Ashish Kamat: Hello, everybody. And welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist in Houston, Texas. And it's a pleasure to welcome to the forum once again, a dear friend, an expert in bladder cancer and someone who's going to talk to us today about a trial that really everybody has been waiting for it to hear about for almost three years now.

Neal, when you presented the CREST results earlier this year, and, of course, you're going to present to us today, it really opened up a treasure trove of data, a lot of important stuff. And clearly, I think in many ways, this is probably the most important trial in the non-BCG unresponsive space right, bladder cancer space with high-risk disease. So please enlighten us. Take it away. Stage is yours.

Neal Shore: Well, thanks very much, Ashish. Yeah, I just thought I'd maybe quickly go through the AUA plenary presentation that we were honored to be able to give. And then I got a few of the slides from ASCO that Tom Powles just gave for the audience. And yeah, as you state, it's really a great pleasure on behalf of all the co-investigators globally.

Standard of care unfortunately high-risk NMIBC, the Ta, G3, CIS, T1, and 40% of patients, in some series, will demonstrate recurrence or progression at two years, and some early preclinical data showing that combining a PD inhibitor with BCG, you upregulate patients with BCG, you upregulate PD expression.

And then in CREST, and there are several other important phase III trials that are going to read out the POTOMAC, the KEYNOTE-676— two very important studies, I think we'll see results on that potentially this year.

Different IOs, different checkpoints, and some different endpoints and different utilizations and the duration of therapies, but importantly in the same population, this high-risk NMIBC population. What's really kind of interesting about this sasanlimab is it's a subcutaneously administered PD blocker.

Here's the CREST trial, three-arm trial, a 1-to-1-to-1 randomization. And as you said, Ashish, these are BCG high-risk NMIBC patients. You see the stratification, CIS, geographic region, Arm A, I call that the combination arm. Sasanlimab once a month for two years in with BCG induction and maintenance, maintenance being at two years.

Arm B was just was just induction BCG, sasanlimab for two years, given subcu every four weeks. And then Arm C, the gold standard, historically based upon SWOG data induction and two years maintenance, although that first SWOG trial, actually the landmark Don Lamm did three years. And then the primary endpoint was event free survival of Arm A versus Arm C. And the definitions are our audience can see here of what EFS is.

It's important, I think, to just note here that these were, in both arms, nicely balanced. Pay attention, I think, to the audience right now the disease stage-- 55%, T1 disease; pure CIS, about 15%; CIS with a Ta or T1 about 25%; and just pure Ta about 25%.

And here's the takehome KM curve-- a hazard ratio of 0.68, your p-value one-sided 0.0095, demonstrating the combinations sasanlimab plus induction maintenance bested induction maintenance BCG. And of course, these were open-label studies. These were not blinded. But nonetheless, one can see the curve separation at about 18 months and widens at the landmark analyses at two and three years.

The key thing here is looking at the recurrence of high-grade disease. It's essentially halved. If you look at the 26, 7.4% versus the 53, 15.1%, so a reduction in recurrence of high-grade disease by a little over 50%.

And then I think this is a really important slide to look at, the forest plots here. Yeah, you can look through age, gender, race. We had a very large Asian population in this study. But probably most importantly is looking at the presence of CIS or T1 disease, forest plot clearly demonstrating the value of the combination versus monotherapy. Some suggestion that the non-TICE population did better than the TICE. But certainly, both populations benefited.

Arm B versus Arm C, remember, that was what I call the Hail Mary pass, to use a football analogy. Really, we didn't see a difference in terms of the EFS. It's interesting how to interpret that. And there are a couple of ways to think about it.

Number one, most importantly is maintenance BCG really matters. And I've heard other people kind think about it and say, well, even though it's noninferior or somewhat equivalent, maybe that's something to think about in the era of the BCG shortage.

And then we looked at overall survival as a key secondary endpoint. They're overlapping, the curves here. I think it's way too early to tell. There really weren't that many death events, but these patients will be followed for further follow-up on the overall survival.

A very important analysis was in the subgroup of patients with CIS who had a complete response. And if you look at that, these are the patients who had a complete response, and we monitored them for how durable was that complete response.

And at 36 months, or three years, have a little over 90% durability in the combination and a little less than 70% durability in the BCG induction maintenance. And it's an interesting phenomenon because those patients don't necessarily have more PD expression. But the data, I think, was very compelling.

From a toxicity standpoint, really nothing new here. And for oncologists, this is old hat, these types of things. Here, you're seeing a little bit more of the lower urinary tract, which is really pretty balanced. But what you do see differently is the expected immune-related adverse events that we've come to know regarding the various PD blockers, almost 18% treatment-related adverse event in the combination to 1.4% in just the BCG induction maintenance.

The majority of these did not really-- we saw a little bit more clearly of rash and thyroiditis types of things. These other things that oftentimes are very significant and need to be monitored, but low single digit percentages. Things like transaminitis and hyperglycemia, pancreatitis are usually resolved with cessation and/or steroids.

There are some concerning adverse events within the class, but you can see they're low single digit percentage, reassuring for the oncology community, are certainly something that you do need to discuss with patients.

Now, recently, Tom Powles presented this at ASCO. He showed the EFS looking at a little bit more detail on the breakdown of CIS with or without Ta/T1, T1 with or without CIS and high-grade Ta.

And you can see the hazard ratios are really pretty impressive for the CIS, 0.53 and the 0.63 on the T1, not as compelling at all with a hazard ratio that overlaps confidence intervals, crossing one of 0.88 for the Ta population. And then again, of course, Arm B versus Arm C-- again, not particularly compelling which was similar to what we saw earlier when we presented at AUA.

So ultimately, the conclusions, Ashish, I said there are two other very significant phase IIIs. This is the first one to report. We published in Nature Medicine just a few weeks ago. Induction and maintenance in combination with sasanlimab given subcutaneously monthly bested from an EFS primary endpoint traditional induction maintenance BCG.

A hazard ratio of 0.68 particular benefit, in the subgroups of the CIS and the T1 patients. So we were very happy to see this. This took a long time to do this study, as the other phase IIIs, a lot of it conducted during the pandemic.

What's unique about this particular therapy is it's given subcutaneously-- and I think not just for urologists but even medical oncologists, who may have some issues regarding throughput, because you can give a subcu. It's a 0.5 cc subcu. So it's not a high volume. And we had no injection site reactions there, I think, might have been reported, something like about 0.5%. So there's a throughput there that could be advantageous.

The second bullet at the very bottom, I think, is uber important, which is, this isn't going to be for everybody. I think this really speaks to the absolute importance of the multidisciplinary team, uro-oncology, medical-oncology, in particular if you're not used to working with checkpoint inhibitors, PD blockers. And then, of course, having a full-throated discussion with patients and their families and caregivers as to their level of risk aversion and risk tolerance.

Ashish Kamat: Thanks so much, Neal, for going through all that data in a very succinct manner, as you always tend to do. I really think, like I said at the very start, like this was a trial, and the results that were long awaited. And to see a significant trial like this, hats off to all the investigators, especially you, for leading it to all the patients, the company, everybody involved.

Might I ask you to drill down a little bit on a few things that come up when we look at this? Because you've always championed using drugs the proper way. And when it comes to BCG, BCG three-year maintenance is something that we've all accepted as a standard.

And if you look at the curves, they separate at 24 months, which is when the BCG maintenance stops. Could you enlighten us as to why it was decided to use only two years of maintenance? And how does that play into your read of that separation of the curves that happens when you stop the BCG maintenance?

Neal Shore: Well, it's a really great question. As you know, in that SWOG trial led by Don Lamb, only about 17% of the patients actually got the full three years. There's a certain level of fatigue. When he did that study, I think that was probably-- it might have been some bother, not only of just showing up to get it, even though it was on a Q6 month basis, after year one.

But then there are some lower urinary tract symptoms and the regulation, the every-- the three week Q6 month, urethral intravesical instillation. So I think there's some just overall fatigue with that.

Another thing, you add on top of it some of the challenges in different parts of the world, certainly in the US, BCG shortages. So I think there's a combination of those factors. I think the other trials, nobody went beyond two years in their maintenance regimens. So there seem to be some consensus upon that.

Ashish Kamat: Yeah, I think the issue, obviously, as you mentioned, was patients get tired. They do develop lower tract symptoms. And anything we can do to shorten the amount of intravesical therapy they get would be ideal, which is why everybody was looking at that Arm B, hoping that you'd hit a home run there. So be it. You couldn't best BCG with just induction alone. But we in some ways expected it. But again, kudos to everybody for trying that out.

With the T1s and the CIS and the young patients where you saw the benefit, those are our patients we want to really in some ways throw the kitchen sink at because we want them to not only save their bladders but also live. Is that the population that you think you are going to recommend this combination up front? How are you going to decide which patients you offer this to and which you might say, hey, for you, let me try BCG alone and maybe add something later?

Neal Shore: Yeah, that's a really, really important question. Really, at the end of the day, how do we make these decisions? Not everybody is fortunate to get their radical cystectomy by Ashish Kamat at MD Anderson. You have phenomenal results. And we have many other colleagues.

And look, we even have some high-volume community centers which get some pretty good results, too. But at the end of the day, getting your bladder removed is a very big deal. Some wonderful data presented by John Gore, the CISTO, is showing that patients actually did better than we thought compared to not getting their bladders removed.

But still, at the end of the day, it's very significant. I think you're right. I think there's a population of patients who are absolutely opposed to having bladder removal and want to be as aggressive as possible, to your point, the kitchen sink approach. But it's a kitchen sink that now has level 1 evidence and the synergy of different mechanisms of action.

But there's also, even for someone who might not be the young fit patient but who's got aggressive disease-- let's face it. CIS and T1, this is aggressive disease-- and then maybe they are, older and maybe have some other comorbidities but are willing to accept the immune-related adverse event profile and say, hey, I don't want to lose my bladder, and maybe I have other comorbidities, but I have good voiding function, and I don't feel up to having a cystectomy for various reasons.

So I think it's going to be kind of across the board. But I do think that if there's someone who is contraindicated, they have other autoimmune phenomenon-- or not phenomenon but comorbidity, or they're really particularly concerned about the risk of an irAE, particularly if they already have some concerns regarding their thyroid function or their even liver or pancreatic function, this is something that you just want to have that good full-throated discussion.

I think studies like this are really cool because it forces all of us to have to enhance our conversation with patients and really be more concise and terse but yet informative. And it's not just us, obviously, it's our nursing team. There are trusted, authentic sources in the internet we can refer patients, too.

I know Anderson has a great website. I use the PCF website for my prostate patients. I use the BCAN website for my bladder cancer patients. So I think it just makes us all a little bit more sensitive to the fact that we've got to have an opportunity to have this shared decision-making.

Ashish Kamat: Yeah, I couldn't say it better. I think I'm going to use that as a closing statement because, again, you've always been a champion of putting patients right at the center of everything we do. And this trial and these sorts of data really highlight the fact that we have to have patients involved in that decision-making when it comes to choosing the treatments.

And it's great now that we actually have a combination that we can offer to patients because for many years, BCG was the king. Even now, it deserves to be at the top. But there is a combination that can improve on the results of BCG. So again, congratulations to you to everybody and thank you so much for taking the time.

Neal Shore: Thanks, Ashish. My pleasure.