The Evolving Treatment Landscape of MIBC and NMIBC

A roundtable moderated by Karine Tawagi, MD, of the University of Illinois, featured discussion on the treatment landscape of muscle invasive and non-muscle invasive bladder cancer.
Panelists Petros Grivas, MD, PhD, of Fred Hutchinson Cancer Center, and Vadim Koshkin, MD, of the University of California, San Francisco discussed some of the latest practice-changing trials in the treatment landscape, as well as the potential of bladder-sparing treatment approaches and the use of ctDNA.

In the first segment, the roundtable examines the evolving treatment landscape of MIBC and NMIBC, including discussion on new trials and treatments.

Watch part 2 of this roundtable: VOLGA, EV-304, and More Practice-Changing Trials in MIBC

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Dr. Tawagi:
We are here at the Uromigos’ annual meeting in Nashville, talking about some really exciting ESMO updates in the space of bladder cancer. I’m Karine Tawagi, I’m a genitourinary medical oncologist at the University of Illinois in Chicago, and I’m pleased to be here with two of my friends and colleagues to talk about some updates in bladder cancer.

Dr. Koshkin:
Vadim Koshkin, I’m a GU medical oncologist at the University of California, San Francisco, and associate professor there. I focus on bladder cancer, and help co-lead our bladder cancer clinical program.

Dr. Grivas:
And I’m very excited to be here, Dr. Tawagi and Dr. Koshkin. I’m Petros Grivas. I’m a medical oncologist in Seattle. I serve as the clinical director of the GU cancer program at the University of Washington and physician and professor at Fred Hutchinson Cancer Center.

Dr. Tawagi:
Well, we’re excited for some updates and some discussions later at the Uromigos meeting, but first we want to talk about some updates that we’ve seen at ESMO and kind of where the practice has been changing in terms of non-muscle invasive bladder cancer. So we did see a couple of updates in this past year. Would one of you want to maybe elaborate on some exciting updates in the field of non-muscle invasive?

Dr. Grivas:
I can start, and Vadim can comment. So non-muscle invasive bladder cancer has such a huge development of new trials. It is actually an unprecedented time to have all these trials, especially with BCG-unresponsive high risk non-muscle invasive bladder cancer. It’s really interesting to see that, because over the years, there was a stagnancy of options.

So we have seen data with SunRISe-1 at ESMO in previous meetings, AUA in other meetings. The SunRISe program evaluates the role of the TAR-200, which is this pretzel that is given intravesically by urologists once every three weeks. And that pretzel is a device that contains chemotherapeutic gemcitabine that is being diffused, let’s say, and delivered intra-luminally into the bladder wall.

And so the data for the TAR-200 given every three weeks in SunRISe-1 as monotherapy in BCG-unresponsive MIBC is pretty compelling – higher than 80% clinical complete response rates especially early on. The big question, of course, is durability of that response beyond the year. The data look compelling. This device is not approved yet, but I think it’s under review by the regulatory agencies, and I think it will be interesting to see what the data so with longer follow-up.

Dr. Koshkin:
Until really just a few years ago we had only just a couple of options for patients with non-muscle invasive disease; they would get BCG, then if they progress, then us and our urology colleagues would have the radical cystectomy talk with them. Then actually pembrolizumab was approved as systemic therapy, but it is systemic therapy. So now, it’s great actually to have a lot of these intravesical options come up as well. There are also recent approvals like IL-15, and now this, the SunRISe program, I think has been really, really interesting, and really a new way, of course, to deliver chemotherapy that’s potentially not just chemotherapy, but actually targeted agents as well.

There are other trials as well, with potential to be transformative in this space and provide additional options for non-muscle invasive disease and also in-muscle invasive disease.

Dr. Tawagi:
Absolutely. I think one of the things with non-muscle-invasive disease is that giving two years of IV systemic pembrolizumab may come with lifelong toxicity. So having these intravesical options that have more localized side effects is a great option for patients. But, of course, we need to see what the durability is going to be from these trials. So I think it’s an exciting realm of a new world in non-muscle invasive bladder cancer and in muscle-invasive bladder cancer as you mentioned. So I would love to pivot and talk a little bit about SunRISE-4 since we’re on the topic of pretzel devices.

Dr. Grivas:
Very interesting. And as Vadim said, with these advancements in non-muscle invasive disease, we can use the same platform and think about the potential impact on muscle-invasive bladder cancer. So SunRISe-4 is an ongoing study. We have it open at UW Fred Hutch, and this is a randomized study where you have the cetrelimab – a checkpoint inhibitor systemically administered – plus minus the TAR-200, that same device given intravesically with gemcitabine intraluminally, and the data we saw, it was not final data, of course, it was the early-cut preliminary data that was presented by Dr. Necchi and Dr. Psutka at ESMO.

We saw a pathologic complete response of 42% with the combination, which is interesting to me when you have cisplatin ineligible patients or those who refuse cisplatin. So this was specifically for these patients, cisplatin ineligible or refusing, 42% pathologic CR rate without giving systemic chemotherapy. A compelling result. Of course, it’s not the final result. The trial is still ongoing and accruing. We’ll have to see, of course, the durability of this benefit.

Again, pathologic CR is a reasonable endpoint in those phase two trials, but I would like to see durability and event-free survival eventually. The question is how does this fit in the context of other trials in this disease? That will be the challenge, I think.

Dr. Koshkin:
I also just want to highlight, this is a very important space. For patients who are ineligible for cisplatin-based chemotherapy for muscle invasive disease, there’s really right now no standard of care for them in terms of any sort of systemic options. We basically take them to radical cystectomy, but of course we want to prioritize clinical trials like this. And there are also a number of trials with, well, SunRISe-4 is one. There are trials of systemic agents that we’ll also, of course, discuss.

So this space I think will be transformed over the next several years. But, I mean, the SunRISE-4 data I thought was very encouraging. As you mentioned, the complete response rates of just over 40% with the combination and then downstaging, so what maybe you would consider a partial response in this setting of, I believe, over 60%. So really, I mean most patients, again, in this very challenging population, could actually benefit from this, which is I think very encouraging.

What I do wonder, and maybe I’ll pose this question as well, is for muscle invasive disease, we really want to make sure to potentially control micrometastases as well. So that’s the importance of having systemic therapy and not just the intravascular delivery of whatever drug you’re giving. So in a trial like SunRISEe-4, patients get cetrelimab. Is that enough in that sort of situation? Especially as we have upcoming trials with the EV-pembro combination; of course, the chemotherapy combinations, things like that.

Dr. Grivas:
I think this is a great question. The challenge we have in this disease and overall is a lack of predictive biomarkers that can help us select patients who may benefit from treatment A or treatment B. And obviously, we’ll have multiple different regimens being tested in clinical trials. The pathologic downstaging is, I think, a very interesting marker metric, especially in phase two trials. But the question is, how does this translate to long-term survival benefit, especially if we don’t have an adequately randomized trial? It’s hard to tease out that question.

So I think it’s very encouraging data, both in terms of the pathologic CR downstaging. And of course, the question that Vadim pointed out, can systemic checkpoint inhibitor by itself add value in cisplatin ineligible patients? Probably not, because these pathologic CR rates seems to be, in my opinion, so far, not higher compared to what we see with chemotherapy. And I think in the context of pembrolizumab and enfortumab trials that are coming, or the VOLGA trial with durvalumab plus or minus tremelimumab plus enfortumab, those trials are more likely to provide some very, very potentially high pathologic CR rates and long-term survival. So I think in the cisplatin-ineligible setting, I think the EV/pembro KEYNOTE-905 and the VOLGA trial are going to impact the future probably when the data come, of course.

Dr. Tawagi:
Absolutely. And I thought one other interesting thing with SunRISe-4 was that there was a slightly higher response in those that had incomplete TURBT. I don’t know if you have any thoughts about that. And just one point, we’re talking about predictive biomarkers and people are getting systemic therapy. I think it’s still really important for us to pay attention to these long-term immune-related adverse events. I know there was one death in the cetrelimab arm form hyperosmolar hyperglycemic coma. So I think that we still want to be very mindful in terms of giving people benign therapies that could potentially have long-term consequences.

Dr. Grivas:
That’s a great point. I think all of us are always making an effort to educate the patients about the risk of immune-related adverse events. It’s a very important reminder, Karine, as you pointed out, to have this education. After treatment, we give patients these cards or written information like pamphlets that if they have any side effects, to call us immediately, number one; and number two, if they go to any local emergency room or local provider, to show them that they’re on immunotherapy so they have full awareness of what that treatment is and what the potential immune-related adverse events can be. And I think that’s a very important point that you raise.