be, again, just a distraction and isn't really relevant.

Ashish Kamat: Have you treated patients now off-trial in the real world with nadofaragene?

Daniel Canter: Yeah, I mean, it's just sort of, I don't know, the floodgates have opened, and I think we've had a couple of patients, actually more than a couple of patients, that are now coming back for their second treatment.

So we started, we're almost in February, so we did our first treatments in October, and now we have I think four or five patients who are coming back for their second treatments.

So I think overall we've treated about 10, 12 to 15 unique patients. And yeah. And so far it's been very well-tolerated. Really no real significant side effects other than some LUTS to speak of.

Ashish Kamat: Yeah, and that's great. And I ask that question because again, people will often wonder, when we did the clinical trial, they go, "Oh yeah, in the clinical trial you can do it, but in the real world, it's going to be impossible to get it in the clinic and deliver it," which it isn't. And I just wanted to highlight that point.

Daniel Canter: Yeah, no, to Ferring's credit, it's been a very smooth process. I mean, again, there's a lot when you sort of get involved, get set up with them, and they have a lot of SOPs because it has to be sent frozen and so on and so forth. And that's really the only difference to your workflow or to a clinic's workflow, just the way you receive it and then you have to put it in the freezer and then the next morning you pull it out and let it thaw. And after that, again, it's exactly like BCG.

Ashish Kamat: Yeah. And then at our place at least, we don't have it on our EMR yet; it's not part of our standard orders. We still have to order it for each individual patient. Have you incorporated it into your Epic or other EMRs?

Daniel Canter: Yeah, we're not fortunate enough to have Epic. We have a different EMR. But yeah, it's been added to the order where we can directly order it through the EMR for each individual patient, for the Adstiladrin or the nano.

Ashish Kamat: Right. So I guess what I'm hearing from you is that once you get it into your system, you haven't identified any barriers that would prevent another urologist who wants to bring it into their practice from adopting it, right? Anything you can think of?

Daniel Canter: No, not at all. I mean, I think, again, when you look in the community, I think there are cost issues to consider, but we've managed them very easily.

I think that, again, we were doing Keytruda for non-muscle-invasive bladder cancer, which, as you know, is not inexpensive itself, and so we had been fine with that. I think that cost is spread out a little bit more because you're either giving it every three to six weeks rather than having a lump sum every three months. But we've worked around that and we have a process in place that's not onerous or that prohibits us from doing it.

But yeah, I mean, essentially, again, I know I'll sound like a broken record, but other than the fact that it's a little more expensive, that most urology practices are used to the buy and bill model, and the fact that you have to freeze it overnight just depending on where you are and then thaw it, the whole workstream after that is exactly like BCG.

Ashish Kamat: Right. Dan, thanks so much for taking the time. I don't want to keep you all evening, but in closing, any high-level summary thoughts for our audience that you want to share about nadofaragene? Anything about it at all?

Daniel Canter: Listen, I think we're just very lucky, and I think patients are very lucky that we now have a proven therapy that's FDA-approved, or actually a second therapy that's FDA-approved for BCG refractory non-muscle-invasive bladder cancer. And I think all urologists, whether they specialize in bladder cancer or not, realize that this is an area of high unmet need.

And so the fact that we have two therapies is really exciting for patients. And I think in order to take the best care of our patients, I really would encourage every practice to do their best to provide this service to patients, or at least send them to practices that do administer it, just because it's really, ultimately, it's all about the best patient care. And that's what I think this therapy does provide.

And the second final thought is that the nice thing about this therapy is that it's intravesical with a very well-tolerated side effect profile very similar to BCG, as I said, that is much different than the side effect profile one would see with a checkpoint inhibitor.

And so that, again, even when you look at the clinical efficacy or the oncologic efficacy and you consider the side effect profile, it really is, I think, a really huge leap forward or huge step forward for patients with BCG refractory non-muscle-invasive disease.

Ashish Kamat: Yeah, and I couldn't agree with you more. It's great for our patients to have options, and the more options they have, the better it is. And the quicker we can adopt these into our practices, obviously the better it is for everybody concerned. So thanks again for taking the time. It was great chatting with you.

Daniel Canter: Yeah, my pleasure. Thanks for having me.