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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urological Oncology at MD Anderson Cancer Center, and I'm joined today by Professor Sam Chang from Vanderbilt University. Sam, you really need no introduction. I mean, everybody here on the forum knows you. You've hosted interviews. Today, I have the pleasure of having you present, and then interviewing you on SunRISe-3, which is really something that everybody's been waiting to hear about. So looking forward to seeing what you have to say, Sam, and take it away.

Sam Chang: Great. Thanks very much, Ashish. I have the honor and privilege of presenting a trial in progress, which is a new reform that the AUA has started, looking at trials that are currently enrolling, and I will actually have the chance to discuss the SunRISe-3 trial. The SunRISe-3 trial, as this title slide shows, is looking at the TAR-200 targeted release system by itself, or combined with cetrelimab, which is a form of immunotherapy, versus the third arm, which is actually BCG. And this is for patients with BCG-naive disease.

These are my disclosures.

What this study does is, based upon the fact that early on the interim results of SunRISe-1, which was looking at patients with BCG-naive disease, there was a signal that this device, which has a combination of a unique delivery system with the chemotherapy agent gemcitabine, may be effective in patients with high-risk non-muscle-invasive disease. We know that BCG has been the standard therapy for decades. And we know it's quite effective, but it does have associated toxicity, and there are clearly those patients that may not respond to it. So, having this targeted release system that's unique, and combining it with a chemotherapy agent that we know is effective, is the basis and rationale behind this trial in progress.

So this is actually the study schema. The key eligibility criteria are for patients with non-muscle-invasive disease that have high-grade TA disease, have CIS, or actually have any T1 disease. And BCG-naive is defined as those patients who have never seen BCG, or have not received BCG for more than three years.

The three arms are the ones that I described. It's the targeted release system by itself, the TAR-200; the TAR-200 combined with cetrelimab; or the third arm is actually BCG. And this is a one-to-one-to-one randomization for patients in this trial with high-risk non-muscle-invasive bladder cancer that is BCG-naive.

If you look at the primary endpoint, it is, in fact, event-free survival. And this is actually a time period from the time of randomization to a certain event. And events would be defined as progression, as evidence of high-risk disease that's found again, any cause death. And for patients with, actually, CIS, it's a period of six months, in terms of whether or not they have disease or not.

Secondary endpoints would be common secondary endpoints. That would include overall complete response rate, looking at time to recurrence, in terms of the rate or length of time, the overall cancer specific and overall survivals, as well as safety signals and patient-reported outcomes regarding tolerability.

SunRISe-3 is currently ongoing and enrolling a significant number of patients. More than 1400 patients have been screened, with more than 900 patients that have actually enrolled. So accrual at this point in this study, that just started actually in March of 2023, the accrual mark is now at 90% of the targeted enrollment response.

Now, people will want to know initial readouts and evaluations. At least we have an idea. Enrollment hopefully would finish here in the next, I don't want to guess or say for sure, but probably easily before the end of the year would be the goal. And then after that, the first readout, in terms of possible failure, would be sometime in the early quarter of, or second quarter of 2025.

So this slide actually acknowledges the entire team. This QR code actually will give you information on the ongoing, actually plethora of SunRISe trials, SunRISe-1, 2, 3, 4, and 5. These all use the same targeted release system. These are looking at different disease populations, muscle-invasive as well as non-muscle-invasive, and with different treatment algorithms. Each of these now is either underway, has finished accrual, or is about to start, actually, enrollment.

So that's an idea of what's going on with SunRISe-3. And I'll stop sharing my slides, and happy to discuss in any way.

Ashish Kamat: Thanks so much, Sam. I appreciate you taking the time. I completely fully understand that you can't disclose any preliminary readout. And full disclosure, I serve on an advisory board for the sponsor, and of course, I'm not going to disclose anything that's not public knowledge either. But with that disclosure, I'm very excited about the potential for this delivery of gemcitabine and this device to be going head-to-head against BCG, which we still have a shortage of. And of course, the combination arm of cetrelimab with TAR-200 is in the trial as well. So, without further ado, and clearly just stick to your opinion here.

Sam Chang: Sure.

Ashish Kamat: But in your opinion, if the arms read out as all equal, do you think that will change the management of high-risk non-muscle-invasive bladder cancer in the US?

Sam Chang: Wow, that is a difficult question to answer that everyone wants to know the answer to, and no one really knows what will happen. As you know, there are so many different things that can affect physician and patient choice regarding next steps. We can switch our therapies for treatments that are exciting that we aren't, or we know that aren't as effective and vice versa. So that's a way for me to stall and to say, will it change therapy? I, in fact, think it will change therapy for several reasons. One, I think although this does require cystoscopy and an exchange of the targeted release system, it isn't as frequent as the once-a-week BCG visits. Secondly, I think there will be continued difficulties with not only the shortage but probably just as frustrating, the lack of actually knowing for sure the uncertainty if BCG is available, yes or no.

I think that really affects clinicians as much as anything, "Hey, I'm going to start an induction course perhaps, and I don't know if in three weeks I will have BCG or not." So it's not only the lack of availability but the uncertainty that really has made frustrating decision choices for physicians. So I think the combination of the fact that it will be more certain in terms of availability, perhaps an easier schedule in terms of spaced-out treatments and evaluations.

And then the third thing is, if all equal, well, we have to define all equal. Are there going to be differences in terms of patient-reported outcomes versus efficacy? Is this going to be better tolerated versus BCG? Are there going to be fewer downstream effects, et cetera? So I think to answer your question, I think it really has a strong chance of changing the current treatment landscape. Will it increase or change dramatically? Depends on the results, depends on the uptake. And honestly, it'll depend early on as physicians start utilizing this device, becoming more familiar with it, what kind of uptake there will be throughout the country, and throughout the world.

Ashish Kamat: So Sam, you didn't have to stall. I love that answer. I mean, because it's true, right? And the best part is our patients would have more options, which is ultimately why we're doing all of this, which is great.

Sam Chang: Absolutely. Absolutely. And to have more choices, I think, especially in a world that had been devoid of choices in reality, as you know, Ashish. You've led so many trials looking at different types of interventions that clearly are now starting to come to fruition. You understand that the patient education and knowledge, at least in the US, has increased dramatically, I think, during our careers, in terms of having these options. And so, that led to my last point of, I wouldn't be surprised if patients themselves, actually, in looking at the data, and understanding the possibilities, may actually influence the decision choices.

Ashish Kamat: Once again, Sam, always a pleasure to chat with you. I'm not going to probe you on hypotheticals, since this is a trial in progress. But once again, thank you.

Sam Chang: Oh, thank you, Ashish. And again, let me take this opportunity to thank you for all your efforts and everything that you've contributed to the science and therapeutic considerations for bladder cancer and urethral carcinoma. You really have become the world's leader, and I know patients are very, very grateful to you. So I want to thank them on behalf of all patients.

Ashish Kamat: Thank you.

Sam Chang: All right. Take care.