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Sam Chang: Hi, everyone. My name is Sam Chang. I'm a urologist at Vanderbilt University. And we are fortunate to have Dr. Sarah Psutka. Dr. Psutka is an associate professor. I know she'll be a full professor soon because the way that she's been able to succeed so much in a short time has been amazing. I followed her academic career from actually the very get-go, and we're fortunate to have her today speak on the SunRISe-4 trial. She's going to talk about a new clinical trial looking at combination therapy as well as looking at immunotherapy when evaluating patients receiving neoadjuvant treatment prior to radical cystectomy. So, Sarah, let's hear what you've got to tell us.

Sarah Psutka: Well, Sam, thank you so much for having me. I'm thrilled to be here, and thank you for your kind words. So I'm really excited to have the opportunity to share some updates on this trial with you today.

The SunRISe-4 trial is a trial that is newly open, and it's a phase II, open label, multi-center, randomized study of the TAR-200 agent in combination with cetrelimab and cetrelimab alone in participants with muscle invasive bladder cancer who are going to get a radical cystectomy, but either are unable to, or refuse, platinum-based neoadjuvant chemotherapy. So the background for this is that, as we all know, the standard of care for the management of muscle invasive bladder cancer at this point is neoadjuvant chemotherapy that is platinum-based prior to a radical cystectomy. The problem is cisplatin-based chemotherapy is highly toxic, and a lot of our patients simply cannot receive it.

If we look back to the early 2000s, only about 13% of patients actually got neoadjuvant chemotherapy. And especially when we get into our older patients, our patients in their seventies and eighties, those rates dropped down to 11% in the late seventies and less than 10% in octogenarians. In updated data sets in the late 2010s, we're doing a little bit better, and about 40%, but still less than half of patients under 70, are getting neoadjuvant chemotherapy. And over the age of 70, only 20%. And of course, that's the majority of our patients with muscle invasive bladder cancer. So the question is, what do we do for these patients, and is there any way that we can provide the potential benefits in terms of overall survival with neoadjuvant therapy prior to cystectomy?

And so this trial is specifically looking at a novel agent, which is the TAR-200 agent, which is an intravesical drug delivery system. So it's a... You've probably heard of it described as the pretzel. It's a continuous gemcitabine-eluting device that is placed in the bladder. And then cetrelimab is an anti-PD-L programmed death 1 antibody. And so we're looking at whether the combination of this locally-delivered chemotherapy in addition to IO-based neoadjuvant therapy can be beneficial compared to IO-based therapy alone.

So in terms of what we know about the preliminary data, so the TAR-200 agent has been tested in a phase I trial, and this is published in Urologic Oncology. The punchline is that this was a small phase I trial that was looking at the safety and tolerability as well as preliminary efficacy data for the TAR-200 agent. There were two arms. One arm were patients who still had a fair amount of tumor in their bladder after the first TURBT greater than three centimeters, and the second arm are the patients who had undergone a maximal TURBT and had less than three centimeters of residual tumor. Both arms received two seven-day cycles of the TAR-200 agent and then went through a radical cystectomy. And the punchline is that in the 23 patients who were enrolled, of which 11 were enrolled into arm one and 12 into arm two, there were no patients who couldn't tolerate the TAR-200 device.

In terms of safety and side effects, the vast majority of the patients did pretty well. There were treatment-emergent AEs in 10 out of the 23 patients. And the most common side effects were urinary frequency, and a few patients had urge-associated incontinence.

Pathologic downstaging was appreciated in four of the arm one patients and six of the arm two patients. The patients who had the maximal TURBTs obviously had a higher rate of complete responses, with three complete responses and three partial responses. So there's preliminary data signal about both the safety and the tolerability of this tool, this device that elutes gemcitabine locally in a continuous fashion into the bladder. And then it also appears to have some efficacy.

And just to show you what this is, so this is the pretzel. It's about the size of I think that's a toonie which, as a Canadian, I appreciate that the company made it that way. And essentially, this is instilled through a catheter into the bladder, and it just wraps up and floats around. And it can be placed in the clinic with a single-use urinary placement catheter, and then it can be grasped and removed. It's flexible, and it sits in the bladder for about 12 weeks at a time.

Now, there's also emerging data that has looked at IO-based systemic therapy as neoadjuvant therapy in patients who can't get cisplatin-based chemotherapy. And this is a recent systematic review that basically shows that when we give IO-based neoadjuvant therapy, we see complete response rates somewhere in the 30 to 50% range. And that's similar to what's been seen with neoadjuvant cisplatin-based chemotherapy, with an average in the 30, 30-ish percent range. Downstaging is seen in 50 to 74%. And of course, though, as you are using these therapies, there are going to be significant adverse events associated. With IO monotherapy, it's about 8 to 9%. When you add chemotherapy, that rate goes up to about 16%. And when you use combined immunotherapy, it's up to about 36%. And surgical complications in patients after IO-based neoadjuvant chemotherapy are honestly on par with what we see with cisplatin-based chemotherapy. And this is just a summary slide for that systematic data that I just showed you.

So the objective here is to evaluate the efficacy and safety of neoadjuvant TAR-200 plus systemic cetrelimab versus neoadjuvant systemic cetrelimab alone in patients with muscle invasive bladder cancer who are going to go through a radical cystectomy, but either cannot receive cisplatin-based chemotherapy or refuse it. And this is the trial schema. So we've talked about the eligibility criteria. We are going to stratify by T2 versus T3-T4a disease. And then there are patients who are also stratified by the completeness of the TURBT, so either a visually-complete TURBT or residual disease burden less than three centimeters in size.

Cohort one, and we're going to try to enroll here. It's 160 patients is our target, and it's a five to three randomization strategy. So cohort one, which we'll hopefully enroll a hundred patients into, will have the TAR-200 device placed in their bladder every three weeks over 12 weeks and the IV cetrelimab, and they're going to receive that for three months. And the cohort two will just receive the cetrelimab. Both arms will go through the radical cystectomy. The primary endpoint that we're looking at here is the pathologic complete response at radical cystectomy. Secondary endpoints, we'll talk about in a moment.

The eligibility criteria. These are adults who have good performance status, so ECOG performance status 0 or 1. They're, again, histologically-confirmed muscle invasive bladder cancer. No nodal or metastatic disease. These are patients who have less than three centimeters of tumor after TURBT, so it's obviously going to be patients who can be successfully debulked with a TURBT. They do have to have a GFR greater than 30, but that will encompass a far larger patient population than those patients who have a GFR under 60 who cannot receive cisplatin. And then they can't have any other active malignancies.

And as I mentioned, the primary endpoint is pathologic CR. Secondary endpoints we're going to look at, obviously, are safety and tolerability and then recurrence-free survival. And then exploratory endpoints, we are going to be looking at patient-reported, cancer-related quality of life. We'll look at the pathologic overall response, overall survival, time to symptomatic progression, and then some pharmacokinetics and biomarker analyses are also going to be explored.

And so there will be a centralized review of the TURBT specimens as well as the radical cystectomy and nodal tissue specimens. We'll do CT scans at week 12 after the radical cystectomy and every 12 weeks up till the end of the study, which is at week 108. There is an optional week six cystoscopy, and then follow-up visits are basically on par with what we would do in standard guideline-based practice.

And this trial was opened in July of 2022. We are now opening and enrolling patients at about 95 sites around the world, and currently have 16 of the targeted 160 patients enrolled as of this week. And then my co-global PI for the study is Dr. Andrea Necchi, and I just wanted to acknowledge him as well. So that's a brief summary of the trial. We are fortunate to have the opportunity to share this at GU ASCO.

Sam Chang: Yeah, so this- In the 2023 meeting, Sarah, a lot of interest in combination therapies and the way to deliver them. Tell me what... From the preliminary data regarding the side effect profile you mentioned from the phase I, the hope then would be by doing something intravesical, combined with the immunotherapy, that would it hopefully decrease the side effects and increase the access to systemic therapy prior to cystectomy? Is that right?

Sarah Psutka: That's the target. So the TAR-200 device is being tested in multiple different settings at this point, as you're aware, through the SunRISe-1, 2, 3 and 4 studies. The tolerability of the device seems to be quite good, although certainly, patients do have some increased urinary symptoms predominantly. The difference here, of course, is that we do have the urinary symptoms, but hopefully we're avoiding some of the systemic chemotherapy-associated symptoms that can be so intolerable that they can negate a patient's ability to receive systemic chemotherapy, or may also be a reason why a patient may refuse to receive systemic chemotherapy.

I showed you that systematic review that just looked at what's been done with chemoimmunotherapy. And certainly, by adding systemic chemotherapy to an IO-based neoadjuvant therapy, there was a pretty significant jump in the treatment-associated grade 3 AE rate. And so hopefully, by limiting the chemotherapy to a local delivery mechanism, we may of course trade some of those AEs for bladder-specific AEs, but hopefully we minimize some of the systemic side effects that might otherwise prevent patients from receiving treatment.

Sam Chang: Can you describe some... Obviously, the investigators have done this, but describe honestly how easy placement of the pretzel, the TAR-200, is. I mean, it is something that can be done in the clinic, for sure. It can be something that honestly takes not much longer than a Foley catheter placement. So tell us a little bit about the nitty-gritty of actually placing the TAR-200, because I don't want that to prevent any sites regarding, oh, a learning curve and this and that. Tell us about placing the pretzel.

Sarah Psutka: I'll share this one picture again, because I think it's probably helpful just to have the visual aid. Yeah, so you can see it's basically a catheter that has a little coude tip that's inserted in the bladder, and then there's a plunger that basically just puts it in. So it's something that can be done without anesthesia in the clinic. As it's deployed, if you can see my arrow here, it just comes out through the end of the catheter and then wraps around on itself so that it can't be extruded from the bladder. And it's relatively quick. I think that in general, it's something... One of the potential benefits of this, again, is it can be done without an anesthetic or with a need to go to the operating room and can be done with the ease with which a catheter is placed.

Sam Chang: Yeah, I think those diagrams are actually really helpful. People have envisioned this pretzel, and people... I know there's been some concerns regarding well, a pretzel, how do you get the pretzel in where it needs to go? But the actual mechanism is simplistic, yet it is... In terms of tolerability, placing it, I think, is really no different from installations that honestly some of these patients have had in the past, Foley catheters, which almost all of these patients have had in the past. So I think that's fantastic. What can we do, Sarah, to-

Sarah Psutka: It's about this big in real life.

Sam Chang: Oh, go ahead. Oh, yeah. Exactly.

Sarah Psutka: I mean, it's funny. It's actually pretty tiny. So it's helpful, I think, to be able to share this with patients as you're talking about it in terms of explaining to them what's going to be floating around in their bladder.

Sam Chang: I mean, if you say pretzel, you think...

Sarah Psutka: Yeah, you think big.

Sam Chang: It's honestly like one of those small pretzels. It's not one of the big pretzels, so, as you describe it. What can we do? We've always... I think urologists have always struggled with enrollment. We've gotten better as a category of physicians. I think radiation oncologists have always done a tremendous job. Our medical oncologist colleagues have done, I think, a fantastic job. This is one that can be more difficult because many times, we have to integrate the understanding. We've made moves towards neoadjuvant therapy, so I think we're doing a better job with multidisciplinary care, but can you comment on what we can do to help enrollment?

Sarah Psutka: Yeah. Well, the truth is, for muscle invasive bladder cancer, as urologists we're the first point of contact for these patients. We're the ones who are diagnosing them with the TURBTs. And usually, we have the first conversation with them and then send them off for neoadjuvant chemotherapy and bring them back for their cystectomy.

But we are the patient's quarterback for their care through localized bladder cancer. And in doing so, we're perfectly positioned to find those patients who the medical oncologists say, "Listen, I can't give you cisplatin because of your kidney function, your hearing loss, your neuropathy, your heart disease or your performance status, whatever else." Now, this trial does require patients to have pretty good performance status, but they can have, as we said, an eGFR of down to 30. So I think that knowing what we know about the benefits of neoadjuvant chemotherapy in terms of the benefits of washing out or mitigating that micrometastatic disease and hopefully warding off those distant recurrences that we worry about so much in our bladder cancer patients, this is something we can offer those patients who otherwise couldn't get anything else.

Sam Chang: Yeah, I think that-

Sarah Psutka: And I think that it's important that we... And we're good now. We're getting better at talking to patients about neoadjuvant therapy. And we've got those partnerships with our med oncs worked out, and our med oncs are very comfortable giving these IO-based therapies at this point. So I think the pieces are all in play.

Sam Chang: Yeah, I think your point is really an important one in that we understand the importance or the effectiveness of platinum-based therapies. But something that I've learned as we go is inadequate chemotherapy is, I think, worse than no chemotherapy at all. And so we already have a group of patients not getting systemic therapy and perhaps inadequate neoadjuvant treatment. So if we can have alternatives that are effective, especially in those that are not truly cisplatin eligible, it really serves our patients quite well.

And I personally could not think of a better quarterback if I had an issue with invasive bladder cancer other than Dr. Psutka. So, Sarah, thanks so much for spending some time with us and enlightening us about this important trial as well as the importance of evaluation of patients carefully and providing them systemic therapy prior to a definitive cystectomy. So thanks again.

Sarah Psutka: Thank you so much for giving us the chance to talk about this.