Zachary Klaassen: Hi, my name is Zach Klaassen, Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined, as always, by Dr. Sam Chang, Urologic Oncologist at the Vanderbilt University Medical Center in Nashville, Tennessee. Sam, thanks for joining us on UroToday, as always.

Sam Chang: Zach, it's always a pleasure and honor to talk to you. I think we are actually going to focus today on one of the kind of—I don't want to use the word "bigger" or "more prominent," but a presentation looking at actually a combination of immunotherapy plus BCG compared to BCG alone in a BCG-naive population known as the CREST trial. So I think there are a few slides that I think would be helpful, if OK with you, kind of going over things.

This was actually presented in the P2P portion of the AUA. That was kind of practice-changing and paradigm-shifting presentations that were put out there. A lot of attention was placed on non-muscle-invasive bladder cancer. But this was actually a trial presented by Neal Shore, looking at the combination of immunotherapy with BCG, and specifically, actually, looking at that combination in a cohort of patients that we actually see quite often and that we actually treat quite often with BCG.

It was a three-arm trial, more than 1,000 patients, looking at actually one arm being Sasanlimab—that is actually a subcutaneous PD-1 inhibitor—in combination with BCG, and that's actually also with maintenance BCG and maintenance Sasanlimab. That was actually arm A.

Arm B actually had a combination of the Sasanlimab, the subcutaneous PD-1 inhibitor, in combination with BCG, but without maintenance. And that was then compared to arm C, which was BCG induction with maintenance BCG. And that regimen was actually one that we're quite familiar with in terms of the induction BCG followed by maintenance at Q3 months, Q6 months, and six months thereafter.

The nice thing about this study was the primary endpoint was event-free survival. And that event-free survival was actually in the event that actually would be prominent or important for us as treating physicians. That would be continued CIS, progression of disease, obviously, worsening of disease throughout. And so as a result, it gives us an idea, truly, of the impact of the combination of therapies as well as the impact on modern-day kind of evaluation of BCG alone, with an induction and maintenance arm.

So if you look at the results, actually a little bit surprising. I think if you were to poll individuals that treat non-muscle-invasive bladder cancer with some early data looking at actually BCG-unresponsive disease, that perhaps an immunotherapy would really not be something that would add, either systemically, either intravenously—when this one is actually subcutaneous—would not actually aid in the benefit. But actually what was found, that there were actually one-third of patients who had a decrease in event-free survival, so a 32% decrease or reduction in event-free survival events in the combination of Sasanlimab plus BCG versus BCG alone.

So I'm struck with this curve, for two things. One, BCG is a pretty good medication. I mean, you're looking at more than, or basically, 3/4 of patients at the three-year mark not having an event with that kind of standard therapy that we've had.

But on top of that, you actually have, actually, a combination that was, in fact, even superior. So I mean, I think all of us were struck by the fact that, hey, there's actually a difference, first of all, and secondly, that there was a statistically significant difference. I don't think any of us were surprised with the BCG effectiveness, perhaps, by the fact that it really bears out all the historical data that we've shown.

Now, when you look at that, and you think, gosh, what does this truly mean, I think this curve here, this slide, shows us the long-term discussion that we can have with patients. Now this curve actually just focuses on the carcinoma in situ patients. So there are less than 100, but very equally distributed, 88 in each arm, looking at the combination of the subcutaneous PD-1 inhibitor plus BCG versus BCG alone.

And what we can tell folks is, OK, if you have a complete response—that's, at any time, a complete response—your chance at three years plus is 92% with this combination. BCG also good, at two out of three. But in this cohort of patients that we always worry about, that have carcinoma in situ—and remember, this was the cohort that the FDA really focused on our single-arm trials in the past that had FDA-approval kind of inclusion, when we look at Adstiladrin and Anktiva.

But if we look at a BCG-naive population, and they have carcinoma in situ, this combination, at three years, more than 90% were actually continued in that complete response rate. So I think impressive in that a cohort of patients, if you get a complete response, there seems to be a significant tail. And we'll see, as follow-up continues, how that goes out.

But there's really a chance, I think, to have a tail that really is long term, which has actually been kind of also seen with certain other medications, looking at the immunotherapy. If you have a response, you tend to have a long-term response. I wanted to mention also that, in this trial, more than 50% of patients had T1 disease. So we're talking about really a high-risk cohort, where we seem to see an event-free benefit with a combination of therapies.

But I think, when you look at side effects, you also always have to consider, OK, what are we risking in giving a medication that seems to have a benefit? And as always, we look at adverse events and complications. And if you look at localized events, the lower urinary tract symptoms, the frequency, the urgency, those types of symptoms, we really don't see a huge difference between the combination of subcutaneous IO with BCG versus BCG alone.

But I think the next slide, Zach, is really the key. And this is the one I think that we'll struggle with. And I don't have it here that I wanted to show you, but you have to always consider the adverse events associated with IO therapies. And not too dissimilar from any IO trial, about 15%, 16% had some significant adverse event associated with the immunotherapy.

And so we need to consider that. We need to, I think, learn about those, especially if you start administering it. I think a key point that all of us would want to emphasize is the delivery mechanism perhaps is different. But the profile of these immunotherapy medications, PD-1 or PD-L1, really are not too dissimilar from each other.

And so I know you had some questions you wanted to kind of discuss, because I just babbled on and on.

Zachary Klaassen: No.

Sam Chang: This would be a perfect discussion.

Zachary Klaassen: That was perfect, Sam. That's a great overview.

Sam Chang: It's an exciting time, for sure.

Zachary Klaassen: Great trial. I know. Before we get into the discussion, let's just take a step back. How great is it that, at AUA, we're seeing phase 3 data, potentially practice-changing data being presented? It really was a great session.

Sam Chang: Yeah, I think, really, kudos to the AUA. Obviously, all our meetings are important—ASCO GU, the EAU meeting, the SUO meeting. But this year's AUA really, I think, presented some very important trials for practicing clinicians. And so I think it really opens our eyes to, gosh, we've got a lot of exciting trials and outcomes coming into play, and we look forward to future results.

Zachary Klaassen: Absolutely. We've seen over the last four or five years, particularly, BCG-unresponsive non-muscle-invasive bladder cancer, a ton of activity. We're now seeing some activity in the intermediate-risk—AUA intermediate-risk disease space. What are your thoughts—particularly this BCG-naive, high-risk non-muscle-invasive bladder cancer, we see these patients every week. How do you see this potentially impacting that disease space, this combination?

Sam Chang: Yeah, I think that's really a question that we're all trying to figure out. Obviously, we are all awaiting FDA approval. And then, once it becomes approved, what's the uptake going to be? What's the educational process going to be? Who are we going to choose in terms of patient population.

And honestly, I think it's unknown. I think, for sure, we as a community have to do, I think, a very important job of educating not only clinicians, but patients of here are our possibilities in terms of therapeutic options. Here are pros and cons. Maybe this treatment is better for you, et cetera.

Now, importantly, in the background of this is the issue of BCG shortage. This is not a subcutaneous IO therapy alone. This is in combination with BCG. So that will also, obviously, come into play.

Zachary Klaassen: Yeah, great points, Sam. I think you mentioned, very aptly, that 50% T1, roughly 70% either T1 or CIS, plus or minus, so really a high-risk cohort. Is there a specific patient profile—let's say we get FDA approval, BCG is available. Is there a specific cohort of patients where that combo may be a little higher at the top of your list?

Sam Chang: Yeah, I think when you identify, just as you said, Zach, the T1 patients, the T1 plus carcinoma in situ, T1 with higher-risk features, I mean, those are the ones we always are concerned about in terms of disease progression, of under-staging, of occult metastatic disease even.

And we're, at this point, so inadequate regarding imaging, regarding metastatic disease. It may be in that cohort of patients that are, quote, unquote, "higher risk," the very high risk, as the IBCG would designate, it's those patients that I would definitely want to talk with our patients about either timely cystectomy or this combination therapy in terms of giving us perhaps the biggest bang in terms of what we have that we can give in a bladder-preserving modality.

And I think, in younger and healthier patients, we have to consider this. The flip side of that is our more frail patients, more comorbidities, already having certain issues with medical conditions, perhaps with only papillary disease. It's those patients, perhaps, that I wouldn't kind of put this forward as the first choice, especially as we do have some BCG-unresponsive alternatives.

Zachary Klaassen: Fair.

Sam Chang: So if BCG is available, consider BCG alone. So it'll be interesting. And as we get more real-world data, I think any type of registry data would be very, very helpful.

Zachary Klaassen: Yeah, absolutely. I think, obviously, the numbers will be small, and it won't be powered to show differences. But seeing how this works in the T1-alone patients, in the CIS T1 patients will be interesting, as well. I'm sure that'll be presented at a future meeting, as well. No, that's great.

The question in the room—we're both urologists. We have some experience with pembrolizumab. In my clinic, we didn't give the pembrolizumab. We managed the patients with medical oncology. I presume this will probably be in the urology clinic. So how do you feel urologists will be with giving subcu Sasanlimab?

Sam Chang: Yeah, I think it's like anything. You have to be prepared, have to be educated. And there's going to have to be an initial lift. So those practices that are already giving pembrolizumab, in a sense, the side effects are not too dissimilar from that at all. And the route of administration is one, obviously, that urologists' offices are quite familiar with.

And so those practices, I think, are already set up. They've set up a mechanism in terms of evaluating patients, checking labs, following up regarding side effects and that type of thing. I've always been impressed with our medical oncology colleagues, who've emphasized that it really doesn't matter who gives the medications, as long as those clinicians are familiar with and are screening for and are asking and evaluating for possible side effects associated with the different types of immunotherapies.

And if they are, it really doesn't matter who actually administers the medications, as long as those practicing and treating clinicians are on top of those possible side effects—the evaluations of all the itises, looking at the thyroid, checking the blood pressure, checking liver enzymes, et cetera. And I think, as practices start this process, it's like anything. If you do something only once a year, you're never going to feel comfortable.

But this is a broad population of patients, just as you mentioned, Zach. And so with a broad population of patients, if there's enough throughput, then I think it'll be enough of a lift past inertia to get practices going. But it's one of those things where I think practices need to be prepared. They need to be educated. And they need to be forward-thinking in terms of, hey, are we going to be able to offer this? If we do it, we're going to have to do it safely.

Zachary Klaassen: Yeah, absolutely. Well said. Last question, Sam—how would you counsel a patient who's interested in this combination therapy?

Sam Chang: Well, I think, just as you said, with intravenous pembrolizumab, with other immunotherapies, obviously, a huge, huge part of our advanced kidney cancer patient population, increasingly important with perioperative invasive bladder cancer, as well as for our advanced bladder cancer patients, the vast majority of these patients see our medical oncologist.

So we've already begun discussions with our medical oncologists in terms of how do we set up a process where we can facilitate a discussion with them, because I think, for our higher-risk individuals who are able to undergo an immunotherapy, who have higher-risk disease, clearly, we're going to start that dialogue of meeting our medical oncology colleagues to start this combination process. And so I think every patient that is a candidate should at least understand the pros and cons of this therapy option.

And as you know, just recently—I mean, we're having this discussion in the spring of 2025. But there are other trials ongoing. There are other trials that have recently reported on a combination of IO plus BCG being effective. And so I think the landscape continues to evolve pretty rapidly.

Zachary Klaassen: Yeah, it's such a fun time for these discussions with our patients because we have options. We have options in different disease spaces. Sam, always appreciate you taking time out of your busy day to join us and have a great discussion about CREST. Any final thoughts, anything we didn't hit on you want to tell our audience?

Sam Chang: I think we can't just sit on our—I don't want to say "laurels." I don't have laurels. Zach, you've got laurels. But I want to say that we can't just sit in the way that we practice 10, 15, 20 years ago, for sure, not—honestly, not even five years ago now, when it comes to non-muscle-invasive bladder cancer. How we choose the different therapies is going to be somewhat nuanced.

I think it's on all of us to learn about these treatments, then decide which ones are we going to be able to integrate into our individual practices, which ones are we going to need to refer, and then also understand the lifeblood of all of these medications are the clinical trials that are still ongoing and have even more exciting options. So I think it is a very good time for our patients with bladder cancer. And as we accumulate more experience, we're going to have more options for our patients.

Zachary Klaassen: Yeah, absolutely. Sam, thanks so much for joining us. And thank you to our UroToday listeners for tuning in.

Sam Chang: Thank you again, Zach, appreciate it.