Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, urologic oncologist from Houston, Texas, and it's a pleasure to welcome to the forum once again a dear friend, bladder cancer expert, someone who's been with us many times, and is here today to talk about a groundbreaking trial that just led to the approval of the TAR-200 device by Johnson & Johnson, J&J.

Sia, thank you for taking the time. Lead us through the study and the data.

Siamak Daneshmand: Thanks, Ashish. So yeah, really exciting times here, right? This is the SunRISe-1 study that's been ongoing for several years and led to the approval of, now we can say it as a name, INLEXZO, this intravesical drug delivery system.

So this all started around 2016 in a Phase 1 trial where this drug delivery system was placed in the bladder prior to radical cystectomy. And the feasibility and Phase 1 tolerability study found to be quite tolerable. What was interesting is we saw, even in muscle-invasive disease, some responses. And later, J&J acquired the system and developed it, and that started these trials called the SunRISe studies.

And SunRISe-1 was the study of the intravesical drug delivery system, and it had three cohorts initially. There was the TAR-200 is the name of the system, TAR-200 plus cetrelimab, which is a PD-1 inhibitor. Cohort 2 was TAR-200 alone. And then cohort 3 was  cetrelimab alone. Again, a PD-1 inhibitor. And this was a BCG-unresponsive space. These are patients who had non-responded to BCG according to the classic FDA definition, which of course you helped develop.

And so as the trial was ongoing and we were seeing the efficacy of the system, cohorts 1 and 3 were dropped. And cohorts 1 was, again, the combination therapy and cohort 3 was the  cetrelimab alone, PD-1 inhibitor alone. And this was based on the fact that the cohort 2 results were very good, and it was thought the benefit to risk ratio of the additional therapy with a PD-1 was probably not worth it. So the cohort was expanded and we ended up with 85 patients in cohort 2.

The results were pretty remarkable. As you know, the CR rates that have been reported with 82% at any time, that's complete response rate at any time of 82%. And we're used to numbers in the 50% range at three months and then 25% of the year. But what we're seeing here is a sustained response of the patients who have responded. Over half of them are still in response at one year. And now overall from the 85 initial patients, 11 of them are out more than two years. So it's well-tolerated, we got great results, and of course now FDA approval and hopefully in our hands soon.

All right, so yeah, as we were discussing, we concentrated on the monotherapy arm, the cohort 2 of this study. And you can see the patient characteristics here. The typical age, 71. Most of the patients were ECOG 0. And importantly, two-thirds of the patients had CIS only, with about a third having CIS with papillary disease. And of course, these are patients who are declining radical cystectomy.

And you can see the results right here. The CR rates were very high. This is a complete response at any time. So 83% essentially CR rates at any time. And this was centrally assessed and we had biopsies, mandatory biopsies, at 24 and 48 months. So you obviously had to have a negative biopsy, negative cytology to be deemed disease-free. So very stringent definitions, as we would expect from a well-conducted trial.

The CR rates were essentially consistent across the subgroups, and it was durable. You can see in the swimmers plot here, there are about 11 patients who are out more than a year. Now, we have several patients now who are out more than two years of completed therapy and continue to be in complete response. And whether you had CIS with or without papillary disease, the response was very similar. The number of prior BCG treatments was very similar, so it didn't matter. All subgroups are responding essentially at nearly the same rate.

It's a pretty rapid onset of treatment, again with most of the patients responding within the three month. Now, re-treatment was not allowed in this trial. So these are just, if you had a recurrence, you were off the trial.

In terms of the safety profile, most of the AEs, the treatment-related adverse events, were Grade 1 and 2, obviously something we're completely used to as urologists who treat bladder cancer. Most of these are the side effect profile that we see with any treatment, polyuria, dysuria, frequency, urgency, and UTIs. There were very few discontinuations with the drug delivery system. I think only four patients had discontinued treatments due to AEs. So most of them are tolerating this quite well. There were seven patients who had Grade 3 treatment-related adverse events, and you can see that in the table here. So for the most part, again, very well-tolerated. Most patients are tolerating this. We're putting this in and keeping it in the bladder for three weeks, then removing it cystoscopically. And this goes on up until months, six or 24 weeks. And then after that it's quarterly for up to two years.

So I think I'm going to stop sharing my slides here and just have a conversation, Ashish, because I'm sure you have some thoughts about this as well and how this fits into our practice. I'm certainly very excited about the results and having this as part of our treatment armamentarium now.

Ashish Kamat:  Yeah, I know. So first of all, Sia, thanks for taking the time and sharing with us. You and I have been involved with this, and you, especially with the initial early-phase data, looking at it in patients, going to cystectomy and looking at this path CR rates in this cohort of patients. So really excited to see that this has finally come to where it is, where it first of all got published today, September the 10th. We just learned yesterday that it was actually approved by the FDA for use in our patients.

A couple of questions that people will, I'm sure, have with this is the tolerability. And it's refreshing to see that very few patients discontinue treatment. You've been using this for many years now. Share with us a little bit how easy is it, not just for you but for your mid-levels or your residents or others, to put it in the bladder, take it out, et cetera?

Siamak Daneshmand:  Yeah, great question, Ashish. And we do have advanced practitioners who are helping with both insertions and removal. So it's extremely easy, to be honest with you. It's something that most urologists are used to. It's a special catheter that that's placed in the bladder and it comes in the kit. And then the drug releasing system unwinds, or sorry, it comes in a pretzel shape, unwinds as it's inserted into the catheter, and we have a pusher that we push it into the bladder. So very easy to place. I think really it takes less than a minute honestly. That catheter has a slight croudateé tip to it that helps in men. And I know that they're working on an improvement on the catheter as well to have more versatility.

In terms of removal, once it's inside the bladder, it retains this pretzel shape due to a nitinol wire that's inside. And of course it floats around the bladder. It doesn't cause that irritation that we see with stents because it's not sitting in one area of the bladder like stents do. Removal is just as easy as removing a stent. You go in there with your flexible cystoscope and a flexible grasper and grasp one end of this and just pull it out. So it is pretty easy. And I know that in many practices, they have advanced practice providers doing the removals as well as the insertions. And one of the nice things about insertion is it doesn't have to be in a cystoscopy suite. The insertion can be done in any room because it's just a catheter.

Ashish Kamat:  Yeah. And one of the things I've heard from patients that have been involved, and especially in Weekend and Think Tank, is that the thought process is, hey, if the urologist is going to look in the bladder every three weeks to pull this device out, there's some sense of satisfaction that they're looking in for the tumor. So the potential negative aspect, which some people have brought up, which is, oh, you got to look in, is actually not a negative in the minds of the patients, which is great to hear from our patients because we do this for the patients. And it's great that they say that.

The other thing is it's a gemcitabine delivery device, and you and I call it the Pretzel. We've been calling it the Pretzel for many, many years. It's got an actual name now, but I think you and I will still call it the Pretzel. But because it's a gemcitabine delivery device, I think hospital formularies, I think us, the community at large, is very used to the side effects, the adverse events from gemcitabine, from a stent. And they're very manageable. So that's another huge plus here.

Sia, tell me a little bit about the mandatory biopsies and the non-retreatment, right? Because again, we know that there are studies right now ongoing where patients are allowed to have a biopsy and then get retreated. This is a study where they were pure. The study design was pure. There was a mandatory biopsy, no retreatment. Tell me your perspective on how this enhances the results in your mind.

Siamak Daneshmand:  Yeah, absolutely. Especially because this is mostly a CIS cohort. Many patients have negative cytologies. And you can be biased and look at a slightly red area and say, "Well, that's probably nothing." And you want your patients to succeed. You want the trial to succeed. But the fact that you have a mandatory biopsy at 24 weeks really speaks of the stringent criteria for calling something a complete response.

And you had two biopsies, right? 24 or 48 months. So I feel like these are truly results that you can trust. We've seen in some other trials where some of the criticism has been you didn't have a mandatory biopsy, and you could certainly have carcinoma in situ lurking behind, especially when we use white light only in the clinic assessments.

So I feel really good about the results. I think it's a very well-designed and conducted study in terms of stringency. And the results are real. And I always encourage people to look at the swimmers plot because that really tells you the entire story of all the patients right there, where they're in their journey, and how many patients are out beyond the year because it's nice to have complete response rates that are very high in the initial part of the assessment. But we want durability, and so far we're seeing good durability of the results. And of course, we look forward to further results as well as we get longer and longer away from our treatment.

Ashish Kamat:  Yeah. One of the things early on was we thought that the combination therapy, I'm sure, I don't want to put words in your mouth, but I thought that the combination therapy would be better than monotherapy alone. In many ways, it's refreshing to find out that the added systemic toxicity of a systemic agent is not needed, right? I mean, that's another big advantage here.

Sia, I'm going to put you on the spot now. Which patient would you not use this in?

Siamak Daneshmand:  That's a good question. I think many of us are using gemcitabine or a docetaxel after BCG treatment. The question is, if you're failing gem/doce, it doesn't make sense to go to gem. I wouldn't say I wouldn't use it in that setting, but it certainly gives me pause. Of course, that's combination therapy. Of course, we know that the drug releasing system and increasing the dwell times is very different than the all previous. We knew that gemcitabine alone has about a 20% one-year response rate. This is much higher. There've been some really elegant studies looking at the drug metabolite at four days after drug delivery system was placed in the bladder.

So it just gives me pause. I'd love to see more data on that, whether it's invested in that setting. Honestly, there are very few. I've been thinking about this actually since the approval, and I'm imagining by next year we're going to have more approvals. I think actually there are more patients who have contraindications to placement of solutions in their bladder than there are the drug releasing system. The reason being these are 50, 7500 cc's of solutions that many patients can't tolerate well, and so I'm thinking this is probably more ideal for those patients.

Or some have incontinence, right? You put some solution inside the bladder in the clinic, an hour later, most of it has come out. You wonder about how much drug actually stayed in the bladder.

So sorry to turn the question around and answer it in a different way, but I think there are actually more indications than the trial originally intended it to be. I think we'll be using it in more patients that we originally intended the trial to include.

Ashish Kamat:  Yeah, no, this is a great problem to have, right, because just two years ago, you were an integral part of the IBCG retreat that we had on how to sequence and what treatment for what patient when we had three drug approvals. Now, we have this. This seems to have knocked the bar up so much higher, right? 82% CR rate at any time. 50% or more of these are durable to be beyond 12 months. You just said the AEs, 8 to 9% of patients with Grade 3 AEs and discontinuation of 5%, and a very patient-friendly administration schedule, right?

So Sia, I know you're busy, but I want to thank you for taking the time, first of all, spending with it us, and congratulations on leading this effort.

Siamak Daneshmand:  Thank you so much, Ashish. Always a pleasure to talk to you and about bladder cancer in general, so thank you.