Vikram Narayan: Yeah, thanks so much, Ashish. It's really great to be with you and the UroToday team here. And obviously, I'm indebted to your mentorship and that of everyone at MD Anderson. So I am presenting the top line results from the BOND-003 Cohort P. For those who may not be familiar, this is a multinational single-arm study for Cretostimogene grenadenorepvec, which is one of the gene therapy agents that is under investigation for high-risk BCG-unresponsive disease. And in this particular presentation, I'm going to focus on Cohort P, which focused on the papillary-only, so non-CIS patients. So for those who may not be aware, this slide is probably familiar for those of us who have been in this space for some time. But the way Cretostimogene works is it's an agent that's an oncolytic adenovirus that selectively replicates in tumor cells that have alterations in the Rb-E2F pathway. And essentially it has kind of a dual mechanism where it causes tumor cell lysis, and then subsequent to the lysis, results in essentially the result of essentially GM-CSF as well as tumor-derived antigens that can stimulate the immune system in patients to help kind of fight these urothelial cancers that are ongoing. And there have been a number of studies that have shown very promising results with Cretostimogene.
One thing that I want to highlight that Cohort P was attempting to address is the fact that we do have a significant unmet need for these folks who have papillary-only non-muscle-invasive bladder cancer. And Ashish, as you know, a lot of our patients and the focus of the FDA and kind of the regulatory pathways have been on CIS, rightfully so, because it is typically the more aggressive entity among other reasons. But we do have a lot of patients who come in with papillary-only disease, no CIS. And while the NCCN and other guidelines have category two agents that are available, because for example, the ones listed on this slide, we have papillary-only cohorts in all of these trials that have led to FDA approval. The question remains, what can we do to improve upon this? And one thing I'll just highlight here with the caveat that you can't compare these trials head-to-head, they all have slightly different nuances. But if you look at the papillary-only cohorts, in general, you kind of see numbers land at around 73% high-grade recurrence-free survival at three months, and then somewhere around 48% around 12 months. And again, this is from a recent meta-analysis of all of these trials.
I want you to remember these numbers as I start to present the Cohort P data. This slide here just basically highlights data that's previously been presented about Cretostimogene in general. We see a lot of anytime CRs, I just want to focus on the landmarked call-outs just because when I'm counseling a patient, usually I'm telling patients, what is the likelihood of you to have a CR at a 12- or 24-month period? It just helps me understand that data better. But you can see it's quite good, 46.4% at 12 months, and then 41.8% at 24 months, and really well tolerated from an adverse event profile as well, which we'll talk about in a minute. This is the study schema, should look familiar to most people. Cohort P looked specifically at folks who had pathologically confirmed papillary-only disease without CIS. It had to be completely resected prior to treatment. So this was not a marker lesion study. And unlike with CIS where you sort of think of the TUR is part of the treatment, the subsequent treatment you get kind of is intended to augment that. In this case, you can think of it more of as adjuvant therapy, right? So you've resected it and then you're giving something intravesically. So the primary endpoint was high-grade event-free survival. An event was defined as any high-grade recurrence, progression, death, or censoring.
And there's some secondary endpoints as well. Here's kind of the baseline demographics of the cohort, kind of what you'd expect and what we've seen with a lot of other trials in this space, right? We had 56 patients. The majority were men, the majority were white, and they're older, kind of our typical bladder cancer population. One call-out is that in this group, 41% of the patients were high-grade T1 at baseline. And as you know, Ashish, these are the patients we'd be most cautious about. So it is worth highlighting that. And the median number of prior BCG instillations was nine, so a very pretreated population. This is kind of the most important money slide right here. First thing to highlight is that the median follow-up is very short. It's only six months, and eight of the patients did get reinduction at the three-month time point. If you look at the overall cohort though, and again, I'll call you back to that previous sort of meta-analysis where we had some sort of where we stand today baseline numbers. What you're seeing here, at least in early data, is really, really good three-month and nine-month event-free survival. So 95.7% at three months, 80.4% at nine months.
You can kind of see the breakdown here if you look at high-grade TA versus high-grade T1. There were no patients who progressed to muscle-invasive bladder cancer. However, there was one patient who was found to have on re-staging metastatic urothelial cancer despite the patient having a clinical complete response. So their cysto and cytology were negative, and that was a patient who had high-grade T1 disease. And kind of highlighting some of the caution that is important when we're thinking about when we take patients to cystectomy, that's obviously a very subjective decision and one that's a conversation that occurs between the physician and the patient and their values and preferences. From an adverse events perspective, most of the AEs were grade one to two. Importantly, there were no treatment-related discontinuations. That's something to call out. I think we're all familiar with folks not being able to complete things like BCG or other treatments. And so 98.2% of patients received all protocol defined treatments, which is really good. So this is data that is really promising. I think again, the caveat is it's early days, but as we see more agents being approved for CIS, it is nice to continue to see some data emerging for the papillary-only patients that we also take care of and have another tool in our armamentarium as the cliche goes. So with that, Ashish, happy to take some questions.
Ashish Kamat: Great. Thank you so much, Vikram, for that presentation. Again, when we proposed to the FDA many years ago to look at us and allow us as a community, when I say us, do single-arm studies we focused on CIS, I should mention, because that's when you clearly have disease left behind and you can see the effect of the drug. So kudos to all the companies and everybody for doing the studies, getting the drugs approved. But like you mentioned, a common problem that we and our patients face is that, okay, these drugs are approved in the CIS because that's what the single-arm studies were meant to do.
Vikram Narayan: Right.
Ashish Kamat: But they're not approved in the papillary cohort.
Vikram Narayan: Right.
Ashish Kamat: So it's great to see data such as these in the papillary cohorts of these studies. But as you know, having done this and being a bladder cancer expert, a lot of it is based on the quality of the resection. Right?
Vikram Narayan: Right.
Ashish Kamat: And the quality of the resection can vary from person to person. You can have someone that does a great resection and has no tumor at a year in a patient, and a poor resection leads to a tumor in that patient.
Vikram Narayan: Yeah.
Ashish Kamat: So when you're looking at all these data here tell me a little bit about your personal view on putting a lot of credence on single-arm studies for papillary cohorts. I think it's great-
Vikram Narayan: Yeah.
Ashish Kamat: ... and our patients need to hear this data, but what's your personal view there?
Vikram Narayan: Yeah, no, I think you're exactly right, Ashish. I think that doing a really solid TUR as you and others kind of help teach me to do, and which I teach my trainees now to do, is at the end of the day, the kind of the bottom line mainstay sort of gold standard thing you have to do to give these patients good outcomes. We talk about all the time, when I see a patient in clinic and they come to me referred for "BCG-unresponsive papillary disease", the first thing I do, and I know you do the same thing, is take them back to the operating room, even if they've had a recent resection. And the reason is because you want to be able to make sure that they truly have had a full resection. I'll do blue light if I have that available at my center, which we do, we'll do a thorough inspection of the entire bladder. If necessary, we'll do mapping as well if that hasn't been done previously, essentially to ensure that these patients have had a really clean, proper, high quality TUR. I think that's number one, the most important thing.
The second piece is, as you know, not every papillary patient is the same. And this is where I think we have some work to do, which is there are some patients who biologically behave differently despite having the same histologic diagnosis. And so that's where I also get a little, I'm not going to say confused, but I think the data is a little bit incomplete in that, for example, that patient we highlighted who had metastatic disease, there is this issue of an unknown factor that you have to think about when you're deciding whether a patient should, for example, go for upfront cystectomy or whether you give some sort of adjuvant therapy. And that unknown factor involves things like where are the tumors located? How many of them are there? Is it multifocal or singular? Is it large volume or small? I know the IBCG has guidelines that help adjudicate this. I know there were recently in the NCCN. Those are kind of tools you can use to help risk stratify these patients, kind of help us get closer to really knowing is this "papillary disease-only patient" the same as the next one? So those are kind of the factors that I look at.
I think these things are nice to have because patients demand, they usually come to you and they say, "Well, what can I do to prevent progression, prevent recurrence?" And so it is nice to have some tools available to offer those patients. But at the end of the day, we have to do our jobs as urologists, high quality TURs, high quality staging, re-resection if needed, and then really kind of using our risk stratification to counsel them appropriately so that you don't have kind of this progression of metastatic disease or other kind of adverse outcomes that you don't want your patients to have.
Ashish Kamat: I got to say, Vikram, that was very well said, and you packed a lot of data in there that I think anyone listening should really take to heart when they're taking care of their patients with this sort of presentation. Really well said, I couldn't agree more. Diving a little bit into the actual data that you presented-
Vikram Narayan: Okay.
Ashish Kamat: ... right, I mean, clearly we say we can't do cross-trial comparisons, but I mean, we do them anyways.
Vikram Narayan: Yeah.
Ashish Kamat: And I think that's something important to recognize when people are looking at that data, that yes, this data definitely looks good, looks promising. But let me ask you, because you've obviously done a lot of work with nadofaragene, and of course you know the field well. Share with us a little bit about your thoughts on looking at different trials and then giving those numerical comparisons when the trial designs were a little bit different, right?
Vikram Narayan: Yeah.
Ashish Kamat: Some had reinduction. I know the answer, but when I ask you-
Vikram Narayan: Yeah.
Ashish Kamat: ... so what do you think about the reinduction factor and how that plays into the actual landmark analysis?
Vikram Narayan: Yeah, it's a great point. I mean, so the factors that you got to look at when you're analyzing these trials, which for the audience, you want to make sure, first of all, is the cohort the same? So we've obviously got the BCG unresponsive definition. We know that requires adequate BCG. We know kind of when the recurrences have to occur for the U to match that definition. That's just one part of it. But the other part of it is how is the dosing taking place and are patients allowed to get reinduction? Now, the reason you're asking this question is because as you and I both know for nadofaragene, that was one of the earlier trials and it was in an era that was different from today where we were a little bit more worried about are we doing the right thing by avoiding cystectomy for these patients? And so if a patient failed, meaning they had high-grade recurrence, those patients were not allowed to have reinduction.
Now, in contrast, other trials that kind of came after that, including Cretostimogene, the one that I'm presenting now, and several of the others that are kind of ongoing, they do allow that reinduction. Nogapendekin allowed reinduction. And a substantial number of patients do get reinduced. And biologically, we understand why this is attractive. We do the same thing for BCG. And we also, of course, have data from our early trials that show that actually it is okay to give these patients a little bit of a runway before you take their bladders out, assuming they're being carefully watched and they're closely monitored. So that's one thing. The other thing to look at is as far as when the landmark assessments are performed, was a mandatory biopsy performed in those patients and at what time those biopsies were performed. So there's a little bit of variability here. Some of the studies do them at six months, some of them do it at 12 months.
That is really important because in all of the cases where, at least as far as I'm aware, of where these mandatory biopsies are done, you usually find some occult disease that a clinical assessment alone would've missed. And I know we had a number of those in the original nadofaragene study where essentially the investigating urologist saw essentially a clean cysto, negative cytology, but on mapping biopsy found actually occult disease. And this actually has the impact, of course, of reducing the total "CR" that you have or high-grade recurrence-free event. And that's really important to know because when you're doing these head-to-head comparisons, if you've got one trial, for instance, that doesn't do that mandatory biopsy and you have another that does, you're going to have artificially inflated kind of numbers. And then the other piece of this is when you have reinduction, you've got to kind of think about, okay, well, if you gave patients reinduction, how many of those patients may have essentially kind of only gotten that benefit after that second one? When do you actually think about where is your time of recurrence begin?
And I know our pharmaceutical partners, obviously they're investing a lot of money in helping kind of develop these treatments for our patients, but we have to be kind of objective about how we think about the numbers that are reported. I made an intentional point not to bring up anytime CRs because I do think that that gets a little bit difficult to tease out from trial to trial. The landmark numbers I think are a little bit easier to do head-to-head comparisons. But to your point, you have to be aware of these nuances in order to make informed decisions and counsel your patients.
Ashish Kamat: Yeah, Vikram, again, a very, very nice comprehensive response to the question, which is great. You covered all these points. But with all that being said, I think the numbers that you presented are really encouraging, really promising. I think it's really great to have data such as these because again, I don't have a crystal ball, but I assume that this will get approved-
Vikram Narayan: Yeah.
Ashish Kamat: ... and when it's approved, we would like to have supporting data in papillary cohorts that allows us to offer this to our patients.
Vikram Narayan: Hope so.
Ashish Kamat: So Vikram, thank you again for taking the time. Always a pleasure. Congratulations.
Vikram Narayan: Thanks so much, Ashish. Appreciate it.