Sam Chang: My name is Sam Chang, I'm a urologist at Vanderbilt University. And I am fortunate to be here with one of the Titans of urologic oncology, Dr. Matt Galsky. Matt is at Mount Sinai and has really been at the forefront of numerous clinical trials, helping to lead and gain further information in a variety of disease states associated with urothelial carcinoma, and actually, other urologic cancers as well.

We've asked, actually, Dr. Galsky today to speak in an area where perhaps he may not have had as much experience in when we're talking about non‑muscle‑invasive bladder cancer. And specifically on the role of immunotherapy, when it comes to treatment of this non‑muscle‑invasive bladder cancer, or NMIBC as it's often referred to. So Matt, first of all, thanks so much for being here, and we look forward to you giving us some highlights from the AUA 2025 presentation on actually a study that surprised many of us. So we'll let you take it away.

Matthew Galsky: Sounds good. Thank you, and thanks for those comments. I do always have a little bit of imposter syndrome when I speak about non‑muscle‑invasive bladder cancer, specifically treatment‑naive disease, because when you actually don't see the disease, of course it's a different experience in treating it. And so I think this is an example of where we're really starting to demonstrate that multidisciplinary care really does need to be multidisciplinary, and in one specialty, maybe being a little bit more adept in prescribing the treatment and managing the side effects, but relying critically on the other to actually visualize the disease and understand whether or not there's a response or not.

So with that background, I'll talk a little bit about CREST, the first of these studies in BCG‑naive non‑muscle‑invasive bladder cancer, exploring the addition of immune checkpoint blockade to readout. This was presented by Neal Shore at AUA.

And of course, we already know that immune checkpoint blockade might play a role in patients with high‑risk non‑muscle‑invasive bladder cancer. Of course, pembrolizumab is approved in some parts of the world for the treatment of BCG‑unresponsive non‑muscle‑invasive bladder cancer, but this is moving immune checkpoint blockade up earlier.

So the CREST study explored patients with high‑risk BCG‑naive non‑muscle‑invasive bladder cancer, high risk defined, as we generally do in the clinic, T1 disease, a high‑grade Ta disease, and/or carcinoma in situ. And there were three arms to the study. And one note about the PD‑1 inhibitor that was used in this study, sasanlimab, is that it's administered subcutaneously with certainly—with a regimen where patients aren't receiving other intravenous therapies—potentially has some attractiveness.

So patients were randomized—big study, over 1,000 patients. Patients were randomized internationally to receive one of three arms. Sasanlimab, the PD‑1 inhibitor, that's administered, again, subcutaneously monthly for up to two years, plus BCG induction and maintenance. So that's arm A. Arm C is BCG induction and maintenance, standard therapy, up to two years of maintenance. And then arm B was sasanlimab plus induction BCG without the maintenance component. The primary analysis was arm A versus arm C with an event‑free survival primary endpoint. And so let's look at some of the results of this study.

So here are the baseline characteristics, and again, a large study. And really, what I want to call your attention to is the high proportion of patients on the study who had T1 disease. So this is really a high‑risk population of patients with BCG‑naive high‑risk non‑muscle‑invasive bladder cancer. To cut to the chase, here's the primary endpoint, event‑free survival.

So events were defined as you might expect in this patient population—recurrence, progression. And you can see here that there was a statistically significant improvement in event‑free survival with the addition of sasanlimab to BCG induction and maintenance versus BCG induction and maintenance alone.

And you can see the effect size here. So here's drilling down on the events, and there's been a lot of attention paid to this, rightly so, but I think there's a limited number of events and one could potentially read too much into this. But you can see that a lot of the benefit here was in preventing recurrence of high‑grade disease. So numerically, that decreased by about half.

Progression was a much less common event on the study, and numerically, there was some decrease in progression. So very, very small numbers for such a large study, of course, but you could see that progression to node‑positive disease or metastatic disease was numerically less with sasanlimab than with BCG induction‑maintenance alone. And you might expect that given that this is a systemic agent having systemic effects. Progression to muscle‑invasive bladder cancer, interestingly, was similar numerically in both arms.

And then here's where you see a lot of the benefit. And this is the CR duration in patients with carcinoma in situ. And you can see that, similar to what we've seen in virtually every other clinical disease state where immune checkpoint blockade has been added to another treatment, not only is sometimes the quantity of CRs higher, but the quality of CR is different as well.

So a CR achieved with X treatment is not necessarily the same qualitatively as a CR achieved with Y treatment. And here, you see that if you achieve a CR with the addition of immune checkpoint blockade, that CR is much more durable. So at three years, 90% of patients remained in CR, and that was a lower proportion of patients who achieved a CR with BCG induction and maintenance alone.

Of course, in the context of that potential benefit profile, we have to talk about the risks. This is a systemic therapy—even though it's administered subcutaneously, of course, it has systemic effects, and it has the potential to cause systemic side effects. The side effects that were observed on this study are really not different than we see with other immune checkpoint blockade, other PD‑1 blockade used in other clinical disease states of bladder cancer or other solid tumors.

So this new agent administered subcutaneously does not have a different side‑effect profile than PD‑1 inhibitors used in other contexts, but the events that can occur, of course, for a BCG‑naive patient population, despite being high risk, we have to balance that against the potential for these systemic side effects.

And you can see that most of the side effects observed, of course, are driven by the BCG component. So lots of local symptoms that are certainly more attributed to the BCG component versus the immune checkpoint blockade, but if we start to drill down on immune-mediated adverse events, which is really the relevant AE profile here, you can see on this slide that about 15% of patients will have a grade 3 or 4 immune‑related adverse event.

And when these events occur, sometimes they're rapidly reversible with stopping treatment. Oftentimes, they require high‑dose steroids, and sometimes they require lifelong therapy for the side effects that we generally don't see get better, but can be managed over time—things like adrenal insufficiency or hypothyroidism. So not to be taken lightly in terms of the side‑effect profile. Certainly requires a shared medical decision with individual patients.

Sam Chang: Matt, great presentation. As we attempt to try to decide which therapy we should choose for these patients with non‑muscle‑invasive disease, I'll be honest, I think many of the urologic surgeons were surprised with these results. We know there are ongoing trials as well. The question I have, is this going to be—give us the mixed picture like we had with some of the adjuvant trials, and with some of the PD‑1 versus PD‑L1? Tell me your thoughts regarding that.

Matthew Galsky: So great question, and before just this morning, I would have been purely speculating about this, but—because several ongoing studies, as you mentioned. And having more than one randomized study testing the same question, reading out the same, of course, provides us with some comfort that we're really seeing a true signal.

And just this morning, there's a press release about POTOMAC, a very similarly designed study using the PD‑L1 inhibitor, durvalumab. Some nuances to the study: durva was administered for a year in POTOMAC; sasanlimab, in two years in this study. The route of administration, of course, different—durva in POTOMAC was given intravenously; sasanlimab subcutaneously.

All of that aside, we have a press release showing that POTOMAC met its primary endpoint. We haven't seen any of those results yet. We'll have to see if the effect size is similar, and then pooling all the results together, really make a decision as a community, but more importantly for individual patients, whether or not the risk is outweighing the benefit or vice versa.

Sam Chang: No, I think that's a really important point. As we gather data in this space, the BCG‑naive and with the combinations versus BCG alone, I think, as we treat these patients, it will be very, very important to also see the final readouts regarding the trials looking at BCG‑exposed as well, and whether or not we initiate BCG by itself or we do this combination therapy.

As we look at the data, there's no question that BCG is effective, but it seems to be, over time, there is some loss of efficacy, and can you then bump that duration response up just as you said? Initial response is important, but that durability is probably almost just as important, clearly. And the combinations so far in multiple trials seem to show a benefit from this.

Tell me now—do you think, and this is just purely a discussion point—do you think now urologists should really include, for these patients with high‑risk, because this would flood your clinics in terms of the discussions that we should have—this is the ongoing discussion of, should urologists do this, should medical oncologists, should all patients? Tell me how you would actually put these studies into clinical practice.

Matthew Galsky: So I'm not as concerned about who administers the treatment versus having a team set up who's familiar with managing immune‑related adverse events and a system in place for that. So patient education, being able to triage calls appropriately. Despite the education that we do, because patients are overwhelmed with their diagnosis, with their treatment plan, they miss a lot of the details that we try and provide.

So as much as we try and educate patients, the signs and symptoms of immune‑related adverse events are very often missed. They're missed by patients, by families, by health professionals who are triaging calls, by emergency rooms. We see it all the time despite these drugs being around now for a while. And so it really requires a team that's familiar with these drugs, being able to elicit the information because, as people always say, patients don't read the textbooks. And there's nothing that I've seen represent that statement more than trying to discern an immune‑related adverse event because they often present very subtly. So the team's important, doesn't matter the specialty in my mind.

Sam Chang: As you think about these patients, I was struck also by the benefit for the T1 patients. Urologic surgeons, and I think you all have picked up on it as well regarding our concern, really, with T1 patients—under‑staging, the undervaluation, the true metastatic nodal potential with patients with this disease. So you wonder if some of these patients, in fact, perhaps had some systemic disease when you saw this difference.

As you evaluate or start seeing more of these patients earlier in the setting of the disease, tell me your priorities when it comes to a discussion of whether or not you initiate an immunotherapy. Is it a combination of effectiveness? Is it the long‑term need for this care? Tell me the variables you really emphasize as patients are trying to decide whether or not to initiate immunotherapy.

Matthew Galsky: So there's really two things in my mind that are probably most relevant, and of course, trying to tease out the ideal patient based on these considerations and based on the data and the limitations of the data is challenging, but we do that all the time in practice—looking at subgroups and trying to look at some of the nuances of the data.

So who's going to be at risk for needing a cystectomy in the short term? And who is going to actually be at risk for developing metastatic disease? We know that a subset of patients with T1 disease, unfortunately, will develop metastatic disease. And I think trying to identify those patients and being a little bit more aggressive with our upfront therapy in those patients does make sense.

Now one can say, well, that's great, but if you look at the events on CREST, there wasn't a decrease in the risk for muscle‑invasive progression. And I think that's true, but I think we have to think a little bit about how trials are done and how endpoints are read out. And that event is the first event. That event is not the only event that occurs in patients.

So if you prevent a high‑risk recurrence, then that's probably—and we have to show this over time—but that's probably going to prevent a progression event in the future. But this is just the first event that's considered for clinical trial purposes, doesn't tell the whole story.

Sam Chang: Yeah, I think your rationale and your thinking in terms of risk stratification make so much sense to me because clearly, recurrence is important, but that recurrence/high‑risk recurrence/progression really makes the difference. And for these patients, just as you say with T1 disease, higher disease, bulkier, higher volume with risk factors like lymphovascular invasion—all those types of things—clearly those patients really give us concern regarding development of metastatic disease down the line, et cetera.

And so I can see where we, just as you say, we try to subset these patients despite the fact these studies really include a whole group, but we try to focus our care. And I definitely think the higher‑risk patients, we definitely need to discuss with patients—here's a young patient who really wants to spare their bladder—what's the best treatment option? And right now, the data—and we'll see more, I guess, presented looking at the combination of immunotherapy with BCG—seems to be effective and beneficial.

So, Matt, it's always a pleasure picking your brain and having you discuss the different trials that are out there. We look forward to the finalization and accumulation of data with all the trials you're currently leading as well, and thanks for spending some time with us.

Matthew Galsky: Thank you.