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Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are videoing live at the American Urological Association 2024 meeting in San Antonio, Texas. I'm delighted to be joined by Dr. Mark Tyson, who is an associate professor of urology at the Mayo Clinic in Phoenix. And we're delighted to have you back on. We've done several recordings lately, so thanks again for joining us.

Mark Tyson: Thank you for having me, Zach. I'm delighted to be here.

Zachary Klaassen: So today we're going to discuss the holy grail for bladder cancer, and other malignancies we treat too, which is really the appropriate sequencing, and how we select these patients. Is there specific characteristics that you look at, whether it be patient, tumor, what prior therapies they've had? How do you put that together when you're thinking about a sequence for a patient?

Mark Tyson: Yeah, so I think it depends on the disease state. For BCG-naive, high-risk non-muscle invasive bladder cancer, obviously, we prefer to start with BCG. There's a shortage there, so sometimes that impedes our ability to get induction and maintenance therapy to patients. So it might then try single agent gemcitabine or gem/doce. But generally, I start with one of those for the BCG-naive patients or clinical trial. There are a lot of really interesting clinical trials in this space too, and coming down the pipe. But once they become unresponsive, then we have this situation where we have a lot of different drugs that we have access to.

And just to remind your viewers, unresponsive patients or patients who have received adequate BCG, which is five plus two induction courses plus two installation courses of maintenance BCG followed by papillary recurrence within six months or CIS recurrence within 12. You can sometimes meet criteria by being a T1 patient who's recurred immediately after induction. But that population of patients, that unresponsive population of patients, we really have a hard time knowing what the right thing to do is. Because we have a lot of really good options. We presented the Creto data this morning. We have Adstiladrin that's already FDA approved. N-803 just got approval this last week, which is exciting. Pembro is already approved, obviously, and there are a few trial concepts involving combination therapy with Pembro.

But I could see a situation five or seven years from now where we have 5, 6, 7, 8 drugs that are approved and we will have, right now, no idea how to sequence them. So what I tend to do is I tend to talk to the patients about all the aspects involved. This is the efficacy data, this is the safety data. This is your particular tumor type. Do we need to do radical cystectomy? Can we avoid radical cystectomy? Can we do intravesical therapy? Do we do intravenous therapy? And I just let the patient decide at this point. But I do think eventually biomarkers and some of the correlative science that's being done now will help guide us.

Zachary Klaassen: It's amazing. I mean, we think about advanced prostate cancer, the sequencing question is always there, and five, six years ago we didn't have this problem in non-muscle invasive bladder cancer. Right. Here we are.

Mark Tyson: That's right.

Zachary Klaassen: I want to focus the rest of the discussion specifically looking at how Adstiladrin fits into this milieu of treatment and maybe in sequencing. Maybe for our listeners, if you can just highlight again some of the key findings from the key pivotal trial published in 2021.

Mark Tyson: So this was published in Lancet in 2021 by my colleague Steve Boorjian in Rochester. It was a big trial, a trial that involved... It's a single open-label design, as is the case for a lot of these trials involving BCG-unresponsive CIS, and that's all FDA-driven. The FDA has accepted complete response as a primary endpoint in patients who have disease because the idea is they have active disease going into the trial and we're going to assess their response over time. Obviously, we want that response to be durable.

So in the case of Adstiladrin, about a hundred patients with BCG-unresponsive CIS underwent a treatment with Adstiladrin, which is a non-replicating adenovirus that administers the interferon, I think transgene, to the bladder epithelium. And that induces inflammation and fights cancer from that perspective. It was very effective. It had a complete response rate of 51% at a time point, and almost half of those were durable at a year. So the patient has about a one in four chance of surviving a year later with their bladder disease-free. Pretty well-tolerated, pretty easy to instill. It's once every 90 days, and so I think it represents another fantastic option for our patients.

Zachary Klaassen: That's great. So if you look at... You mentioned the instillation once every three months, which is attractive to patients. If you look at your practice and patients that have received Adstiladrin after BCG therapy, is there sort of a cohort that kind of leans towards it or you lean them towards it? How does it fit into your sequence sort of in the milieu of treatment options we have?

Mark Tyson: Well, up until now, I mean for unresponsive patients up until the approval of Nadofaragene, we had basically Pembrolizumab, Gemcitabine, gem/doce, or any of the other chemotherapies or clinical trial. And then Nadofaragene came along, it became product ready, and I think most sites launched in the fall and now we have this other option. So the way I've personally sequenced it is I've talked to patients about both options, essentially Nadofaragene, which is standard of care intravesical, well-tolerated, versus a clinical trial. And I let the patient choose because it's kind of up to them at the end of the day anyway. And I think as long as you have well-tolerated therapies on clinical trials, to me that's still a very reasonable thing to do for patients.

Zachary Klaassen: Do you find that there's patients that really glom onto the fact that it's once every three months? It's less travel, it's less hassle. Are there aspects of that that patients really appreciate?

Mark Tyson: They do, especially patients that are traveling in. They can come in, they can get their cysto in the morning, their Adstiladrin in the afternoon, and they come back 90 days later. So a lot of people really like that. And so I absolutely think that the logistics is a key aspect for Adstiladrin.

Zachary Klaassen: What about biomarkers in terms of selecting patients for Adstiladrin or maybe selecting them away from it? Are there aspects that you're looking at? Anything on the horizon biomarker-wise that will help us sort of guide this sort of sequencing?

Mark Tyson: I'm not currently using any biomarkers to select patients for therapies, although I think that there are some trial concepts, THOR-2 and others that rely on FGFR3 sequencing, which I think is very reasonable. But I'm not personally using any at the moment, although I do think five or seven years from now we might be.

Zachary Klaassen: What about BCG-naive space? I know you mentioned BCG shortage. I've used a lot of gem/doce in that upfront setting. We've got the bridge trial going on to show hopefully not inferiority between those two, but in the BCG-naive setting, is there any trials or any real-world utilization perhaps for Adstiladrin?

Mark Tyson: That's a great question. Adstiladrin has a trial open, ABLE-32 for BCG-naive intermediate-risk patients. That is a randomized trial comparing Adstiladrin, I think, to TRBT alone. We may need to fact-check that. I haven't yet opened the trial, but it is—

Zachary Klaassen: It's using those patients.

Mark Tyson: It is. There is an Adstiladrin concept being considered in that space. Creto has PIVOT-006 obviously, and Keynote has some trials open as well, BCG in combination therapy with Pembrolizumab. And then obviously SunRISe-3. Those are the big ones, plus Max's BRIDGE trial, obviously. So I think that's kind of the high points for the BCG-naive trials.

Zachary Klaassen: Awesome. It's an exciting time. I mean, every meeting we come to, it seems there's new data being presented, whether it be SUO, AUA, ASCO, GUASCO, EAU. So I think we're in that space, as you mentioned, the next five to seven years, we're really going to see the sequencing hopefully with biomarker selection, appropriately triaging these patients.

Mark Tyson: And I would actually say, make the point, I'd kind of give the FDA a lot of credit. And there's a lot of people who within our field, Seth Lerner and Ashish Kamat and others who pressed them to be innovative and to think innovatively. And they did that. And I give the FDA a lot of credit for accepting some kind of outside-the-box thinking in terms of what are we going to accept as endpoints? What are we going to accept as durable responses? And that really, I think, helped spur development in our field. And so it is a very exciting time. I completely agree with you.

Zachary Klaassen: Always a good conversation. Any last-minute take-home messages for our listeners?

Mark Tyson: There's going to be a number of options that are available to our patients in the next few years, and Adstiladrin, Creto, TAR-200, N-803, all of these for the unresponsive patients represent fantastic options, and I'm looking forward to seeing how they continue to be developed in the next few years.

Zachary Klaassen: Absolutely. Thanks so much, Mark. It was a great chat with you.

Mark Tyson: Nice to see you, Zach. Thank you.

Zachary Klaassen: You bet.