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Sam Chang: Hi, my name is Sam Chang. I’m a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center. And we are quite fortunate to have one of the true leaders in GU Medical Oncology, Dr. Daniel Geynisman, who is associate professor at the Fox Chase Cancer Center. He actually is their chief of the division of GU medical oncology.

And he is going to give an update. He and his colleagues at Fox Chase truly have been some of the leaders in utilizing a perioperative kind of treatment regimen in an attempt to really see if we can obviate the need for cystectomy for some of our patients after they undergo systemic therapy. So I'll have Dr. Geynisman give an update and details. They had a recent JCO article on their trial. And so thank you very much, Dr. Geynisman, for spending some time with us. And we look forward to your presentation.

Daniel Geynisman: Oh, sure, thank you. Thanks, great to be here, Dr. Chang, and really happy to share some of our work. So I want to share this update, really, on behalf of all the investigators. And even more than listed here, you can see in the bottom right, we did recently publish this in JCO, our phase II trial of risk-enabled therapy after neoadjuvant chemotherapy for muscle invasive bladder cancer.

And really, the idea before we go into the design is, I think, familiar to most listeners, which is that patients with muscle invasive bladder cancer have a huge degree of morbidity as part of their treatment. Not only are we giving them chemotherapy; they’re then undergoing a cystectomy, which is life altering. And although, certainly, we can, for the most part, preserve quality of life, it certainly would be nice not to undergo a cystectomy, or even undergo trimodality therapy, which can have some long-term consequences to the bladder.

So really, way back in, I guess now, 2015/2016, our question really was, can we appropriately, in any way, select patients with muscle invasive bladder cancer who we do not need to give chemoradiation, or for whom we don’t need to have a cystectomy, while, of course, preserving key oncologic outcomes—disease-free survival and overall survival?

And really, what that turns into is a question of, can we find patients who are great responders to neoadjuvant chemotherapy, who then we know are destined to have wiped the T0 disease at surgery? But if we had a crystal ball, can we then avoid cystectomy? And this was attempted in the past. There was a SWOG trial published in 2009 that tried to do this with chemotherapy. That was stopped relatively early because there were patients who were recurring and who actually ended up having muscle invasive disease, who the authors predicted would not.

But what our group has worked on as well, and really led by my colleague, Betsy Plimack, was looking at some DNA damage repair gene mutations and their association with YPT0 status. And what she showed in several trials and several data sets is that mutations, such as ones in ATM, or RB1, FANCC, and ERCC2, seem to really predict for an excellent response to neoadjuvant, cisplatin-based chemotherapy that seemed to select patients for YPT0 disease. And we know, clearly, from multiple data sets, that patients with no residual disease at the time of cystectomy are the ones who have excellent long-term outcomes. For the most part, they do not recur. And so we said, OK, can we find these patients before a cystectomy and then spare them that cystectomy as a result? And so that was really the design of RETAIN 1.

And so what you can see here is that patients would come in with a TURBT—that’s their TURBT number one—and they would all receive three cycles of accelerated MVAC, standard-of-care neoadjuvant cisplatin-based chemotherapy. And while they’re getting that, their tissue was sequenced (it was done by Keras) for one of these four mutations. And by the time they were done with chemotherapy, we would have a result of this. And those patients that would have a mutation in one of the four genes would then undergo a TURBT number two, and if at that time they had no residual disease—this was, by the way, done systematically, not a random TURBT, but it was systematically mapped—and if they had no residual disease and they were mutation positive, they were allowed to go into this active surveillance arm.

Everybody else—and there’s a lot of information here—was really recommended to receive some form of treatment. And because this trial was a bladder-sparing approach trial, in the spirit of that, we allowed patients to have intravesical treatment for non-muscle invasive disease, or chemoradiation, or cystectomy, depending on how much residual disease they had. And that’s the four different categories that you hear.

It’s important to point out, although it may seem like this is a randomized trial, we were not randomizing patients. They were not randomized before between the four groups. Everybody went through the pathway. Everybody could go on to active surveillance. And then we had a benchmark that we were trying to hit for the group in its entirety. So the primary endpoint was metastasis-free survival at two years for the entire group compared to historical benchmarks, with the idea that if we can mimic the historical benchmark where everybody would get a cystectomy and we can then spare that cystectomy for a proportion of these patients, then that’s a win. We’ve spared some patients the morbidity and the long-term consequences of a cystectomy.

And so what we then found is that we had quite a few patients sign consent. I have to say, this approach, as I think we can imagine, was quite popular. I mean, patients wanted to participate in this trial. They wanted to participate in the follow-up trial to this, which is actually also now completed and will be presented initially at GU ASCO next month. This was a popular approach.

There were some who weren’t eligible or not evaluable, usually because they only were able to receive one cycle of MVAC due to some sort of side effects. And in the end, we had 70 patients in the intent-to-treat population. And you can see how this breaks down, where 45 were mutation negative or had some residual disease, and then 25 were mutation positive and had absolutely no residual disease, the best that we could tell. And those were the per-protocol active surveillance group.

And you can see that, obviously, the patients who were mutation negative or had residual disease, many had definitive therapy, whether that’s a cystectomy or chemoradiation. Some did have intravesical therapy—remember, that was allowed on the trial. And then there were some patients that went on to active surveillance, even though they were not true per-protocol active surveillance, because that’s what they chose. They had their minds set on active surveillance, and it was somewhat difficult to dissuade them, even if that’s not what we recommended.

And this is the swimmer plot of all 25 patients who went on to active surveillance. And you can see the various classifications of what happened to them by the dots and their color. You also see the mutations that they had on the right. And we did allow both pathogenic mutations and VUS mutations to, again, mimic real-life scenarios.

And I think the few things I want to point out is, number one, there were patients who went on to active surveillance, have remained on active surveillance, have never had a recurrence, and have kept their bladder. So, for example, patient number 24 here is a good example. There were also quite a few patients—and we’ll touch base on that again—who developed non-muscle invasive bladder cancer as their recurrence or as their first recurrence. And some of those patients, unfortunately, even if they ended up having a cystectomy, went on to develop metastatic disease. And patients with metastatic disease are the ones in red. And there were quite a few of them here. And there were certainly quite a few patients who also ended up having cystectomy anyway at the time of recurrence. So this approach, certainly, just even by looking at the swimmer plot, one can immediately see is, I would say, nowhere near perfect and needs refinement. But there are some patients who truly benefit and continue to benefit as we speak today.

This is the Kaplan-Meier curve for metastasis-free survival. And this is divided into the active surveillance group and the non-active surveillance group. You can see very similar curves. And so you can see our primary endpoint was approximately 24 months, so right around here. So we’re slightly below 80% metastasis-free survival at two years, and it plateaus here, although, obviously, there is some censoring. Here is the overall survival, which looks pretty good. You can see it’s a little bit better for the active surveillance group than the non-active surveillance group. And that makes sense, because the active surveillance group are already selected patients. They’re patients who seem to be free of disease after neoadjuvant chemotherapy; they had some mutations that probably predict for a good response. But in either group, the overall survival for this muscle invasive bladder cancer group is quite good. The other caveat I’ll put in here is that the majority of these patients were, really, the best that we can tell, clinically T2 patients, who were stage II patients. There were very few stage III patients here. And really, that’s sort of all I wanted to show in terms of the slides. And we can probably talk more about it as we discuss this.

Sam Chang: Dr. Geynisman, that was fantastic. It gives us, honestly, probably a real-world attempt of trying to identify the patients who are most likely to be able to safely retain their bladder. And I think what we’ve learned is that we’re not yet perfect on being safe—which I think, incredible kudos to you all in mapping out this strategy. Tell me, what are you all’s next steps in terms of—is it changing the mutations you identify? Is it going to be changing the neoadjuvant protocol?

Tell me, this is such important work because now we have all these trials looking at perioperative systemic therapy that combine therapies but really have, in the middle of it, bladder removal. This is an attempt, obviously, to obviate that. Tell me, what are you all’s next steps?

Daniel Geynisman: Yeah, no, that’s a great question. This is really a first step, I think, in a journey to try to refine this approach. And I think I didn’t write it there. But I would say that, as we speak today, at least as of our publication, 46% of active surveillance patients were still alive and without metastatic disease and with their bladder intact. They may have needed some intravesical therapy, but otherwise, their bladder is intact. They weren’t radiated. And they’re alive.

So because of that, I think there is a significant push to refine this approach. How do we make it better? Because, really, patients love it. They want to do this. And I think you hit on some important points, I think, all of which are correct. First of all, our systemic therapy has to be better. And we’ve already seen steps towards that.

Dr. Galsky published a trial in Nature Medicine where he utilized gemcitabine, cisplatin, and nivolumab—so immunotherapy combined with cisplatin-based chemotherapy—and I think had very promising results in terms of patients who were identified for active surveillance, remained on active surveillance without recurrence, where I think the immunotherapy, both neoadjuvantly and adjuvantly, helped.

We just finished RETAIN-2. And as I mentioned, it will be presented next month at GU ASCO, where we combined MVAC with nivolumab. Nivolumab was just given in the neoadjuvant setting. But I think those results will also be interesting to look at.

And then, as, of course, everybody knows, the new standard of care, I would say, for systemic therapy in the metastatic setting is using enfortumab vedotin with pembrolizumab—a very active combination. And there is a trial also led by Matt Galsky that is going through the Hoosier group that will explore that combination within this approach. So hoping to have even better systemic therapy, so you really, truly, eradicate all the disease. That’s number one—better systemic therapy.

Number two is, I think, we have to try to do better imaging. So, for example, using MRI to image the bladder and try to be a little bit more precise than the CAT scan, and using bi-rads imaging. Dr. Nechi from Italy has really been pioneering that work. And I think that will be important.

And then I think what a lot of us are excited about is some sort of a combination of ctDNA and urinary DNA from tumors to try to really identify those patients who are at the lowest risk, who may not have any ctDNA and are not shedding any urinary tumor DNA, to maybe help us select the cream of the crop.

Part of the problem is, if you look at the current data, the sensitivity of all of these approaches is not great. So individually, none of them, including the mutations (which, actually, we didn’t talk about, but we did not find, actually, to be that helpful and that predictive of finding the right patients), none of the approaches in and of themselves are perfect. I think it’s going to be the combination of all of them—better systemic therapy, looking at ctDNA, looking at the urine, really doing a good job with mapping TURBTs, where urology is critical.

And also understanding—and this is one of the things, I think, that we learned—which is that if you’re going to put somebody on active surveillance and that patient recurs in the bladder, we take that extremely seriously. I think that patient, unless there’s something otherwise known, really should go to cystectomy. A lot of the patients who develop metastatic disease in our trial first recurred in the bladder. Because they were already in that paradigm of preserving their bladder, really wanted to preserve it, we tried to do everything for that to happen. And I think, unfortunately, some of these folks didn’t recover with metastatic disease and potentially could have been saved by an immediate—I'll call it maybe salvage—cystectomy. So I think it’s important to consider that as well. So I think all of those things.

Sam Chang: That multifactorial process you said, I think, is going to be essential for all those different reasons that you outlined. And I did notice—and I was going to ask you, I’m glad you brought that up—if you looked at your swimmer’s plot, as you stated, there were several with non-invasive disease in the bladder that you look at an extended period of time, and then they develop metastatic disease.

And clearly, that extended period of time, you all were doing everything you could to save their bladder. That would have been everybody’s attempt—intravesical therapies, whatever, repeat TURs. But it’s interesting because I feel the same way: I think unless it’s very superficial, very small…but even then, that recurrence, that’s a hint of things still lurking inside the bladder. And it goes to your point of we’re not so good with—yeah, we’re trying MRI, we’re trying blue light cystoscopy, we’re trying all these things to try to really evaluate.

But man, that bladder is not an easy—it’s not like inspecting your pinky. It is three-dimensional. It moves. Volume affects it. That’s what makes it, obviously, really, really complicated.

Daniel Geynisman: Exactly. And that’s why I think, when we have these discussions, one of the first things I say is, this is not a standard of care. If you’re a patient who wants to participate in this, really should try to look for a clinical trial. I would not recommend this at all in the community to start doing this. It’s just not ready, I think, in my opinion, for prime time. And very close surveillance, very regimented surveillance is important. And so those things are just hard to do.

And as you said, Alex Kutikov, he really is working on developing and did develop these bladder-mapping, very specific approaches. And he showed very well that you can look at the TURBT and things look great. And then at the time of surgery, there’s all of this disease lurking submucosal.

Sam Chang: 25%, 26% of the time, they said. All of a sudden, there’s stuff that you never would have appreciated.

Daniel Geynisman: Exactly.

Sam Chang: And these are expert—yeah, I mean, that data was always quite sobering for us. Because everybody—yeah, we really wanted to catch that things look really good. And so, I think that point is really good. And a point that will be difficult to measure but will be so important for these trials is the TUR and how much residual disease is there really versus not, multifocal versus not? So I can see, as you all put this together, there’ll be basically an algorithm of all these different risk factors that you’ll need to take into account. Because clearly, the multifocal high volume is different from a small T2. So it’s the heterogeneity, not only of the cancer itself, but of each patient, that is a difficult point as well.

Daniel Geynisman: Yeah. And from the data from New York, from Columbia and Memorial, we know some of these folks who, even in the past, simply after TURBTs refused to go on to cystectomy. Some of them do really well and—

Sam Chang: Survive, yes.

Daniel Geynisman: Yeah, never recur. So how much is our neoadjuvant chemotherapy pushing the bar up? Is this really a natural history of what we’re showing? So before, again, this becomes prime time, you really have to prove, I think, that you’re making significant gains here and you’re doing it safely. That’s key.

I mean, because as clinicians, obviously, everybody feels terrible if you think that you could have saved somebody. And because of some approach, the recurrences otherwise wouldn’t have occurred, especially when somebody has metastatic disease. Although I’d say on the flip side—and there’s a couple situations like this that happen—where we give neoadjuvant chemotherapy, we start active surveillance, and almost immediately, somebody develops metastatic disease. Well, those are patients who we actually wouldn’t have helped at all with the cystectomy. They would have gone to a cystectomy normally, and exactly the same thing would have happened, and we wouldn’t have helped them at all. So there’s a flip side to this. And how you thread the needle there, we just need better approaches to do that.

Sam Chang: No, that’s a really good point, both sides—that undertreatment versus overtreatment versus the treatment where we would have made zero difference. Just as you said, from a surgical standpoint, if somebody develops metastatic disease three weeks after cystectomy, the cystectomy did nothing. Now, all we’ve done is delay future care, as they recover from their cystectomy.

So now, I think that with this disease process clearly life-threatening, clearly, though, we have so many more alternatives to consider than we did a decade ago and definitely compared to 20 years ago when I started doing all this as well.

Dr. Geynisman, thank you so much for spending some time with us. And thanks to you and all your colleagues at Fox Chase. The surgeons, the med onc staff, the rad onc staff have really, really become leaders in this area of evaluating and treating in both neoadjuvant and adjuvant type settings. So we look forward to the presentation at the 2025 ASCO GU and for more publications as well.

Daniel Geynisman: Yeah, thanks for that opportunity. Yeah, I think we have a great community, I think, in urothelial cancer and bladder cancer—really trying to push the envelope, and really trying to improve care and lives for all our patients. So I think it’s a really—it takes a village to do this.