Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center in Houston, Texas. And it's a great pleasure to welcome today, Professor Sam Chang. Of course, Sam needs no introduction to the UroToday world or to the urology oncology world. He is a renowned expert in bladder cancer and a dear friend and is going to chat with us today about the results of the QUILT study, which he presented recently at GU ASCO and which has raised a lot of discussion and a lot of anticipation amongst the world of people taking care of bladder cancer. Sam, looking forward to discussing and I'll hand the stage over to you.

Sam Chang: Ashish, thanks so much for those kind words. I think when we talk about experts and leaders in the field, there are those that are truly representative of an international presence and respect and you're at the top of the list. And so I just wanted to make sure everybody understands kind of your international presence and really appreciate all your efforts. As I know, all our patients do, with urothelial carcinoma.

I was fortunate to be actually just an investigator on this trial. And so I'm actually, I presented this on behalf of the other investigator looking at IL-15 superagonist N-803 is how I know it. And basically what we're looking at here is looking at a, I'd say a unique agent, first in class that utilizes a combination of mechanisms of actions. first, actually a mutation that enhances the IL-15 subcomponent that actually makes it a more strongly binding agent to the IL-2 receptor. In addition, by actually adjusting the IL-15Ralpha subcomponent, there's better and more unique trans presentation to a certain one of the IL-2 receptors that actually help promote the growth of our simulation of the natural killer cells, as well as CD8 T cells, without actually decreasing its activity by binding the regulatory cells. And finally, the IgG1 Fc component actually increases the half-life. Cytokines tend to have actually very short half-lives. By adjusting this subcomponent, that half-life is actually increased and as a result, a longer time being able to do what we hope it's doing.

Which is what we think maybe this combination of basically priming the microenvironment of the bladder with BCG. Dr. Kamat and all of you I'm sure are familiar with a little bit regarding how BCG works but there's a thought that at least the innate immune memory makes a difference with BCG. And with this in mind, there's a combination of actions that may be occurring. One would be actually looking at giving BCG by actually increasing the innate response of what's actually there. You have monocytes, you have macrophages that actually get exposed, and by once getting exposed, they're better able to, if another antigen comes, be able to be more effective in eliciting an immune response. What we think N-803 does is actually boost this. N-803 we know, actually enhances actually natural killer cell recruitment, as well as T cell stimulation. And by doing this and stimulating the innate immune memory response, we think that perhaps we get a better response in terms of killing tumor cells.

This was initially thought possible with phase one data looking at N-803. And as you all understand, phase one data is dependent upon actually looking at safety, looking at different dosages, and where the maximally tolerated dose was. And so there were nine patients with non-muscle invasive bladder cancer. But interestingly enough, at the two-year mark, all nine of these patients actually had a complete response or no evidence of tumor recurrence. And so this safety data definitely showed some type of positive, actually therapeutic efficacy.

And so as a result, a phase two trial began looking at actually a CIS component that had either the CIS alone or CIS in combination with Ta and T1 disease, as well as a papillary cohort, which is a combination of Ta or T1 disease. And each of these patient cohorts were patients that had BCGn response to disease, either with CIS disease within 12 months or Ta/T1 disease within 12 months with CIS in six months with papillary disease. These patients were then given six weeks of a combination of BCG and the N-803 and possibly re-induced as well with the endpoints being actually complete response for the CIS group and no evidence of papillary disease at the 12-month rate with the papillary group.

As one would expect, this was an older population. A number of these patients actually had a number of BCG doses. Actually, the median number was 12 for both cohort A, as well as cohort B when it comes to the number of doses. A heavily pretreated group of patients.

And when looking at CIS, this is just the Kaplan-Meier curve looking at the 12-month response rate, a complete response rate of 62% at 12 months, and a significant percentage of patients overall. Almost half or just over half at 24 months actually remained without evidence of disease with CIS.

When looking at the subgroup analysis, these subgroup analyses were actually based upon the subgroup analysis looking at actually pembrolizumab and immunotherapy that has been recently approved for BCGn responsive disease, and importantly, actually, all the subgroups that were then teased out, again, showed efficacy or benefit when given the combination of therapies.

When looking at the papillary cohort, a similar I think response rate that tended to last for a long period of time. At 12 months, 57% disease-free rate. At 24 months, again, almost half of these patients were without evidence of disease. It tends to retain durability.

Again, when looking at the subgroups, looking at all the different subgroups, again, there seems to be a benefit to this combination therapy.

When looking at the side effect profile, I think importantly, the most common side effects were those associated with lower urinary tract symptoms. These were grades one, two. There were some grade three, but not a significant number. And importantly, there were no grade four, grade five treatment-related side effects or significant adverse events associated with immune-related type side effects. And importantly, this actually would make sense based on the PK data on the phase one data, which showed that there was no actually systemic IL-15 levels that were recorded after N-803 was instilled in the bladder.

This is a shout-out and another example, of how Ashish has been a true leader here. This is actually a basis of after FDA discussions regarding what would be important in terms of efficacy or something that would be considered an effective therapy. And this came out actually a year before the study actually really started going. And if you look at it from a CIS standpoint, the authors actually concluded that a 30% percent durable response rate at 12 months and 25% at 18 months would be clinically meaningful. And for the BCG group that was unresponsive with papillary disease, the thought was actually 30% at 12 months again and 25% at 18 months also would be clinically meaningful. And so for both of these cohorts, those patients with CIS, as well as those with papillary disease, we seemed to have reached these and perhaps even exceed these possible goals.

That's it. I'm going to stop sharing my screen. That's a brief overview on the data and Ashish, happy to talk to you about some of the questions that you may have and some hopefully as time goes on, we'll be able to answer as better as well.

Ashish Kamat: Thank you so much, Sam. Thank you for taking the time. Clearly, you have a busy day and taking half an hour to spend it with us is really great. Have a quick question for you about the data. It's very impressive. The data that you presented as the reception you got at GU ASCO and as we all know is extremely impressive. What do you think is going on? Do you think it's because we finally got mechanistic base combinations that we're seeing this bump over what many of us thought would be a benchmark hard to meet? Why do you think that this therapy is so much better than what we've seen in the past?

Sam Chang: That's a great question. To be honest, nobody really knows. This is a hypothesis in terms of, are we boosting the trained memory, the innate immune response? It seems to make sense. This is a group that was heavily pretreated with BCG and they continue to have disease. Then you have a group that this combination seems to have been effectively treating them. Why? Well, there is data that shows that it's the patients that are able to develop this innate immune response. There's a slide that I didn't show and it was in those patients that you had the long-term response and success with BCG. Whereas, those that didn't seem to elicit this innate immune response, didn't seem to respond. And so perhaps we're better able to boost that immune response with recruitment of more effective natural killer cells, more the T cells, et cetera.

It's hard to tell why. It's one of the reasons why you start, you see the initial data with a phase one and you hope that there's going to be a response. We have enrolled, I think we're the second-highest enroller within this trial. And to be honest, I started this trial picking because a friend of mine from Nashville became kind of the pharmacy director of a small company that then got bought out and then got bought out. And we started enrolling patients and clearly, we've had some failures and clearly, we've had some people that have responded. And similar to the data, the tolerance of it is I think without question and it just seems that those that do respond seem to continue to respond. The failures and this is data that I still don't know the answer to is, those patients that did not have progression, worsening of symptoms, worsening of disease, that the investigators did think there showed some progress or some change were allowed to reinduce these patients, Ashish. At that three-month mark, similar to what we do with BCG, they were allowed to have a repeat induction.

And clearly, we had patients that were re-induced that were then disease-free, either had a complete response at six months or had no evidence of papillary disease recurrence at six months as well. Long answer to a simple question. Unfortunately, I don't think it's an absolutely evident answer. It does make sense in terms of some of the mechanisms that are done. And now the question is, do you add other things to increase that immune response? Do you do things that increase antigen, either presentation or further boost immune response? Lots of different possibilities as companies consider how you combine mechanisms of action. Very similar to what the combinations of BCG plus the systemic immunotherapies, BCG plus other therapies as well to try to boost it. And I wouldn't be surprised if there's going to be combinations, other combinations, with this agent if it gets FDA approved if it continues to show benefit and response.

Ashish Kamat: Yeah. Obviously combining systemic agents with intravesical therapies has the potential advantage to treat micrometastatic disease when you have the highest risk, the T1 high grades and we all wrestle with how can we save lives and bladders at the same time. Yes, that combination clearly makes intuitive sense. But one thing I would I say is that, if you look at the toxicity data that you presented, it's remarkable. These patients tolerated this so well and adding a systemic agent that has systemic toxicity, I think, is something that we have to really weigh carefully the pros and cons. But let me ask you a question about the toxicity data. This combination seems to be better tolerated than BCG alone. Because in BCG we see at least 50, 60% of patients complain of dysuria. Here you had 28%. Is that something you saw in your patients? Was there something about the combination that you think is actually helping decrease the BCG alone side effects?

Sam Chang: I couldn't say that. I couldn't say that the combination is better, has less side effects or that it's due to the N-803 that you have decreased side effects. I can just say that in our patients, it was remarkably well-tolerated. Now, there were no intolerant BCG patients that were enrolled to start with. In all honesty, these were patients that got BCG, that handled BCG well. We already sorted out those patients that were intolerant to BCG or couldn't handle other intravesical therapy. Maybe you've already self-selected Ashish, a group that can tolerate more BCG because as you know, certain patients are going to have trouble with tolerability, especially over time.

Those patients tend to present at least in our hands, the ones that really struggle, tend to present sooner. And as a result, we're not going to be as easily able to give them more intravesical therapy. And so this combination and we have these patients on maintenance and I haven't had to have a single patient who's responded, have to stop this medication. Part of it is, I think they're all encouraged that they don't have cancer and they want to continue but we haven't had anybody that had to stop the maintenance therapy due to side effects. It's pretty encouraging.

Ashish Kamat: Yeah. One question I had and I'm sure others may have asked you this as well, but do you know if there are discussions that the sponsor is having with the FDA to potentially allow this combination with any strain of BCG, or is it going to be tied to the strain that's being studied right now?

Sam Chang: Great question. I don't know the answer, to be honest. I don't know if the company's going to talk to the FDA about different strains and this and that. The only strain in this study was what was available in the US and that was the Merck strain. Good question. I don't know the answer.

Ashish Kamat: Because obviously Merck has committed to increasing production but even with best-case estimates, it's probably going to be 2027 before their plan kicks in and is able to give us BCG. I sure hope it mechanistically makes sense that any BCG would work with any of the three but I don't know if you'll be able to use it in combination on anything else or not clear the fence on the regulatory system.

Sam Chang: Yeah, I think that's a really good point too, Ashish, because we're hopefully with Dr. Svatek's study and the SWOG study, we'll have an alternative that shows some benefit. But right now we don't know. And so it is up to the FDA in terms of whether they would limit it or not. And just as you said, if the plant is ready in the mid-2020s, they can't start massive production right away. It'll take time to get that rolling and to manufacture. Clearly, it's a disadvantage to have this combination. And a question I thought you were going to ask is, well, what about N-803 by itself? And as part of the study populations and part of the studies, the FDA requested, actually a subgroup analysis of just patients that received N-803 by itself and 10 patients, and actually, we contributed quite a few of those patients, the single-agent N-803, there was not enough a signal to say that we should go ahead and continue studying this group. Because there didn't seem to be enough of a clinical benefit.

Ashish Kamat: Yeah. And I didn't ask that question because you were asked that at GU ASCO and you handled it really well. I had that response. Sam, you and I have chatted about many things, including bladder cancer for a long, long time. And I could go on chatting with you forever but in the interest of time and to wrap it up, let me just hand the mic back to you. You've had it most of the time but let me hand it back to you to leave our audience with some closing thoughts, your thoughts on this study, maybe something that surprised you, something you're looking forward to, something you could share with us.

Sam Chang: Yeah. I think I want to harken back to what you said regarding systemic therapies and the possible side effects associated with them. I think the systemic immunotherapy inroads and the antibody-drug conjugates that we have for more advanced disease, they're all going to be used sooner in the disease process. And clearly, there've been big steps but as the urologic surgeons that diagnose and treat these patients initially, I think Ashish, you would agree that the vast majority of patients, as well as physicians, if we can get an intravesical therapy that can effectively treat these patients before they get BCG unresponsive, even if they have low risk, high risk, if we can treat them successfully with minimal side effects, then I think we've made great strides.

I think separate from this and this is something you and I have both worked on is we need to continue to improve I think risk stratification. I think more importantly if we can avoid unnecessary cystoscopy in lots and lots of patients, that's one of the soapboxes that I'm trying to get on is if we can get some kind of markers that'll help us define who and who doesn't have bladder or upper tract cancer or both. I think then we've made really a step in the right direction. But I look forward to seeing what happens to N-803. The data I think is very promising. And obviously, I look forward to getting it out in peer review and a manuscript actually reviewed then on obviously what the FDA has to say. But thanks again, Ashish. And look forward to seeing you again in person soon.

Ashish Kamat: Absolutely. Thank you so much, Sam.