TAR-200 in Combination with Cetrelimab for BCG Unresponsive Bladder Cancer (SunRISe-1) - Siamak Daneshmand

May 12, 2023

In this conversation, Siamak Daneshmand joins Sam Chang in discussing a new treatment option for bladder cancer called TAR-200. TAR-200 is a pretzel-shaped device that delivers gemcitabine, a chemotherapy drug, directly into the bladder over a specified period of time. The conversation focuses on the late-breaking abstract of the SunRISe-1 trial, which evaluates the efficacy of TAR-200 in BCG unresponsive bladder cancer patients. The trial consists of three arms: Cetrelimab alone (a PD-1 inhibitor), TAR-200 plus Cetrelimab, and TAR-200 alone. The preliminary findings show promising results, with a complete response rate of 74% in the TAR-200 arm. The therapy is well-tolerated, and patients continue treatment for over a year. The Cetrelimab alone arm also shows a small percentage of responders, similar to systemic therapy alone. The conversation highlights the ease of administration and tolerability of TAR-200, with minimal bladder irritation observed. The ongoing SunRISe trials explore additional treatment combinations and patient populations, indicating a positive shift towards personalized and minimally invasive bladder cancer treatments.


Siamak Daneshmand, MD, Associate Professor of Urology (Clinical Scholar), Director of Clinical Research, Keck School of Medicine, University of Southern California, Los Angeles, CA

Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center

Read the Full Video Transcript

Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee and work at Vanderbilt University Medical Center. And I am in the presence of greatness. I'm quite privileged. It's really an honor to have Dr. Sia Daneshmand from USC. He doesn't need an introduction. He's a professor there at USC and clearly is one of the world's leaders in bladder cancer, in urothelial carcinoma. Oh, and also on the side he does RPLNDs treats testes cancer and treats other cancers. But we're going to focus actually on ... people call it the pretzel. It's a TAR-200. I'll let you describe the medication that's basically gemcitabine being infused in a polymer that is placed and then removed. But we're going to talk a little bit about the late breaking abstract, because I don't know much about it, since it's late breaking. But why don't we focus a little bit about the history that you have with this device and how this has all evolved.

Siamak Daneshmand: First of all, Sam, thank you very much. It's a pleasure to be here with you. Likewise, you're the bladder cancer king and I-

Sam Chang: No, this is a mutual kind of love society, so we'll ... Maybe this whole bro fest conversation, that part will get cut, hopefully not, but go ahead.

Siamak Daneshmand: All right. Well, I got involved with this device early on in the phase one trial that was being run by TARIS. And this was basically the pretzel, which like you said, gemcitabine tablets put in this pretzel format is ... there's an osmotic pump that's created and it eludes the gemcitabine within the urine over a specified period of time. The phase one was over a one-week period. They've reformulated it so that it does it over three weeks now. So these pretzels, as you said, are put in the bladder. They coil up like the two ends of double J-stents. They're very small, the size of two quarters, and they float around in the bladder releasing the gemcitabine over time. The advantage being that the drug is delivered over a longer period of time. We're used to the one hour, two hour dwell times, and that may not be enough.

And so this is over a one-week period. You can see peak concentrations in the bladder early on and it lasts for seven days. And importantly, there's no systemic uptake of the drug. And they've done some really nice elegant studies looking at the metabolites and how they're present in the bladder but not in the serum. So those were phase one. And we started to see a signal in patients having some responses with some actually having CRs prior to cystectomy. We're doing cystoscopies, photo documentation. So that led to, then Janssen took over the TARIS program and have started these SunRISe trials, the SunRISe-1, 2, 3, 4. And the one I'm presenting tomorrow is SunRISe-1, which is this device in the BCG unresponsive space. So there are three arms, three cohorts to this study. One is Cetrelimab alone, which is a PD-1 inhibitor.

Sam Chang: And that's given systemically.

Siamak Daneshmand: Systemically.

Sam Chang: Intravenous.

Siamak Daneshmand: Exactly.

Sam Chang: All right. Okay.

Siamak Daneshmand: So that's the usual route. And then it's TAR-200 plus Cetrelimab and TAR-200. So three cohorts and individually that way you can see what each component is doing.

Sam Chang: And this is in BCG unresponsive patients?

Siamak Daneshmand: Correct.

Sam Chang: As defined by the FDA in terms of-

Siamak Daneshmand: Exactly.

Sam Chang: -recurrence within six months versus 12 months, depending upon. And it's CIS only or is it CIS and papillary?

Siamak Daneshmand: It's CIS plus/minus papillary. Yeah. Yeah.

Sam Chang: Got it. Got it, got it. And so as a late breaking abstract, you'll be presenting the data and this discussion that we'll have will be after you present that late breaking abstract at a AUA 2023. Tell us some of the key findings.

Siamak Daneshmand: Yeah. So really, really exciting findings. These are the preliminary findings, obviously. So we're presenting on cohort two and three, which is the Cetrelimab alone and the TAR-200 alone. We're not presenting the combination therapy, so cohort two and three. So we have 22 evaluable patients for the TAR-200 and 21 for the Cetrelimab alone arm. And the complete response rate for the TAR-200 is 74%. These are very, very high. The median duration of response has not been reached. The average follow up is about 11 months. And we have several patients who are now over a year. These things are put in, there's a maintenance therapy as well. I mean, these things are put into the bladder first on a Q3 week schedule. And then later, after six months, it becomes a sort of quarterly schedule. It goes on beyond one year. So it's very well tolerated.

I'll show the tolerability of both the TAR-200 and cetrelimab. Very few patients have come off the trial because of intolerability. In fact, we have one patient in this cohort who was taken off the TAR-200, was removed. But otherwise everybody else retained it. And everybody, except for one patient, who has had a response, continues on treatment. So very exciting results. The Cetrelimab alone arm, same safety profile we've seen with other PD-1 and PD-L1 inhibitors, basically very, very similar. The efficacy is also similar. It's about 36, 37% in that cohort alone. So it seems like this may be a way to go for the sustained release medication.

Sam Chang: Right. So let's focus on the Cetrelimab alone arm. In small numbers and obviously early data. But it is reassuring from a systemic standpoint that there is a small percentage of patients that do seem to respond. And this is at the three-month mark, is that right?

Siamak Daneshmand: Yeah. Yeah.

Sam Chang: All right. So not too dissimilar from the high thirties of pembrolizumab in terms-

Siamak Daneshmand: Exactly.

Sam Chang: -of the response. And how long do they stay on the Cetrelimab? Is that every three weeks? Every four?

Siamak Daneshmand: It's every three weeks and it's given for a year.

Sam Chang: It's given for a year.

Siamak Daneshmand: Yeah.

Sam Chang: So again, not too dissimilar from the pembrolizumab.

Siamak Daneshmand: Right.

Sam Chang: So we have a small percentage of patients that respond to systemic therapy alone. So now let's look at this intravesical therapy, which from a urologic surgeon's standpoint, the familiarity of doing cystoscopies, placing something, following, is along the lines of something that we do every day. So in those patients at the three month, three out of four responded.

Siamak Daneshmand: Yeah. Yeah.

Sam Chang: And so these are basically with CRs. And CRs at that point were determined by biopsy, by cytology and cysto, appearance. How is that determined?

Siamak Daneshmand: Yeah. All of it. So visual, obviously, cystoscopy, cytology, and these were central. And then a biopsy is required at the 12-month mark.

Sam Chang: At the 12-month mark. Yeah. So basically then these patients were visually basically without disease, cytology without disease. Impressive results and well tolerated.

Siamak Daneshmand: It's very well tolerated. I've had a number of patients on the trial and I can tell you that for the most part, because this thing is floating around in the bladder and it's not fixed in position like a stent is where it gives you that trigonal irritation, you don't see the same irritation because it's not in one place. It's really floating around. Now obviously we've had patients who've had urgency and frequency and those things we are very familiar with and we treat them with any one of the antimuscarinics, anticholinergics, whatever have you.

Sam Chang: Right. It's not too dissimilar from any intravesical therapy patient that we get.

Siamak Daneshmand: Exactly.

Sam Chang: Any reason or do you all just not ... the data wasn't mature enough that the combination hasn't been presented yet.

Siamak Daneshmand: Exactly. The data wasn't mature enough for that. So this cohort two and three are the ones being presented now, well, the data.

Sam Chang: And it's a one to one to one randomization, is that correct?

Siamak Daneshmand: Correct. Yeah.

Sam Chang: I see. Okay. Great. And so the primary endpoint of this, was it basically complete response at three months? That's the primary endpoint, right?

Siamak Daneshmand: Yeah.

Sam Chang: And then obviously you'll see the one-year mark, you'll see how long, et cetera.

Siamak Daneshmand: Yeah. The primary objective is complete response assessed at the various time points. And we haven't reached a median duration of response either. As I said, the median follow up right now is about 11 months at the point of data cutoff. And we have ongoing ... obviously patients coming in and results ongoing.

Sam Chang: So anecdotally, what does the bladder look like as you replace the pretzel? Does it look inflamed? Do you get any of the mitomycin C calcifications? Tell me just anecdotally, I know it's not in the abstract, but I just wanted to talk to the expert of what does the bladder look like?

Siamak Daneshmand: Yeah. So I've done a number of these because I was involved in the phase one trial and we've put them in and taken them out. Put them in again. And so I've had a lot of opportunity now to see the bladder. And like I said, it's really well tolerated. Because at first I thought, yeah, we're going to see this whole red bladder like mitomycin. But think about it, even from the switch from intravesical mito to gem recently with the perioperative gem placement, we're already seeing a big difference, right?

Sam Chang: Sure. Agree.

Siamak Daneshmand: Mitomycin is the one that causes that really just heavy reaction and some idiosyncratic reactions when you get the terrible mitomycin chemical burn. And then BCG of course has some patients who, during maintenance especially, have these beefy red-

Sam Chang: Yeah. Beef red. I mean, exactly. That was funny. We said that at the same time. I mean, yeah ... It's just-

Siamak Daneshmand: Which is the same thing. But we're definitely not seeing that-

Sam Chang: I had steak last night. Little plug for Gibsons. Great classic steakhouse, in Chicago. But that's exactly what I was saying. And not-

Siamak Daneshmand: Yeah. So this-

Sam Chang: -all patients but some, so that's why I was wondering what should I expect to see?

Siamak Daneshmand: No. These are lower doses of gem given within the mini tablets. And again, because it's floating around the [inaudible 00:09:59] It's more about the duration and the concentrated gemcitabine and the duration of treatment being seven days.

Sam Chang: And the release over time. Yeah, I see.

Siamak Daneshmand: And the release over time. So the insertion is very easy and it's done through a special catheter. And it's like you said, urologists are very familiar with this. A catheter is placed in the bladder. It's got a lumen in and basically you uncoil this pretzel, put it in, and then we have a pusher just like you have in any other system. And it pushes the pretzel in the bladder. As soon as it's in, there's got a nitinol wire that makes-

Sam Chang: That causes it to spring.

Siamak Daneshmand: Spring.

Sam Chang: The analogy that I tell our folks. Now, I have not put in as many as you, but it's like, to me, passing a stent with a pusher where it's straight and then once you're in the right place you get the curl and you drop it in then and take things out. And then I know early on, the recommendation, and I think it makes sense. Early on, you should scope and make sure that it's well curled, that it's not hooked to the bladder neck. With time I don't think that's necessary, but I think early on I absolutely would recommend it because you want to make sure that it's in the location most likely to help benefit their patients and that type of thing.

Siamak Daneshmand: And we've learned things and I've heard stories obviously, and we've held meetings where people weren't sure, is it in one part of the coil? Is it in a prostate in a patient with a big prostate, like you said, best thing to do is just take a quick look. But also, like you said, with enough experience, this is a really, if you watch us do it, a two-minute procedure. You put this thing, once it's gone ... Because it hubs all the way to the end and you know you've dropped it in because urine's coming out of that tube.

Sam Chang: Right. You see ... Exactly.

Siamak Daneshmand: And so you keep some urine in the bladder to make sure the bladder's still somewhat distended when you drop this thing in. But always, yeah, visual inspection. We were required to do so in the phase one. We're not required on this trial. But yeah, very well tolerated. And taking it out is also very easy. It's like any other stent. You grab some part of it, usually the end, you're supposed to ... and it uncoils and comes right out.

Sam Chang: Right. And it's soft and it's-

Siamak Daneshmand: It's very soft. Yeah. It's just like any other stent. Again, it's within the armamentarium of any urologist. So we're not asking a big procedure you need to-

Sam Chang: Right. To do something totally different. This is not [inaudible 00:12:12] this is ... which I think lends to any treatment in terms of familiarity and then that increases comfort. And that to me increases the likelihood of success, and being able to do something like this. So I think very exciting findings. There's no question. What are we looking at in terms of, and this is the last question to see if we use, when do we think that this trial will be complete? I don't know the numbers that we're looking for.

Siamak Daneshmand: It's a global trial and there's several hundred patients. So the numbers are coming in. I don't have the numbers with me right now but it's accruing well globally. And I think we'll be going on for another year or two to get the adequate numbers for the three arms. And then there are the other SunRISe trials, which are also exciting. Those are getting going as well in the neoadjuvant setting, in immediate risk patients and so on and so forth.

Sam Chang: Right. And then looking at patients that maybe will be getting radiation therapy as opposed to cystectomy. So lots of combinations in terms of the-

Siamak Daneshmand: Not in intermediate risk, but exactly, in patients who are unfit for cystectomy, there's an arm where SunRISe-2 is TAR-200 plus Cetrelimab versus chemoradiation. So it's completely different.

Sam Chang: Yeah, yeah. Exactly. Treatment paradigm. Think about what ... Yeah. No, I think that what I find exciting is there are signals of new treatments that are out there and that's only begging for more treatments out there that hopefully will build on others and be able ... We talk a lot about this avoidance to cystectomy. It's something that you do all the day, your quality of life [inaudible 00:14:05] is quite high with everything that you all have done at USC. But we both agree if we've got an effective treatment that we can avoid bladder removal, patient's going to be most of the time better off with his or her bladder intact.

Siamak Daneshmand: Absolutely.

Sam Chang: As opposed to-

Siamak Daneshmand: No, I completely agree. I think you know I'm a big proponent for a cystectomy and invasive disease in patients with high risk, very high risk, high-grade T1 with extensive lamina propria invasion, LVI, things like that, that are very high risk. But for this patient population-

Sam Chang: Of CIS of TIA-

Siamak Daneshmand: CIS, TIA recurrence, disease who may progress to that, we do have other options for them. And I think that previous push to cystectomy, we're saying, "Oh, hold on, wait a minute. We do have these clinical trials. We have other options for these patients." And like you said, the more of this we do, the more it opens up other treatment options and you can imagine, well, why gemcitabine in this person when we can put something else? And that trial just opened, there's a new trial, TAR-210, which has Erdafitinib in the-

Sam Chang: Oh, fantastic.

Siamak Daneshmand: -tablets for patients with intermediate risk disease and other cohorts as well, BCG unresponsive who have FGFR3 alterations.

Sam Chang: Right. I mean, that to me again, exciting using personalized precision medicine of those individuals that have certain FGFR mutations you then target and then enhance the delivery of that medication. I mean, it's definitely an exciting time.

Siamak Daneshmand: Without the systemic side effects. I mean, that's the key, right? Because it's in the bladder, so it's privileged space and we have lots of other options.

Sam Chang: Right. Right. Yeah. So as much as we appreciate and love our medical oncology colleagues, I love being able to use some of their agents and delivering it in a better way. And I think that's fantastic.

Siamak Daneshmand: It is. Yeah.

Sam Chang: So see you. Thanks so much. Really appreciate the time and look forward to the late breaking abstract.

Siamak Daneshmand: Thank you, Sam. Thanks so much.