TAR-200 Monotherapy for NMIBC Durability and Dwell Time

Roger Li, MD, Vitaly Margulis, MD, Kyle Rose, MD, and Paul Crispen, MD share their perspectives on the SunRISe-1 trial and the evolving role of TAR-200 in treating BCG-unresponsive bladder cancer. The discussion highlights the practical benefits of intravesical sustained-release systems, such as TAR-200, their patient-centered advantages, and the promising durability of response observed in clinical trials.

Watch part four of this series: Combination Therapies in Bladder Cancer: Insights and Challenges

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Dr. Li:
So segueing into the SunRISe data, so SunRISe-1 has been reported a couple of times now. And I think the longer the follow-up, it seems like the results become more impressive. So even before we go into the results, all of you had had experiences with TAR-200 or TAR-210. What kind of practical tips can you give us as urologists dealing with this intravesical system?

Dr. Margulis:
Well, first of all, it’s a very easy application and retrieval. It keeps the urologist engaged. In each placement or removal of the device, you get to assess the bladder at the same time. It seems to me, again, anecdotal evidence, but seems to be supported by preliminary data, it’s very well-tolerated. The treatment discontinuation rates are low, most patients are able to tolerate it, even the patients in whose bladders were previously treated. Because I think the sort of amount of substance in the bladder is minimal, and so the patients do well with it.

Dr. Rose:
Agree completely.

Dr. Crispen:
Yeah, I agree with everything that Vitaly says. Patients tolerate it well. I think they do… The engagement of the urologist is very important to these patients. A lot of them we’ve been treating for many years, and so they like to stick with us as their providers before moving on or seeing a radiation oncologist and their medical oncologist for their care.

Dr. Li:
So at some places, I think the advanced providers are doing these procedures to place, and also extract, these devices. Is that the case at UF or Ochsner or UT Southwestern?

Dr. Crispen:
We have not done that. Our only experience is with the clinical trials and for that reason we have the investigators and sub-investigators complete all those procedures.

Dr. Rose:
Ours is the same. So for our clinical trials, there’s documentation that’s needed. And so as site PI, I feel most comfortable doing it myself, so we can stay as consistent as possible.

Dr. Margulis:
But you bring up a good point. Right now, yes, it is usually the physician provider that would handle this. But in the future, I think our physician extenders take on a lot of the burden. It’s not a complicated procedure, so I think it’s a good way to get them engaged, as well, and offload some of that.

Dr. Li:
Absolutely. And if you’re talking every three weeks cystoscopy procedures, that adds up, too. There’s going to be a lot of these patients coming in every three weeks. And I think also talking to some of the folks from Mayo Rochester who’ve implemented this system, the APPs who are doing this, they claim that there’s a huge satisfaction rate with more procedures that they’re doing. So I think at both ends, it’s a win-win situation.

So we’ll just briefly go through the top-line results from the SunRISe-1 Trial. Again, these were, I believe, presented at ESMO recently. And so, there are a couple of different things that stood out to me, but I wanted to get you guys’ take on this as well. So from the TAR-200 monotherapy arm, it seems like that was the highest complete response rate at 83%. It went down to 46% for cetrelimab, which is the P-1 inhibitor. But the combo arm also actually didn’t do as well as the monotherapy arm. So just wanted to get your initial thoughts on that?

Dr. Crispen:
Very encouraging results, obviously. I think the cetrelimab arm performed as well as the other agent out there, pembrolizumab, at that complete response rate. So that’s a little encouraging to see some consistency there. That point you brought up about the combination arm versus the TAR-200 monotherapy arm, a little surprised that they didn’t do at least as good. Who knows, as we get more data and the data’s matured, maybe they’ll balance out as well. I don’t know why that adding cetrelimab to the TAR-200 would’ve decreased efficacy there. But just looking at that initial percentage for the TAR-200 monotherapy, I think that’s very impressive and encouraging.

Dr. Li:
And I would say, even at 68% with the combination, it’s not shabby compared to a lot of the other agents that are out there. So certainly, you have to take into account the toxicity of the combination.

Dr. Rose:
I was just going to comment on that, thinking back to the systemic toxicity of pembro, we’re extrapolating, we’re also thinking forward about our conversations we’re going to have with the patient. But to offer a monotherapy as opposed to a systemic intravesical combination, I think it has a lot of patient appeal to it as well.

Dr. Li:
For sure.

Dr. Rose:
And when we counsel these patients, I think that’s something they can look forward to and something that simplifies their treatment plan.

Dr. Li:
And then going to the durability of the response, it seems like even at 12 months the Kaplan-Meier survival rate, it’s still really good, 57.4% for the TAR-200 monotherapy, 56.7% for the combo, and down to 22.8%. So for the monotherapy with the PD-1, it seems like very comparable to pembro.

Dr. Margulis:
So I think to me, honestly, first of all, I would say I was very excited secretly that the combination arm didn’t do as well as the monotherapy arm. Because logistically, as you know, to coordinate a systemic infusion and intravesical administration, it’s just another level of complexity. And so I’m glad that the monotherapy probably is the way that we’re going to go here. But I think what’s impressive to me about this clinical trial is the durability. With other agents in this space, you get a really robust CR any time response. When you look at a year or two years, of course a lot of these, from my projections, the data doesn’t look as good. And here you have durability of response. And so that to me is very important and encouraging.

Dr. Rose:
Absolutely.

Dr. Li:
And I think that’s something that patients look for. We are so concentrated on this three-month, six-month CR rate. But when patients are coming in for a salvage therapy, they’re looking to retain their bladders long-term, not necessarily just for the short-term.

Dr. Margulis:
Yeah, I just in general have a little bit of an issue with the CR at any time end point, because I know I can go and burn the bladder cystoscopically, and I’m going to get a CR at three months, no problem. So it’s a durability really that stands out to me in this clinical trial.

Dr. Li:
And so how much of that do you think it’s the actual continuous elution of the drug, that you’re treating the bladder at all times essentially, versus any of the other drugs that we’ve tested in this space? You have the infusion, but patients are essentially without the agent, especially if you’re considering ablative therapy.

Dr. Crispen:
I think dwell time is important, and we’ve seen that for other agents as well. Well, if it’s upper tract, you’re in mito gel, dwell time is important. You’ve seen UGN-102 in the bladder. Looks like dwell time is important there, so I’m not too surprised. I think that it’s a great way to approach it. We like to try to compare different treatments, different strategies. And we might have a comparison out there for TAR-200 versus just intravesical gemcitabine. There’s the Alliance trial.

Dr. Li:
That’s right.

Dr. Crispen:
Right, 311803. Those results will probably be out in the next couple of years. But that one, for those who are not familiar with it, it’s pembrolizumab for a year, induction, just single-agent gemcitabine, and then maintenance every three weeks throughout the year. And so we’ll see. That’ll be a great comparison to see if that combination and if that dwell time is really important.

Dr. Li:
So I didn’t actually realize that it was an every-three-weekly infusion throughout the entire year.

Dr. Crispen:
For the pembrolizumab, right?

Dr. Li:
Oh, for the pembro, but not for the-

Dr. Crispen:
For the maintenance, yes.

Dr. Li:
For the gemcitabine it’s just the induction?

Dr. Crispen:
Induction, no, and then plus that every three weeks, that maintenance. That’s right.

Dr. Li:
So you’re infusing gemcitabine every three weeks as well?

Dr. Crispen:
Yes.

Dr. Li:
Wow. So that’s a lot of treatment for the patients.

Dr. Crispen:
It is.

Dr. Rose:
It is, but I think back to your question, Roger, about using an intravesical pretzel and the benefits of that. A lot of these patients we see when they come to see us and they’ve got BCG-unresponsive bladder cancer, they have less than functional bladders as it is. And so, dwell time is a critical component for them. A lot of these patients can’t hold it. We’re prescribing oxybutynin to elderly patients, which you know have cognitive side effects, just to get them to hold the agent in. I think getting a intravesical, sustained release platform was critical. I think that is what industry is going to be looking to do with multiple agents going forward.

Dr. Li:
Yeah. Well, so going back, Paul, to the Alliance trial, are patients tolerating this every three weekly infusion? Because, you’re asking them to actually, to Kyle’s point, to hold the infusive in their bladder?

Dr. Crispen:
So I can’t speak for that trial in general. And the number of patients that I’ve put on that trial, I think it’s like six or seven. So I don’t have a tremendous amount of experience with it. I think my experience with that is using just the gem/doce. And to Kyle’s point, even with those patients, getting them through that two hours, sometimes that one hour can be a big challenge with that catheter in place where we are having to add these medications and do that. It’d be interesting to compare the tolerability and to see how many patients can get all of those treatments compared to maintaining a pretzel for three months.

Dr. Margulis:
Yeah, I agree with this. I have just two points. I would say that we do have some retrospective data of gemcitabine in BCG failures. And the data of course doesn’t look as good. Right?

Dr. Li:
Right.

Dr. Margulis:
I think if I remember, again, retrospective small series, but it’s a year complete response rate something in the range of 20%. So there must be something different. And obviously, dwell time is that, I think. It makes sense, intuitively. If you put gemcitabine into the bladder, best case scenario, it’s one hour dwell time versus I think, if I remember the data correctly, for the TAR-200 product, you get detectable levels of gemcitabine in the bladder for up to a week. So that’s basically seven days of dwell time versus one hour. That has to make a difference.

Dr. Li:
And I think that’s kind of like the beauty of the TARS system in general, is not only is it able to deliver gemcitabine, but of course we know in the TAR-210 product, we’re also delivering erdafitinib, which actually, if I remember correctly, there’s a three-monthly detection of the erdafitinib within the bladder and the urine. So the patients are truly getting continuous therapy. And I think that’s really exciting that we have this platform now that can deliver multiple drugs within the system.