Gary Steinberg: Okay. Thank you very much for inviting me. Again, I think that this is a real potential paradigm shift in the way we treat non-muscle-invasive bladder cancer. I was very happy to be part of the trials with Merck looking at single-agent pembrolizumab, a checkpoint inhibitor for BCG-unresponsive carcinoma in situ non-muscle-invasive bladder cancer. One of the things that we understood is that while the results were good, they weren't clearly good enough, and that as we see in all of oncology, when we're working with checkpoint inhibitors, that the initial results are good, but we clearly need to do better. So, that's led us to combinations. So, as we see in oncology today, we've got multiple combinations with additional immunotherapies and/or chemotherapies.
So this is a trial that was done. We started this trial. Actually, we started planning this trial in 2019, and this is looking at patients receiving the combination of BCG, which is our gold standard, plus sasanlimab, which is a subQ instilled checkpoint inhibitor. It is a PD-1 inhibitor similar to class with pembrolizumab and nivolumab. So this is a study looking at patients with BCG-naive, high-risk non-muscle-invasive bladder cancer. It was a multi-institutional, multi-country trial. We've presented the initial data at the ASCO meeting in 2025, and now we are looking at some subgroup analyses. So this is a group of patients looking at what we're calling a very high-risk non-muscle-invasive bladder cancer. Again, BCG-naive. Again, the way we define this is we use some EAU guidelines to determine what we're talking about with the very high risk. Just to reiterate or go over the CREST trial design, it was a patient population of BCG-naive, high-risk non-muscle-invasive bladder cancer. Of note, the patients had not received any previous checkpoint inhibitors or immunostimulatory agents.
They were randomized into three arms. We're going to really focus on arm A and arm C. Arm B was giving patients BCG induction with sasanlimab induction, but only using sasanlimab alone during the maintenance regimen. The arm A was giving sasanlimab plus BCG induction and maintenance. And then our control arm was BCG induction and maintenance. These patients received up to two years of therapy. We looked at primary endpoints, especially looking at event-free survival in group A through C. The reason why we're not going to present the data on arm B was that arm B essentially performed it no differently than arm C, which was the induction and maintenance of BCG arm. Parenthetically, that may lead to helping us with BCG shortages and that giving the sasanlimab as maintenance instead of BCG maintenance will have the same results as the BCG induction and maintenance, but certainly no better. So we were clearly looking to improve on our efficacy. Just looking at the baseline demographics, these two groups were matched, the group A and group C, approximately 350 patients in each arm. They were pretty comparable in terms of age and race, ECOG performance status, smoking history, and stage and grade.
More importantly, we had approximately 27% with TA in the study arm, 30% in the maintenance and in the control arm, the BCG induction plus maintenance, T1 58 versus 55, pure CIS about 14.8 versus 14.2, and the combination of CIS plus or minus TA, T1, about 25% in each arm. So, overall, looking at the overall population and the intent to treat following these patients, we needed to follow these patients out for quite some time to really see some separation of the curves. I think the important thing is, and which is really, really important for all of us moving forward is looking to see the arm, see how well BCG alone did. So BCG induction and maintenance in high-risk non-muscle-invasive bladder cancer did quite well at 12 months, 85.3% event-free survival, 79.9% or 80% at 24 months, and even 75% at three years. I think that when we're quoting statistics on recurrence and/or progression for patients with high-risk non-muscle-invasive bladder cancer using BCG, we're looking at older data. I think that with more modern data, more modern technique, more rigorous induction and maintenance therapy, potentially even using enhanced cystoscopy for our TURBTs and repeat TURBTs, we're doing a lot better than we thought we were doing in the past.
But most importantly, when we look at this event-free survival, there is a hazard ratio of 0.68 at 36-month, median follow-up 36.3 months of 82.1% with the BCG induction and maintenance and sasanlimab versus 75% roughly in the BCG induction and maintenance alone, and that was a P-value of 0.0095. Then when we tried to look at these subgroups, and again, when we look at subgroups, you have to do that with a bit of a caveat, a little bit of grain of salt, and that to really truly be robust data, you have to do the study with the subgroup alone and not as a subgroup. So you have to be very careful when you're looking at subgroup analysis. But when we look at the hazard ratios of this subgroup analysis, we see that patients with pure CIS had a hazard ratio of 0.52 or 48% reduction in events. When we look at CIS with or without TA or T1 0.53, without TA, T1, 0.52, T1 with or without CIS 0.63, T1 without CIS 0.7, high-grade TA with or without CIS 0.88, and high-grade TA without CIS 0.86. I think that what I was most interested before we got the results of this data was to look at that CIS population.
As you know, all of the papillary disease was completely resected. So we're really looking at that CIS population as a treatment, although this is a randomized trial, but I think that that is probably the most robust information we could hang our head on. Again, subgroup analysis, it's not the whole study. Then when we look at this very high-risk disease subgroup, and so we defined this very high-risk disease subgroup as CIS with or without TA, T1, but if you had TA high grade plus CIS, it had to have at least three risk factors age greater than 70, multifocal disease, larger than three centimeters in diameter, T1 without CIS also had to have three risk factors greater than age 70, multifocal disease greater than three centimeters, or the CIS plus or minus T1 or TA that just had to have one risk factor, which was either greater than 70 multifocal or greater than three centimeters. That's CIS plus T1. When we look at this very high-risk disease subgroup, we see a hazard ratio or we see percent of a hazard ratio of 0.34. We see 84.3% in the sasanlimab plus BCG induction and maintenance versus 61.5% in the BCG induction and maintenance alone at three years. Clearly, we're starting to see more separation.
This is important because I think that the urologic community is going to want to understand who are the patients who we are going to recommend this therapy to upfront. Then I think that one of the other critical issues that we have or something that is kind of hypothesis driving is that by using BCG in a checkpoint inhibitor upfront, sasanlimab, are we able to prevent the development of BCG-unresponsive disease? Again, once we start having BCG-unresponsive disease, the standard of care is radical cystectomy or alternative therapy. We do have some FDA approved therapies, but clearly we would like to prevent patients from developing BCG-unresponsive disease. We see that not only do we get a fewer events with the BCG sasanlimab group, but that we have a durable complete response rate, and that is from 91.7 or 92% to 68%. So not only are we fewer events, but the events or the success is a durable response, which is something that is one of our secondary endpoints. I mean, the event-free survival is clearly an event point, but duration of response is critically important for the patient and for the treating physician. Now, however, there's no free lunch, and I think that that's what we really need to hone in on, which is why we're doing this subgroup analysis is because there's no free lunch, and that when we look at sasanlimab versus BCG, we clearly see all of the immune-related adverse events.
Now, again, sasanlimab should be easier to give. It's a subQ inoculation. You don't need an IV infusion center. You don't necessarily need to send the patient to the medical oncologist if you are prepared to deal with the immune-related adverse events. So even though it's a subQ inoculation, it is a systemic checkpoint inhibitor, and we see all of the systemic checkpoint inhibitor grade three and four immune-related adverse events that we see as a class with checkpoint inhibitors. So that again, the objective is to try to identify those patients who upfront may be best candidates to receive a checkpoint inhibitor with their BCG in the high-risk non-muscle-invasive bladder cancer population. In conclusion from this trial, and again, this was over a thousand patients, 1,055 patients in an international trial, the CREST trial was the first study to show a statistically significant prolongation of event-free survival compared to BCG induction and maintenance alone. Prolonged event-free survival with the sasanlimab was observed across disease stage subgroups with potential enrichment in certain subgroups. In patients with very high-risk non-muscle-invasive bladder cancer for whom radical cystectomy may be the standard of care, sasanlimab plus BCG showed prolonged event-free survival. However, this is an exploratory analysis limited by small sample sizes.
The safety profile is essentially the same as each individual agent so that we don't see any edited immune-related adverse events from BCG and sasanlimab, but we certainly see the grade three and four immune-related adverse events from sasanlimab that we see in any checkpoint inhibitor. So, this certainly may have the opportunity to change our treatment paradigm and our pathway for patients with very high-risk BCG-naive, high-risk non-muscle-invasive bladder cancer. Having said that, we certainly need to potentially do these subgroup analysis as their own standalone trial with large numbers to define that. Then more importantly, we do have some additional data that has come out recently from the POTOMAC trial, which was using BCG plus durvalumab and the BCG-naive, high-risk non-muscle-invasive bladder cancer.
We have data from ALBAN, which is looking at BCG plus atezolizumab versus a BCG alone. Hopefully soon we'll also see data from KEYNOTE-676 in the BCG-naive, looking at BCG and pembrolizumab versus BCG alone in the high-risk BCG-naive population. Certainly, also in KEYNOTE-676, we're hoping to see the data in the BCG-exposed population that had additional BCG versus BCG plus pembrolizumab. I think the one take-home from looking at the three trials, the CREST trial, the POTOMAC trial, and the ALBAN trial is that there was not a consistent message and efficacy in all three trials. While the overall hazard ratio in the CREST trial and POTOMAC trial were similar at 0.68, in the subgroup analysis of the carcinoma in situ population in the POTOMAC trial, the hazard ratio was one. I think it was 1.01. I think in the T1 high grade in the POTOMAC trial, it was about 0.62, I believe, somewhere between 0.62 and 0.68.
So again, not seeing consistencies across the board. More importantly, in the ALBAN trial with BCG and atezolizumab, it was a negative trial, and there was no difference in the BCG and atezolizumab versus BCG alone in the high-risk BCG-naive population. Again, I think that the answer is a little unclear. Potentially, the pembrolizumab data may help lean us one way or the other. But nonetheless, I think that if in this data, and again, randomized trial, 1,055 patients, clearly there is an event-free survival benefit in the combination of sasanlimab plus BCG, albeit with immune-related adverse events where the oncologic community and the urologic community and the patient community is going to need to come to some consensus as to which patients may benefit most from this therapy upfront.
Ashish Kamat: Thanks so much, Gary. That was a tour of force. I mean, you covered so much information in a short time, including some of the questions I was going to ask you. So, let me just summarize briefly, and then I'd love to hear your take on this. First of all, kudos to all the investigators for the CREST trial, and of course, the other trials that you mentioned. Doing a trial like this was really needed, and it was really encouraging. Yes, we had one negative study, we can talk about why on a separate topic, but it was great to see two studies showing that we can improve upon BCG and also recognizing that BCG today really works well, but we clearly need to improve upon it, right?
Then doing these subsequent analyses, as you mentioned, is fraught with caveats, but recognizing that when we see patients in the clinic, we're going to want to have this discussion with them saying, "Hey, for you, I think the risk is justified because the benefits are huge." And that's where these subgroup analyses come in. So, in a nutshell for people listening, which are the patients based on this presentation and based on all you know about the trials, which are the patients that you today would say, "Hey, for you, I think you should consider getting this in addition to BCG?"
Gary Steinberg: Yes, that's an excellent question. I really do believe that for me, the most powerful data from this database is the carcinoma in situ population. There's no question, if you've got a younger patient, and younger let's say mid 60s or 66, let's say 50s, mid 60s and so forth, otherwise a robust patient, a multifocal disease, high-volume carcinoma in situ, high-volume TA, high grade or T1 high grade, these are the patients that I think that it's potentially beneficial to see if we can upfront eliminate their recurrence rate. Patients hate recurrences. Yes, we're also concerned about progression and we don't have enough progression data on these patients. It's really we're looking at recurrence data, but patients hate recurrence, physicians hate recurrence, everyone hates recurrences, and so that if we can upfront identify those patients most at high risk for recurrence, then I think it's worthwhile.
So, I think that the T1 high grade plus CIS in my mind is a good group. TA high grade, I would be very reluctant, I think, to give them the potential immune-related adverse events from checkpoint upfront with the caveat that we don't have enough data from this trial to say that we can't give everybody BCG, and if they do recur, they become BCG exposed that we can't add the checkpoint at that point. That's actually the most important study that we need to complete. That's the KEYNOTE-676 trial with pembrolizumab and BCG, and I think that that would be an important study to look at with sasanlimab as well. I personally think that the urology community is going to be very enamored with the possibility of being able to give the checkpoint inhibitors themselves and not have to include the medical oncologist because that can be logistically difficult in many practice settings. Having said that, they need to understand very, very clearly that they're going to need to monitor for those immune-related adverse events.
Ashish Kamat: Yeah. No, great points again, Gary. I mean, everyone's going to be wanting to jump on the bandwagon, but recognizing that if you take a 50-year-old and give him or her lifelong thyroid replacement, that's not benign as well, right? So recognizing the right patient using maybe pathology-based markers, AI. Who knows? There's so much work that can be done, but like you said, people have to be cognizant of the potential toxicity and be very selective. Gary, as always, a pleasure. Thank you so much for taking the time. Really enjoyed this.
Gary Steinberg: Thank you.