Introduction

DR PAL: So, I’m Dr Neil Love, just kidding! I’m Monty Pal, very nice to meet everyone here. I’m going to be moderating today’s sessions, which is titled Cases From The Community: Urologic Oncology Investigators Provide Perspectives On The Optimal Management Of Urothelial Bladder Cancer. I think you’re going to really enjoy the program. We have some really, really stellar panelists, Dr Matt Galsky from Mt Sinai, Ashish Kamat from MD Anderson, Stephen Williams from UTMB, just phenomenal, phenomenal investigators.

We do have clinicians here in the meeting room in front of us for those of you that are online. We have some networked iPads that are available. If you want to look at the program slides, you actually don’t need to wait for us to go through them; you can actually slide right through.

There’s some survey questions as well that we’d like you to take a peek at. And this is the really important part — if you want to ask a question, do feel free to type that into the iPad and they’re going to pop up on my screen here and we’ll try to tackle those as we go through the symposium today.

And please don’t forget to complete your evaluation.

Now if you’re attending via Zoom, and what I’ve heard is there’s over 200 people attending online virtually, so you have the same capabilities there. You can review all of the program slides. We’d like you to answer survey questions. Definitely feel free to be engaged with the folks here in the room and ask questions. And don’t forget to complete your slides for CME credits.

Now, keep in mind that everything that’s happening here today is going to be audio recorded and video recorded. You can watch this at any time. You can find more info on researchtopractice.com.

So, with that, we are just going to go ahead and dive right in. I have a couple of notes here on commercial support, which I’ll zip through here. These are also available in your sides. You can see all of our relevant disclosures listed. And this is, I think, really going to be a program like no other. Dr Love and his team have really worked hard to solicit a lot of opinions from folks who are in community practice or at academic centers, who have tough and challenging cases. And you’re going to get a glimpse of our treatment strategy for those as we go through the evening. So I’m going to really pick on Dr Williams and Dr Kamat, especially Dr Galsky since he’s a medical oncologist, too. A brilliant guy.

So we’ll go through a couple of challenging cases through the evening.

These are all-star panelists here. You’re going to hear from them individually throughout the course of the evening.

Available Data with and Ongoing Investigation of Novel Agents and Strategies for Non-Muscle-Invasive Bladder Cancer (NMIBC) — Ashish M Kamat, MD, MBBS

DR PAL: And with that, we’re going to get right into Module 1 here. So this is going to be available data and ongoing investigation of novel agents and strategies for non-muscle-invasive disease. We’re going to sort of take you on a continuum tonight. We’ll certainly discuss muscle-invasive disease, and we even have a focus, despite this being a urology meeting, on metastatic disease, towards the end of this discussion here.

So a quick survey question. How many patients in your practice with non-muscle-invasive bladder cancer have been treated with an anti-PD-1 or PD-L1 antibody such as pembrolizumab? You guys can take a moment to take a peek at that.

Some of these survey questions were administered prior to the program. So you can see here that there’s a number of individuals here who are still gaining experience with this phenomenon. We do have a handful that are quite seasoned with more than 5 patients in their practice receiving these therapies.

So with that in mind, why don’t we start hearing from our expert panelists here. I’m going to turn it over to our AV folks to play a vide from Dr Laura Bukavina from Philadelphia.

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome back to our real-world case library, as we did this morning in prostate cancer. And again, this evening, urologists and medical oncologists will present capsulized cases from their practice of urothelial bladder cancer, beginning with a case from Dr Laura Bukavina who has a 70-year-old man with persistent non-muscle-invasive disease after multiple therapies.

DR BUKAVINA: Standard BCG times 2 induction. Patient underwent gemcitabine and docetaxel induction. He was further enrolled into the durvalumab trial and then ended up having cystectomy. And his final pathology was TisN0.

So discussion points. How do we know that high-risk patient who’s going to potentially have recurrence of disease that’s not going to metastasize, versus the patient who’s going to metastasize? And the question really for discussion within this non-muscle-invasive bladder cancer is can we use ctDNA to sort of risk stratify patients?

DR LOVE: Dr David Taub has another case that demonstrates the clinical spectrum of non-muscle-invasive disease, an 82-year-old retired dentist.

DR TAUB: He had microscopic hematuria. He got a non-contrast CT scan. It showed a 2.2 cm bladder stone and pretty much concentric bladder wall thickening. And then I looked and there’s just papillary cancer everywhere, covering the whole bladder.

My only question for the panel is with that amount of disease, would anyone look at doing a cystectomy on that guy, rather than 3 or 4 TURBTs?

DR LOVE: Finally, Dr Paul Markowski has another case of non-muscle-invasive disease that reflects the sudden entry into this area in the last couple of years of the use of the immune checkpoint inhibitors.

DR MARKOWSKI: She was referred to see Medical Oncology because they’d now found Tis, right at her ureteral orifice. Cystectomy would be kind of the standard of care.

She’s not a great surgical candidate and she’s adamant that she doesn’t want to have surgery. We started her on pembrolizumab. This is the first time I’ve used a checkpoint inhibitor for non-invasive disease.

DR PAL: So a couple of really interesting cases there and probably a couple of pearls. I’m going to turn to my surgical colleagues first, Dr Williams, Dr Kamat, Steve and Ashish, what would you guys do for that patient that Dr Taub presented? You saw the film there, fairly extensive non-muscle-invasive disease. Are you going to subject that person to multiple TURBTs? Are you going to take them to cystectomy? Stephen, what do you think?

DR WILLIAMS: I think this is an excellent point, particularly with diffuse non-muscle-invasive bladder cancer, even though it may be a low grade, it presents itself as a conundrum of where the patient — patient risk factors, but then also, too, determining the safety and efficacy of the treatment options we have. And I think radial cystectomy in an appropriately counseled patient, having that discussion can be a suitable option.

DR PAL: Ashish, do you agree with that?

DR KAMAT: I do in some ways, but I do want to clarify one thing. If that woman had documented high-grade bladder cancer, then, yes, I would counsel the patient and consider early radical cystectomy. But we often see that picture in patients who actually don’t have high-grade balder cancer. And if it’s a low-grade bladder cancer, then it clearly behooves us as surgeons to rely upon our skill and resect all the tumor and not take that patient’s bladder out. And if it takes 2 or 3 settings, that’s fine. What I have also done is used gemcitabine and docetaxel as a chemo ablative therapy, resect as much as I can, go in with gemcitabine/docetaxel. Do the induction phase, and then go back in for a second look, allowing the chemotherapy to work.

There are prospective studies along these lines undergoing — taking place in the UK, for example, where they’re using either heated chemotherapy or combination chemotherapy purely for this sort of a situation.

So, if it’s low grade, I would do everything I can to try and save the bladder. If it’s high grade, I’m actually worried it’s invasive disease, I don’t think it’s going to be NMIBC on final pathology.

DR PAL: Very interesting. Matt, I told you I was going to save all the hard questions for you. So Dr Bukovina had brought up the scenario around biomarkers, specifically asking about ctDNA. What do we know about ctDNA? And you don’t need to confine your response to non-muscle-invasive disease. In general, does it have a role in bladder cancer?

DR GALSKY: So, yes, not a lot of data in the non-muscle-invasive bladder cancer setting yet, but certainly will be soon in muscle-invasive bladder cancer setting. ctDNA in a large, randomized Phase III adjuvant study was shown to be incredibly prognostic for recurrence and might identify patients who benefit from adjuvant therapy. And so, I think it definitely has a role in personalizing perioperative systemic therapy decision-making.

I think the particular question that was answered raises the question, can one use a combination of ctDNA in the blood and urine tumor DNA to try and identify patients who are destined for local recurrence versus metastatic recurrence. And certainly some emerging data with urine tumor DNA that suggests that it’s also a useful tool.

DR PAL: And just a really quick question for Ashish, perhaps. Any biomarkers that you’re routinely getting in this particular setting?

DR KAMAT: In the setting that Dr Bukavina presented, we actually convened the panel several years ago to look at all the markers that are available and what allows us to predict those patients that will do worse. It actually is just clinical pathological features. So the patient’s age does matter, that’s in the AUA guidelines right now. Sex matters. That’s also in the AUA nomogram. But just things such as T1 substaging — is it T1a? T1b? Is it into the muscularis mucosa? Obviously, not the muscularis propia, because that’d be T2. These are much more relevant than any biomarker currently in existence, so do biomarkers. But I would say that’s still a research tool.

DR PAL: Makes sense. Makes sense. We’re doing perfect on timing here. We’re going to segue quickly into a survey question that was asked to the audience a bit earlier and that should appear here on the next slide.

So what is the age of the oldest patient in your practice who’s undergone cystectomy? While we’re reflecting on the answers from the group over here, what’s your record, Stephen?

DR WILLIAMS: Ninety years old.

DR PAL: Ninety. Now to you, Ashish.

DR KAMAT: So, one of my patients just literally a few months ago, was in New Mexico with his grandson, took a picture that said bladderless and proud of it. Got up in a hot air balloon at the age of 98 and sent a picture to me.

DR PAL: Oh, that’s incredible. Wow! That is very cool. So it looks as though most of the audience sort of coalescences around the range of 81 to 85, or there abouts, as being their oldest cystectomy. But we could maybe dive into the details of that a little bit later.

We’re going to go through a couple of more case from Dr Morris and — actually, both from Dr Morris here, and this is quite timely. I think it will relate well to your talks.

DR LOVE: The next case was originally presented at the AUA meeting last year by Dr David Morris. The patient had BCG resistant non-muscle-invasive disease and was on a clinical trial of the FGFR inhibitor, erdafitinib.

DR MORRIS: He’s still doing great.

DR LOVE: Really? Did he have side effects?

DR MORRIS: He had mouth sores and mucositis. And so,  he’s currently on a 2-weeks on/1-week off cycle and tolerates it well. And the bladder is the best that I’ve seen it look in 6 months.

DR LOVE: Really?

DR MORRIS: So it’s very surprising to me. He’d failed everything available and really has no other options. It’s been better tolerated than I thought, once we got through the initial phases.

DR LOVE: And remind me, this is a patient who wasn’t a candidate for cystectomy?

DR MORRIS: No. He’s like in his late 80s and barely functional enough to get to the office.

He did have some phosphate issues. We had to adjust the dose.

DR LOVE: And he’s responded?

DR MORRIS: So his last cysto-bladder biopsy was benign. So he hasn’t had recurrence. We’ve been about almost a year. The TAR program is trying to move that so you can get away from some of the mouth issues because it would be erdafitinib into the bladder through the pretzel. And he’d be the perfect candidate for that sort of drug because then he’s not even having to tolerate it by taking it.

DR LOVE: Wow! Yeah, sure! That is really amazing. Putting erdafitinib in the pretzel. Wow! That sounds interesting.

DR MORRIS: We’re probably the largest accruers to their Phase II study. We had, I think, 9 people who were non-cystectomy candidates, who did the gemcitabine version, and we still have a handful of those. That’s been years ago, who are still in surveillance with non-recurrent disease.

You feed it through a catheter and it basically springs into the bladder and then folds up into a little pretzel. And it just floats on the inside of the bladder alluding drug into the lumen of the bladder. And then when you’re done, like over 3 weeks, it all dissolves out of the pretzel, you look back in with a scope, grab it, and it just kind of folds up and pulls straight out.

DR LOVE: Wow. And then you put the other one in?

DR MORRIS: Then you put a fresh one in.

DR PAL: So, we’re actually going to have a lot of discussion around the pretzel for both Stephen’s talk and Ashish’s talk. But maybe we could tackle this erdafitinib-treated patient here. Matt, what do we know about FGFR3, which is sort of ostensibly the target of these drugs, in this non-muscle-invasive setting?

DR GALSKY: So we know that FGFR mutations are more common in low-grade papillary disease, and so certainly, probably the right clinical disease state to develop FGFR targeted therapies.

While we don’t have a lot of experience treating patients with papillary disease only in the medical oncology clinic, we do have a lot of patients with metastatic disease who have tumor in the bladder who we hear the same thing, that tumor in the bladder melts away.

DR PAL: I’ve definitely had that same experience. And Ashish, I think you guys at MD Anderson are really doing a lot of pioneering work with FGFR3 inhibitors in these early settings. Can you tell us a little bit about what’s going on there?

DR KAMAT: So the thing with the FGFR3 story, like Matt said, it’s much more common in the low- grade non-muscle-invasive cancer. And because of that, treating these patients with low-grade disease where it’s not a threat to their life, it’s a nuisance factor, with a toxic agent, was really not something that took off. But in the higher grade tumors, and it’s a smaller percentage that are still FGFR3-positive, there it certainly it has a role to play.

So it’s been a little late coming in, mainly because the patient population that would have benefited the most as far as the actual mutation, was the one that would have benefited the least from a toxicity profile. Looking at higher grade tumors or metastatic patients of course, there’s a perfect place for it.

DR PAL: And what’s your advice here, as I know Dr Morris gave us this sort of global overview of how he’s managed his patient, but as you think about using FGFR3 inhibitors, other kinase inhibitors, what is your partnership like with the medical oncologists at MD Anderson? What is that shape taking so far?

DR KAMAT: We’re fortunate that we have some excellent medical oncologists that are colleagues and friends, and really bladder cancer clinics are all multidisciplinary. So, we partner completely — we don’t do ERDA, we don’t do IO therapy — my medical oncology colleagues will do that. Similarly, they don’t try to do cystoscopies. We do that. So in our center, there’s no trying to migrate one or the other. At the same time, at the AUA about 7 or 8 years ago, we were asked to hold courses for urologists that want to do this in their practice. And that’s certainly a role for urologists providing systemic therapy. I’m sure there are many in the audience here that do it yourselves. So we do have courses at the AUA for that, but since you asked me, at Anderson it’s completely handled by our medical oncology colleagues.

DR PAL: And Stephen, what’s your setup like? Are you doing some of the systemic therapy regimens on your own? Are you working hand and hand with your med oncs?

DR WILLIAMS: So we actually have — our institution has a collaboration with MD Anderson, so very much similar setting as Dr Kamat just mentioned. And I think it’s so critical, particularly with cancer, but in bladder cancer as well, is having that multidisciplinary approach, counseling. And then something that Dr Moore mentioned as well is the TAR200 device, where urologists can perhaps have a more integral role with erdafitinib placed inside of what would be deemed called the “pretzel” and we’ll get into more detail with that later.

DR PAL: Perfect. Well, before we round this section out over here, I think it’s worthwhile — we’re going to go through this a little bit later — but reviewing some of the FGFR3 inhibitor related toxicities. Matt, can you give us a quick perspective on what we should be looking out for with those agents?

DR GALSKY: So skin and nail toxicity is quite common. That can often be dose-limiting and require dose delays, dose holds. Elevated phosphorus — phosphate — is a class effect of these drugs. And usually that can be managed with phosphate binders. And we have dose modifications. And so, I don’t have a lot of patients who are stopping drug because of that. It’s more skin and nail.

DR PAL: Got it. Good reminders. Ocular toxicities, etc, those are all things we need to keep in mind with these drugs. They can be quite complicated.

So we’re going to move to the next slide here and I’m going to actually turn the podium over to Ashish who’s going to be guiding us through novel agents and strategies for non-muscle-invasive disease. Now, I just want to let all the speakers know you’ve only got 10 minutes, and I’ve got a button here, if you exceed that and you’re going to be dropped down into another world where Stephen and Ashish become medical oncologists and, oh my god, Matt’s to become an urologist. He’ll have to operate. That’s scary.

Ashish, why don’t you go ahead and take us through this.

DR KAMAT: I’m going to stand because I can’t see the screen. So again, I’m going to talk about novel agents and strategies for non-muscle-invasive bladder cancer.

If you look at the evolution of urothelial cancer therapy, again all of you in the room know this here, most of the advances were in the metastatic space. There was this explosion of IO agents in 2016. But when it came to non-muscle-invasive bladder cancer, really didn’t have anything. We only had BCG. Then we had valrubicin. And of course, pembrolizumab was approved in the year 2020 for patients with CIS that had failed BCG and had BCG-unresponsive disease.

So why was this? This was partly because of our experiences in the past. If you look at the approval of valrubicin, which was approved in 1998 for patients with BCG-refractory CIS, it was approved based on a CR at 6 months of 18%. So that by itself was low. But then look at what happens to these patients when they hit the 2-year mark. Their DFS is only 4%. So only 4% of patients that are getting this salvage therapy are actually free of disease at 2 years. And based on this, there was sort of like a reluctance on the part of the regulatory agencies to really approve any other drugs unless they came in with really strict, rigorous criteria and well-designed clinical trials.

Now, pembrolizumab was one of the first drugs to be looked at into this new paradigm of BCG unresponsive disease. So if you look at the newer studies coming out, and KEYNOTE-057 certainly was one of those, that is based on the new guidance from the FDA on BCG unresponsive disease.

Like I said, this was an open-label, single-arm, multicenter study, which led to the approval of pembrolizumab on January 8, 2020, right before COVID hit the world essentially. And this was the money slide form that paper. Essentially, the CR of these patients that were reported, this is what we presented to the FDA actually, was 40.6. and importantly, and what actually impressed a lot of us, was the duration of response. We weren’t expecting that, with a median duration of response for these patients that had responded to pembrolizumab was 16.2 months. S clearly, meeting a lot of the bars that many of the experts had set in different guidance documents that we had put forward to the FDA in which the FDA had adopted.

If you look at the baseline characteristics of patients in this study, very classic for what we see in our bladder cancer clinics: patients that have BCG unresponsive disease, essentially those that have failed an induction and 1 maintenance course of BCG, are exactly this demographic. I put the little box around the reason for patients entering the study. Most of the patients that entered the study, entered the study because they refused a radical cystectomy. Not because they were not candidates. Not because they were too old or any other reason. And again, that is what we see in our clinics. Most patients that come in that have not responded to BCG will refuse a radical cystectomy, even though that is the number 1 recommendation in every guideline, AUA, EUA, SIU, IBCG, whichever you look at.

Of course, when you look at toxicity with systemic agents, they do exist, and everyone here knows this. But I put this up mainly to emphasize to the urologists that are thinking of doing this in your clinics. When we see patients that have non-muscle-invasive bladder cancer or who have undergone radical cystectomy, if they call the clinic and they say, hey, we’re having diarrhea. Residents and fellows and nurses will say, don’t worry about it, it’s normal. It’s not when you’ve given this patient systemic agents such as pembrolizumab. So keep that in mind.

Now, pembrolizumab was the one that’s approved for BCG unresponsive disease, but of course, other agents have been looked at as well. SWOG-1605 looked at atezo. If you look at the curves and the number here, they’re almost exactly the same as were seen in KEYNOTE-057. The CR at 6 months, because this study looked at the 6 months, was 27%. But if you look at the curve and you kind of predate and postdate and look at it, the curve really just overlaps with the pembrolizumab curve. And the 12-month estimation for the CR is 48% of the patients that were a CR at 6 months.

So really, the numbers are pretty much the same.

Now, what’s next, right? WE have the activity of IO agents in the metastatic space, in the muscle-invasive space. Of course, now we have pembrolizumab approved for BCG unresponsive disease. We’re clearly looking to move these drugs into earlier disease spaces. BCG “exposed” is the term that’s been proposed by the International Bladder Cancer Group, and it’s been adopted by the FDA, to denote those patients who have not responded to BCG but don’t meet the classic definition of BCG unresponsive disease.

In this patient cohort, you need to have a control arm. So, again, for those that might not be familiar, in BCG unresponsive patients who can have a single-arm study, and that counts for registration, but if patients are BCG “Exposed” or BCG naïve, you need to have a control arm. And the control arm should be BCG because the response to BCG is 65- to 80%, depending upon which of these cohorts the patient falls into.

But clearly, we have KEYNOTE-676, which again is BCG versus BCG plus pembro in patients who have failed after 1 course of BCG. There’s Checkmate 7G8 with nivo. There’s the ADAPT study.

In the BCG naïve study, the POTOMAC study, which is BCG against BCG plus or minus durva, has finished accrual, but we haven’t really seen the reports out for almost 2 years. And we don’t know why. We just don’t know. Even when you talk to the PI, Morgan Ripray, he’s not sure why they themselves haven’t seen the data.

But there’s similar studies, the ALBAN study is with atezolizumab. And CREST is with the subcutaneous formulation of sasanlimab.

Now what’s impressive, and this slide is actually a few weeks’ old, but this is data that’s going to be presented here at the AUA, looking at CG0070 with pembrolizumab. So, CG0070 is a gene therapy that’s targeted against RB1. And it, in combination with pembrolizumab, is being looked at in patients with BCG unresponsive disease.

We haven’t in bladder cancer seen results like this to date. I mean this is overall CR rates of 88.9%. CR at 12 months is 75%. Really, very phenomenal data. Again, it’s a smaller number of patients but if this pans out — it is too good to be true —but even if it pans out at half these numbers, I think this is certainly something that will be very valuable for our patients.

Nadofaragene is a gene therapy that was developed at MD Anderson. Completed a Phase III, single-arm, multi-center, open-label study. The numbers with the gene therapy with nadofaragene, very similar to what we saw with pembrolizumab. The CR rate in patients with CIS at 3 months was 53%. And roughly half of these patients maintained that CR at month 12, to give a 12-month CR rate of 24.3%.

The advantage of nadofaragene over, say, pembrolizumab, is that it’s an intravesicle formulation. It’s given once every 3 months so it’s easier for the patient to tolerate. And the side effect profile is a lot more familiar to urology clinic: it’s more localized; it’s more dysuria; it’s frequency urgency. So, again, it’s not approved. It’s been in the hold process of FDA review for the last couple of years for reasons other than efficacy, because the efficacy data does look fairly good.

QUILT, again this slide is a couple of weeks’ old. Updated results were presented this morning at the Plenary session. QUILT is N-803, which is IL-15 superagonist fusion protein, and it’s given in combination with BCG. And when you look at the patients that are BCG unresponsive, and again this combination therapy, you can then see here that the median duration of response is close to 20 months in these patients. And the probability of being disease-free is 58.6% on this slide. This morning’s Plenary, I believe it was 60%. So clearly exciting molecules and agents and therapies that are available for our patients.

Now, of course, chemotherapy has been around forever for bladder cancer and also with non-muscle-invasive bladder cancer. There are different ways to get enhanced chemotherapy into the bladder. You can put it in a gel formulation, which is the pictorial on the left of the screen. You can heat the chemotherapy which is either with microwave or just by actually heating the solution. That’s the 2 devices on the right. And the TAR-200 is what I’ll spend a little bit on.

This is where there’s a plastic silicon stent-like device that has chemotherapy impregnated into it. I’s put into the balder and then release the gemcitabine which is the TAR-200 formulation, over a period of weeks. So you get the slow release of gemcitabine, kind of like the metronomic dosing that you do, but you get higher concentration in the bladder.

And then, based on a lot of studies that were done, dose finding, and in the pre-cystectomy population, this is the Phase IIb TAR-200 plus cetrelimab study in the patients who are BCG unresponsiveness. There are 3 cohorts essentially — 1 is TAR-200 plus cetrelimab. 1 is TAR-200 alone, because clearly, it does activity. And, of course, piggybacking on KEYNOTE-057, we’re also looking at cetrelimab alone in these patients in this overall. It’s called SunRISe-1.

EV, again as we all know, is approved for patients with metastatic bladder cancer. It’s antibody drug conjugate that targets Nectin-4 and delivers the payload of MMAE. There’s a Phase I study currently ongoing with EV as an intravesicle formulation at MD Anderson. We had the first 2 patients enrolled on this trial. And again, mechanism of action-wise, and purported — if you look at the data from the metastatic setting, clearly looks exciting.

We can’t ignore chemotherapy that’s out there. So gemcitabine and docetaxel is kind of the de facto standard in the country right now for these patients. It’s a regimen that was proposed by Mike O’Donnell. And again, you can see here that in patients that get gemcitabine and docetaxel, very high percentage of these patients are free of high-grade disease at 1 year, 58% for papillary, and 50% for CIS.

I just want to emphasize to this crowd that bladder cancer patients clearly need to be managed in a multidisciplinary fashion, whether that’s metastatic disease or localized disease. We’re all part of a team. And only as a team can we clearly make a difference to our patients.

And with that, I think I’m on time.

DR PAL: Wow, beautifully done. Well done, Ashish. Thank you.

So we’re going to jump right into some Q&A. we’re getting a lot of great questions coming in through the chat channels there. The first one actually dovetails with something that I was thinking about. So the data you presented was really compelling for CG-0070, for nadofaragene, for the IL-15 superagonist. Do you think that these agents are on a trajectory, and this is a tough question, to supplant pembrolizumab in the way that we’re using it right now?

DR KAMAT: Short answer, yes. I do think so. And that’s simply, and in some ways, pembrolizumab was the first on the scene, but they were a victim of the study design trial, right. So on the study, if a patient had a non-response at 3 months, they had to come off study. So they couldn’t get more pembrolizumab. I suspect in the real-world if you are allowed to redose these patients, the numbers would have been higher as far as the response rates and the durability. But because of that, in many centers, providers, including my medical oncology colleagues, are hesitant to recommend pembrolizumab for patients that do have other options. And pembrolizumab itself is coming out with conjugates, co-formulations in combination with CG.

So I think single-agent IO therapy is not going to be the way.

DR PAL: I see. I see you nodding your head, Stephen. I guess my question to you is, amongst these different therapies, and this is really challenging to predict between CG-0700, between nadofaragene. You’re going to talk about TAR-200, IL-15 superagonist. Based on what you’ve seen so far in terms of efficacy and tolerability, what would you suggest might potentially be a winner among these? Or is it too hard to say? I’m really putting you on the spot with that one.

DR WILLIAMS: You certainly are! No. I think it’s quite provocative. I think the combination therapy, as Dr Kamat mentioned, I think that’s going to be the key and the way to go. And I think I’ll more beautifully show this I think in the muscle-invasive bladder cancer setting.

DR PAL: Got it! I tend to agree. That’s really what we’ve done in medical oncology, right, is really sort of pair therapies with one another and really optimize impact.

Ashish, what you said about BCG was striking. And there’s certainly a very reasonable response rate associated with it. But admittedly, it can be tough for patients. Is there ever going to be an opportunity for us to get BCG out of our algorithm, or do you think it’s always going to be a mainstay? I noticed those BCG naïve trials all have that BCG control arm.

DR KAMAT: So BCG has been around forever. And the issue with BCG is that there’s a current shortage across the globe. There’s not enough BCG available. Too many patients need it in North America. Even at MD Anderson, sometimes there’s not just enough BCG to give our patients. And because of that, and this shortage has been going on since 2014, so over the last 8 years people have tried to come in with therapies to supplant BCG. And from a toxicity profile, if you look at the evolution of the toxicity profile of BCG, a lot has been recognized to allow us to decrease the toxicity profile. And a lot has been done to allow us to increase the efficacy profile.

So I guess that’s a long way of saying currently, the way we manage bladder cancer patients right now, BCG has an efficacy of 80- to 85%. And the toxicity, of dose-limiting toxicity, where we can’t get a patient to finish a full 3-year course of therapy, only 15% of patients can’t finish 3 years.

So the old historical numbers that people throw about and BCG is hard to tolerate, is not that true anymore. Things have evolved. And none of these new agents really, unless they really hit that bar of 85%, are likely to supplant BCG. Unless there’s no BCG, then you have no choice.

DR PAL: That’s a really interesting point. I wonder if that’s going to happen for us in medical oncology, as our experience with IO matures. I mean we’re definitely getting more comfortable with these agents over time. And before, everyone used to shy away from doublets and what have you. Now with nivo/ipi and other regimens, I think there’s a certain comfort level that’s being established in the community.

That sort of dovetails into a question that I had for you, Matt, which is someone in our chat here has asked. If steroids are needed while on immunotherapy, what’s the max dose that you would prescribe? And is it okay to potentially maintain systemic therapy with IO during steroid treatment?

DR GALSKY: Steroid treatment for what? Did they specify?

DR PAL: Presumably IO toxicity. But they didn’t mention which one.

DR GALSKY: So for IO toxicity — for the majority of IO toxicities, that necessitates holding IO if steroids are being given waiting for that outside effect to resolve. Tapering steroids. And then, depending on the severity of the toxicity, that determines whether or not it’s reasonable to restart a new checkpoint blockade.

So for most toxicities we wouldn’t give steroids at the same time.

There are some that we would, rheumatologic toxicity. Sometimes low dose prednisone, you can continue IO. But for most, you stop. Treat the side effect. And then consider restarting if the side effect was not very severe.

DR PAL: I tend to agree with that paradigm. I guess the risk-benefit equation changes a teeny bit in this non-muscle-invasive cancer setting doesn’t it, versus metastatic disease, Matt, where most of the treatments that we’re rendering are palliative? Do you find yourself perhaps more willing or less willing to deal with severe IO related toxicities for a non-muscle-invasive patient?

DR GALSKY: No question about it. No question. You have to weigh the risk versus the benefits based on the individual patient setting. And I think in the perioperative setting that becomes an issue as well.

DR PAL: Yeah, excellent discussion.

Novel Therapeutic Approaches for Muscle-Invasive Bladder Cancer (MIBC) — Stephen B Williams, MD, MS

DR PAL: Well, we’re going to shift gears here and our next section is on muscle-invasive bladder cancer. We’re going to talk here about the more phenomena of non-muscle-invasive disease, in fact. In the past month, how many patients did you see whose primary diagnosis was non-muscle-invasive disease? Was it 0? 1? 2 to 5? Or more than 5? And we’ve got a pretty savvy audience here. A lot of folks have seen more than 5 patients with non-muscle-invasive disease.

We’re going to pivot again to some vides here, the first from Dr Hafron.

DR LOVE: In the last case, Dr Morris commented on his experience with the use of TAR-200 in clinical trials, and I also asked Dr Jason Hafron about his experience with this interesting device.

DR HAFRON: It’s a tube and it emits a low dose of gemcitabine, that pulses gemcitabine at a very low level. And you take this tube, load it with gemcitabine, and drop it in his bladder or her bladder and it literally, once it’s implanted into the bladder, it literally curls up and looks like a pretzel.

DR LOVE: Any tolerability issues with patients?

DR HAFRON: It’s pretty well tolerated. I mean it’s pretty impressive because our first trial we did, and it was presented at ASCO, was we did T2, cystectomy-ineligible patients, and we saw a response rate about 40%.

We’ve been using gemcitabine forever as an intravesicle agent. But what these guys will say is that we’ve been using it wrong and that the 2 hours that the gemcitabine is in the bladder is not enough.

DR LOVE: While TAR-200 has shown some interesting data in muscle-invasive disease, currently there are a lot of questions about the use of immune checkpoint inhibitors in the adjuvant and neoadjuvant setting, as demonstrated by a case from Dr Hafron of a 76-year-old man with T2 disease who received neoadjuvant chemotherapy with gemcitabine and cisplatin.

DR HAFRON: The patient developed elevated creatinine to 3.49 and essentially acute renal failure. It was decided to abort neoadjuvant chemotherapy and proceed immediately to robotic cystoprostatectomy with ileal conduit and pelvic lymphadenectomy.

Pathology demonstrated multifocal, high-grade urothelial carcinoma in situ. Invasive urothelial carcinoma was not identified. Sixteen pelvic lymph nodes were negative.

My question is, in this patient who could not tolerate neoadjuvant chemotherapy, based on his pathology report, would anyone recommend adjuvant chemotherapy at this point?

Would anyone consider adjuvant immunotherapy for this patient?

DR PAL: Well, why don’t we dive right into that second dilemma there from Dr Hafron. Matt, maybe I’ll throw this to you. Matt led the way with Checkmate 274, a study looking at adjuvant nivolumab in muscle-invasive disease. And for a patient like this, they can’t get through the full course of neoadjuvant treatment, you take them to the OR. They still got some, I supposed moderately concerning features on pathology, when would you think about using adjuvant nivo?

DR GALSKY: Yeah, this comes up once in a while for patients who don’t get an adequate neoadjuvant course. But I think the dilemma is that we don’t know what adequate is because the 4 cycles that we give, it’s really arbitrary. And so, for someone who has this pathology after receiving some neoadjuvant chemotherapy, I would monitor.

I think in the era of ctDNA, maybe we can make those decisions in a more informed way. But for now, I would observe a patient like that.

DR PAL: That’s interesting. And that’s pretty much aligned with what I would do under the circumstances, too. But what about this phenomenon of further adjuvant chemotherapy? I’m not sure if there’s a great possibility of this patient getting it, but do you ever do that, neoadjuvant chemo followed by adjuvant chemo?

DR GALSKY: I don’t. I mean certainly with this patient who developed renal failure with cisplatin and cisplatin-based chemotherapy being the only perioperative chemotherapy that’s shown benefit there, there wouldn’t be a compelling reason to give a different chemotherapy afterwards.

DR PAL: Absolutely. We’re going to get into a really lengthy discussion around TAR-200 later on during our talk today, so I won’t belabor the point here. But maybe you can just give us a little preview, Stephen, of your experience with it? Tolerability profile, and so forth to date. Any thoughts?

DR WILLIAMS: So I think the tolerability, it’s very well tolerable. But particularly we’re focused, we have opened at you institution is SunRISe-2. So that’s in the muscle-invasive bladder cancer setting in those patients that are cystectomy-ineligible or -refusing. In that trial as well we’ll get into more detail. We change the TAR-200 device periodically. And in the initial studies themselves in the neoadjuvant setting, it’s approximately 50% response rates. It’s quite impressive. But also too, the safety profile has already been demonstrated.

DR PAL: Got it. And let’s flip it back to the adjuvant scenario for just a second. Ashish, envisioning that you have that same patient, didn’t make it all the way through neoadjuvant treatment, still had some residual disease, although non-invasive disease at the time of surgical pathology, what are your thoughts there around further adjuvant IO?

DR KAMAT: If the patient has non-invasive disease, I would do what Matt said. I mean I would just observe that patient. I wouldn’t necessarily even recommend adjuvant IO therapy for that particular patient.

Just going back to the question you asked Matt about chemo before and after. When Randy Millikin was at Anderson, we actually did a randomized study looking at pre- versus post-, like 2 cycles before, then cystectomy, and 2 cycles after. And the results were very comparable to giving a full course of chemotherapy beforehand. And at least in those days it seemed like the patients tolerated that regimen better, just from a chemotherapy recovery standpoint.

So if there is some reason that the patients not doing well with the chemo, we will sometimes do that, do a few cycles before, do the cystectomy, and then do chemotherapy afterwards. But again, I agree completely, you want to get the chemotherapy in first, if you can.

DR PAL: Sure. Sure. Fair enough. And cisplatin-based chemotherapy to be clear in that setting, without a doubt.

DR KAMAT: Absolutely.

DR PAL: Why don’t we go to the next slide here. We have a quick survey question, regulatory and reimbursement issues aside, would you generally include a checkpoint inhibitor in the initial management of a 66-year-old man with muscle-invasive bladder cancer who’s not a candidate for bladder resection due to cardiovascular issues?

It’s a yes or no question. And we can take a look here. About 60% of individuals actually suggested the answer to be yes here, with about 40% voting no. We’ll get some thoughts on that shortly, but first let’s dive into some more video cases here from Dr Markowski and Dr Morris.

DR LOVE: The challenge of patients who either are not candidates for cystectomy or refuse the procedure is further illustrated in a case from Dr Markowski.

DR MARKOWSKI: This 66-year-old gentleman, he had gross hematuria. Has very extensive cardiac history. So, just poor performance status overall from his cardiac history, CKD. Not somebody who’s going to be cis-eligible.

Found to have a papillary high-grade tumor. PET scan showed no distal disease, so it was a Stage II invasive urothelial carcinoma.

So this is a patient that was not a candidate for cystectomy.

One of the main questions was, what’s the best chemotherapy options along with — when doing concurrent chemo/RT in bladder-sparing approaches? So cis-ineligible patient with needing bladder-sparing approach for localized invasive bladder cancer, what other chemotherapy options for him?

Is there a role for adjuvant immunotherapy in these patients who have undergone bladder-sparing treatment? So, concurrent chemo/RT. We have patients after a cystectomy now, we are using immunotherapy, checkpoint inhibitors.  Is there still a role for patients who’ve gotten bladder-sparing approaches?

DR LOVE: The clinical questions that arise in the management of patients with locally-advanced urothelial bladder cancer is further illustrated by a case from Dr Morris, a 62-year-old man who ended up with metastatic disease.

DR MORRIS: This is a patient presenting with high-grade muscle-invasive clinical T3 because of hydronephrosis. He had a nephrostomy tube placed, and unfortunately his renal function did not improve.

So we discussed possible neoadjuvant chemotherapy before cystectomy but were concerned that he might not be able to tolerate or get cisplatin.

He had a cystectomy, T3 with positive lymph nodes, and he was evaluated afterwards for adjuvant chemotherapy.

In addition to that, he had had tissue testing from his cystectomy and was FGFR3 positive. How focused do urologists need to be on obtaining tissue testing at the time of cystectomy or even high-risk TURBTs?

DR PAL: So I’ve got to tell you, I love that second case because it’s a great segue into study that me and (inaudible) are running, it’s a Phase III trial looking at an adjuvant, infigratinib, in patients just like this who have had resection, who have residual disease, who are FGFR3-positive. So, I’d certainly think there’s probably a role to investigate trial-based options like that. But let’s just opine on that for a moment. Matt, what are your thoughts there? Role of genomic profiling in this patient population at this point?

DR GALSKY: So right now, not necessarily actionable to know that information in the perioperative setting. But because of the time it takes to get testing back and because often times tissue is not in the same location, and so you hunt it down, I do think about starting to send genomic testing for a patient who has high-risk muscle-invasive disease, thinking that I’m probably going to need that information in the future.

And then just the FGFR3 thing, I think everyone’s probably aware of this, but we talk about these things as positive or negative, but it’s actually the presence of an activating mutation in FGFR. And when we talk about positive and negative, sometimes we’re thinking about immunohistochemistry. So very different testing here.

DR PAL: Yeah, absolutely. Absolutely. And this whole premise isn’t there that FGFR3-positive tumors may be a little less immunotherapy responsive. I’ve seen some literature supporting that premise. I’ve seen some nice papers that you’ve actually produced, Matt, suggesting perhaps there’s of a disparity in IO response. Where’s the pendulum swung on that issue?

DR GALSKY: My own opinion, I think it’s p-parg gamma signaling in those luminal tumors that’s driving this less T-cell infiltrated tumor, and the FGFR3 just happens to be an innocent bystander there. So when you really look at the FGFR question, there’s not a correlation.

DR PAL: I’m curious about practice at MD Anderson, Ashish. Are you guys routinely getting genomic profiling done in this population of patients with muscle-invasive disease?

DR KAMAT: We are. But again, it’s not, as Matt said, it’s not a clinically actionable reason for that. it’s part of our protocol, tissue banking, etc. So we do it, but for the most part it ends up being a research question.

DR PAL: Stephen, is that pretty consistent with your practice as well?

DR WILLIAMS: Exactly. I think for research purposes obtaining the molecular profiling; however, not to guide clinical practice at this point until we have prospective studies.

DR PAL: But I think your points are all very well taken. It really is quite thoughtful and I think helps us on the backend as medical oncologist when we’re sort of scrambling to get some of this genomic data, to have that at our fingertips. Without a doubt.

The second case scenario — maybe, perhaps it was the first one — it’s actually, I think, quite challenging. You have a patient who isn’t a candidate for cystectomy. We give checkpoint inhibitors because we can give them. Is that the right thing to do in that setting? What’s been your practice Matt, in that context?

DR GALSKY: So I think for this patient, of course the first thing is can the patient get radiation, and that would be a standard treatment option for a patient with muscle-invasive bladder cancer who is not a great surgical candidate. And if so, then there’s a number of chemotherapy regimens that can be administered with radiation. We tend to give low dose twice-weekly gemcitabine. Certainly well tolerated in a patient population with comorbidities. So that would be an option.

The issue of adjuvant immune checkpoint blockade after chemoradiation, that issue hasn’t been addressed yet in a randomized Phase III study. That is a paradigm in lung cancer. So one would think that that could be an approach, but we don’t have data for that in the Phase III setting. There is a Phase II study that’s looked at that.

DR PAL: Got it. I’m just wondering about failures, non-metastatic failures in this context, Stephen. If you see patients who have gone through chemoradiation and they have local recurrence, are you occasionally taking these folks to cystectomy, or is that just too morbid?

DR WILLIAMS: No, I think it’s a standard protocol. We follow a particular algorithm for those patients that undergo trimodal therapy. And if they are deemed failure, but more importantly, pre-emptively, prior to starting that therapy, that is obviously a risk and counseling that we have for them. So salvage cystectomy would be obviously, an option for them.

DR PAL: And what do you tell patients about that issue, salvage cystectomy? What are some of the risks associated with that, to cystectomy up front?

DR KAMAT: Not  too many, to be honest with you. Really. So a lot of people talk about radiation therapy and say, oh, if the patient has radiation therapy the surgery is just impossible. It’s not, right. The surgery is a little bit more challenging, but it’s not something that I would tell the patient not to do radiation therapy because surgery gets that much more challenging.

The one thing the patient does lose is the option to have a neobladder. Again, it’s not 100% white or black thing, but for the most part if they’ve had chemoradiation, radiation to the bladder, then the sphincter mechanism, etc, does get to a point where that neobladder comes off the table. But the surgery itself is a little more challenging, but it’s something we do and it’s — again, it’s not a reason not to consider radiation therapy.

DR PAL: Good to know. Good to know. Very helpful. So I’m going to turn it over to you, Stephen, and walk us through the next section here on muscle-invasive approaches.

DR WILLIAMS: So thank you. I’m going to stand up as well to see my slides here. So thank you very. much for allowing me to present Novel therapeutic approaches for muscle-invasive bladder cancer.

So we’re going to dive right into the neoadjuvant setting, and particularly this is localized disease. So neoadjuvant cisplatin-based chemotherapy, and we’ll just say for fit patients.

So as we all know, neoadjuvant chemotherapy is a guideline recommended treatment. However, over the years, we’ve also noticed that the survival benefit is approximately 5% when looking at meta-analyses. And this is a radical cystectomy survival calculator that I developed with my colleague sitting to the right of me here, where we actually see in real-world evidence, and this was discovered in a large SEER Medicare cohort, validated in the Texas Cancer Registry Medicare cohort, approximately 1% survival benefit. So, this is one of numerous other calculators that are developed, but we developed internally here.

So there is opportunity to actually improve neoadjuvant chemotherapy. and there are several advantages that are described here – neoadjuvant cisplatin-based chemotherapy improves survival. It’s often better tolerated in a neoadjuvant setting, as we talked about before, than an adjuvant setting, or opportunity to administer thereof.

Potential for maximizing the impact on patient outcomes by administering the drug at the earliest point in the natural history of the disease makes logical sense. In addition, we also have tissue availability from TURBT and radical cystectomy which offer further opportunity to study biomarkers to help guide our clinical trials.

And then lastly, surrogate endpoints of responsiveness to therapy, which we’ll discuss in more detail, including pathologic CR, to enable early risk stratification to select patients who would be most likely to benefit from this additional therapy.

There are IO/chemotherapy neoadjuvant combinations for muscle-invasive bladder cancer described here. And what we’re able to describe is approximately 34% pT0 rates. However, when we look at single agents as well, that also goes down somewhat.

Phase II studies exploring neoadjuvant immunotherapies, once again these are the various studies and we’ll dive in as we describe some more studies. It’s approximately 30 to 40% pT0 rates.

And in Phase III studies here, which is important, is that these studies are largely based on cisplatin-ineligible versus cisplatin-eligible. But I think what’s so critical here is now a time more than ever that we’re exploring and diving in and seeing which of these therapies and trials to help guide further management.

There are 3 trials integrating IO in the neoadjuvant regimens here that are described. But I think it’s a busy slide, but largely these are cisplatin-ineligible versus cisplatin-eligible. And that’s critical when we’re analyzing these studies.

So there are several key unanswered questions for perioperative immunotherapy. What is the optimal schedule, duration and time to cystectomy for these regimens? Because largely these are based and guided by our prior neoadjuvant chemotherapy trials.

And what are the most accurate surrogate clinical endpoints to predict overall survival?

And then are IO + chemo, IO + IO, IO + ADCs are more effective than single agent therapy in randomized controlled trials? And can we select patients who will likely benefit form neoadjuvant IO based on a biomarker? And i would alike to argue biomarkers.

What is the best sequence of neoadjuvant, adjuvant and maintenance lines of therapy?

So this guides us into our subsequent discussion in regard to adjuvant therapy. And as Dr Pal has provided this editorial, adjuvant chemotherapy is an unmet need, I would argue as well that IO therapies and other targeted agents is a similar unmet need.

IMvigor010 is a perfect study to lead us into this segue, where adjuvant atezolizumab versus observation or placebo, looking at patients that underwent radical cystectomy or nephroureterectomy. So these are both upper tract as well as muscle-invasive bladder cancer. Particularly in patients that had, after undergoing treatment with neoadjuvant chemotherapy, ypT2 to T4a, or those patients that have persistent T3-T4 or N-positive, and not treated with neoadjuvant chemotherapy were enrolled.

And what we’re able to see here is there is no difference in disease-free survival in the intention-to-treat population. But I think what’s critical here, and Tom Powles has elegantly described, is that circulating tumor DNA portends to a poor prognosis. And this was observed both in the observation arm as well as the intention-to-treat, which could be depicted here as well.

Another study that we did mention briefly is the CheckMate 274 which is a Phase III randomized study, understanding adjuvant nivolumab versus placebo in patients with high risk muscle-invasive urothelial carcinoma.

And what we could see here is that we actually were able to see a disease-free survival as well as survival benefit in the intention-to-treat population, but really getting also DF Bjorin was recently published, also there was no difference in the health-related quality of life between those that underwent nivolumab versus placebo.

There is a paradigm shift and I think you all have witnessed as a common theme here in regard to delivery systems. And we mentioned briefly non-muscle invasive bladder cancer, now we’re moving into the muscle-invasive space. And also particularly we’ll talk more detail now about the TAR-200 device.

The TAR -200 device, as was briefly mentioned, alludes, in this case, as gemcitabine. And one could see the concentration maintains for approximately 7 days. In the proof-of-principle study, the TAR-200-101 in the neoadjuvant setting for patients that went radical cystectomy, TAR-200 was not only deemed safe and well tolerated, but had a 50% pCR or pPR.

These helped guide the current Phase III trial mentioned earlier was the SunRISe2 trial which is ongoing and accruing approximately 275 patients per arm. Those patients that are deemed radical cystectomy ineligible or not able to undergo or willing to undergo radical cystectomy, comparing the TAR-200 device which would include gemcitabine plus cetrelimab versus trimodal therapy.

And moving now into the neoadjuvant setting is SunRISe-4, which is TAR-200 plus cetrelimab versus cetrelimab alone.

So lastly, I think this is another pivotal study in regard for EV, which we described before as antibody drug conjugate, ADC directed to Nectin-4. And focusing on cohort H, which is the EV-103 Phase Ib/2 trial. These are cisplatin-ineligible T2 to T4a patients that underwent radical cystectomy and pelvic lymph node dissection, which 3 cycles of neoadjuvant EV were administered.

And the results here, although there are a limited number of patients, 22 patients, all patients underwent surgery. In addition, the pCR rates is 36%. But importantly, this is well tolerated and no patient had a delay to surgery. And this further supports current Phase II and III studies that are currently evaluating EV in the muscle-invasive bladder cancer setting.

So, this is a picture of a SpaceX hovering over Tomorrowland in Disney World. I have to 3 children, full disclosure. So with that being said, Tomorrowland is no more. We’re in a very exciting time in bladder cancer and we have novel therapeutic option approaches. Multidisciplinary care for bladder cancer is paramount. And it’s a very exciting time in bladder cancer holistically.

Thank you very much.

DR PAL: Terrific talk, Stephen. Really nicely done. Really nicely done. So I actually live not far from Disneyland, as you know, and really does seem like we’re approach Tomorrowland with all these great new strategies and treatments that we have for bladder cancer here.

So maybe I’ll jump in with a question for you, Stephen, and that is in the context of patients with muscle-invasive disease, who have variant histologies, how does this data apply? And maybe we won’t even comment on the data here per se, that might be too far-reaching. But what is your standard of care? Let’s say somebody comes in with squamous histology. Are you giving them neoadjuvant chemo?

DR WILLIAMS: So full disclosure. Dr Kamat is my mentor and I’ve done extensive work with him in regard for variant histology. So, squamous, we’ve done some prior work with micropapillary. It depends. With the pathologic reports, I don’t know if institutional dependent, but squamous differentiation doesn’t get me a whole lot hot and excited. However, if it’s pure squamous differentiation, I think that is a moment of pause and perhaps proceeding with upfront radical cystectomy for those patients that have muscle-invasive bladder cancer, localized, non-metastatic. That would be essentially my recommendation treatment of choice.

DR PAL: And since you mentioned micropapillary, maybe I’ll turn this one over to Ashish. What are you doing for those patients?

DR KAMAT: So, the thing with micropapillary, it’s a disease that’s evolved, us, and our understanding of it over the years, right. So if you look at the non-muscle-invasive space, the micropapillary tumors respond less well to BCG. That’s known. And if someone has T1 high-grade micropapillary, cystectomy is clearly the option.

If you look at the more invasive tumors, muscle-invasive tumors per se, Mario Fernandez, he’s not here, but when he was a fellow with us, he looked at our series, which is the largest series, and if you can get cisplatin-based chemotherapy into those patients, their response rate is less than the non-micropapillary, but still enough that cisplatin-based chemotherapy is worth it.

If you can’t get cisplatin, and again not that we should do carbo-based therapy, but if you do carbo-based therapy in patients with micropapillary disease, the delay in cystectomy really is horrible. So if you can get cisplatin-based therapy, neoadjuvant chemotherapy is still advisable. But anything else, straight go to cystectomy.

DR PAL: Okay, those were tough, because, as I had mentioned, I’m saving the hardest for Matt here. So what about adeno in this setting? Adeno is tough. What do you do in that context?

DR GALSKY: I mean pure adeno; I tend to recommend upfront cystectomy. If there’s glandular differentiation, then I tend not to let differentiated histology, differentiated variants influence my decisions about neoadjuvant therapy. I think those entities are so incredibly heterogeneous and they’re either heterogeneous because pathologists call them differently, or because of intratumoral heterogeneity. But I have not found in my clinical practice any consistency in outcomes in those patients.

DR PAL: Got it. Yeah, that is a really challenging scenario, isn’t it? Stephen, now I will get to Tomorrowland. So we do actually have ctDNA at our disposal and we could certainly order it in clinical practice. Have you started to do that amongst your patients with muscle-invasive disease as a means of triaging them in terms of adjuvant therapy? Or do you think it’s a little too soon for that?

DR WILLIAMS: I think it’s a little too soon now for clinical practice. Once again, from a research standpoint, we are collecting biomarker circulating tumor DNA. However, it’s not yet ready for prime time for clinical practice in my opinion.

DR PAL: Yeah, I think that’s fair. Matt, you’re leading a lot of this work. What do you think?

DR GALSKY: I’m seeing it being ordered a lot in our institution. And I think that we have to do the prospective studies to establish clinical utility or else we’ll lose the window of opportunity to do that.

DR PAL: Yeah. No, I think that makes sense. Now I’m going to bring up this age-old debate Matt, which is cisplatin/gemcitabine versus dose-dense MVAC. It’s’’ something that probably has come up at our discussions at meeting like this for the past decade or so. What are your thoughts there? What’s become your preferred regimen here?

DR GALSKY: I think it’s splitting hairs to be honest. I think we have so much in the way of novel therapies that need to be explored in this disease that we really need to move past that. We have randomized studies which show inconsistent results and aren’t adequately powered to address that specific question. VESPER didn’t do it. The SWOG study wasn’t designed to do it. It was a biomarker study but the path CR rates line up pretty well.

So I view those regimens as pretty equivalent, although I know some of my colleagues are very convinced by VESPER.

DR PAL: Yeah. Please, Ashish.

DR KAMAT: I just want to make a point. I completely agree with what Matt said. I think the bigger problem is the fact that still a large percentage of patients in the United States who should be getting neoadjuvant chemotherapy are not even getting it. So then, which agent to use? Whether it’s dose-dense MVAC, which we tend to prefer, or gem/cis, is a secondary issue, right. We need to get more patients to actually get neoadjuvant chemotherapy that should be getting it.

DR PAL: That’s a terrific note to end on.

Current and Future Front-Line Management of Metastatic Urothelial Bladder Carcinoma (mUBC) — Matthew D Galsky, MD

DR PAL: So we’re going to shift gears here now to domain that certainly still involves the urologists to some extent, although perhaps more heavy medical oncology leaning, and that’s metastatic urothelial cancer.

So we asked the audience here for a patient with responding or stable disease after first-line chemotherapy for metastatic disease, would you generally recommend maintenance therapy with a checkpoint inhibitor? Matt’s led some of this work. It looks as though, 76% in total suggested that they would, but half of those individuals only if PD-L1-positive. We do have about a quarter of individuals suggesting no.

Let’s move on here. We have a couple of great scenarios Dr Taub and Dr Hafron are going to walk us through.

DR LOVE: Metastatic urothelial bladder cancer is highly variable in clinical presentation. Dr Taub is treating a patient who had prior trimodality bladder-sparing therapy previously, but developed metastatic disease 1 year later.

DR TAUB: He was in great condition. As you know, in South Florida, 75 is pediatric sometimes. I tried to advise him that cystectomy was the treatment of choice.

His wife was really driving a lot of the decision-making, decided that they’d prefer a bladder sparing approach. He also had like an episode of AFib . His bladder cancer actually caused maybe some ureteral obstruction. So he needed bilateral percutaneous nephrostomies.

We went and got a PET CT scan and he had metastatic disease, unfortunately, to his sternum, which I have not seen too commonly. I wonder how the panel has seen that.

And then he also had, some pelvic lymphadenopathy which ultimately yielded ureteral obstruction necessitating percutaneous nephrostomy tubes.

He got subtherapeutic chemotherapy because of his renal insufficiency and so maybe also another possibility would be immunotherapy upfront. And so I wonder what the panel would think about those approaches initially.

DR LOVE: A key clinical variable in assessing patients with newly diagnosed metastatic disease is tumor bulk and symptom status. Dr Hafron’s case of a patient presenting with extensive peritoneal carcinomatosis illustrates this point.

DR HAFRON: This is a 69-year-old otherwise healthy man who presented to my office with gross hematuria and 3 months of worsening urinary frequency, urgency and nocturia. A transurethral resection was performed which showed high-grade urothelial carcinoma, poorly differentiated variant, invasion into muscularis propria.

Here is the CT of the abdomen which demonstrates abnormal eccentric wall thickening of the urinary bladder predominantly involving the right aspect and superiorly. The anterior wall, as you can see by the arrows, measured up to 2 cm.

Also in the same scan, CT of the abdomen demonstrated enlarged retroperitoneal lymph nodes, which are circled on the scan on the screen.

And finally, in the same scan, CT of the abdomen demonstrated a focus of mass-like attenuation enhancement seen in the lower peritoneum just anterior to the urinary bladder.

He’s not a candidate for surgical resection, what first-line chemotherapy would you consider in this patient?

DR PAL: Great scenarios there. I’m going to actually really bring up something that Dr Taub had hinted at in his discussion there, which is cystectomy being the treatment of choice. This always comes up. Ashish, you look you’re 25, but you’re one of the longstanding voices in  the field. I’m going to start with you though. I recently saw somebody throw up on Twitter, I’m sure you saw this, too, a retrospective analysis with propensity matching, comparing the 2 techniques. So what is the gold standard for muscle-invasive disease? How do you counsel patients around these 2 options?

DR KAMAT: So the gold standard for muscle-invasive disease still remains radical removal of the organ that has the disease in there. That being said, trimodal therapy does have a role to play, right. So it’s something you need to counsel patients on.

The counseling should go around this way, if the patient has many years ahead of him or her, the trimodal therapy will cure him or her for a short time, but then non-invasive and invasive recurrences in the bladder and symptomatic issues — bladder dysfunction, the so-called bladder cripples that end up coming to us where we have to do salvage cystectomies 5 to 8 years down the road where the bladder becomes thin like a thimble — is a real issue, right.

So the longer a patient has to live, whether it’s just being young or even if they’re older and don’t have many comorbidities, the less likely it is that the radiation therapy or trimodal therapy will provide long-term durable quality of life and control of the bladder cancer. So radical cystectomy is the standard of care there.

And of course, nowadays with orthotopic diversions, quality of life — I don’t know if you saw, but there were several abstracts presented. The quality of life as reported by the patients — I mean patients go out and win soccer scholarships, they play professional sports, having undergone a radical cystectomy. So radical cystectomy from 25 years ago when I started is totally different from the way we do it now, right? I mean it’s a lot more evolved and patients do much better with that. Does that answer your question?

DR PAL: It does. It does. Very well said, in a reasonable amount too, taking on a very, very complex topic. I appreciate that.

Maybe I’ll pitch this next one to you, Matt. He brought up, Dr Taub in his comments, the idea of IO upfront for this patient with metastatic disease versus what actually happened in this case, which was chemotherapy followed progression and then perhaps IO. How do you tend to lean in this population? That’s a very complex discussion, isn’t it?

DR GALSKY: It is, although the pendulum has swung, and I’ll share some of the data. But right now, the bulk of data does support using platinum-based chemotherapy upfront. So it swung from chemo to front-line immune checkpoint blockade, back to front-line chemo.

DR PAL: Yeah, absolutely. I definitely tend to agree with you there.

Just to round out this discussion around maintenance therapy, Matt, why don’t you just give us a quick preview of the data there in the primary study that really sort of addresses that topic.

DR GALSKY: So the concept was, that immune checkpoint blockade was initially approved for patients who progressed despite platinum-based chemotherapy. It was non-cross resistant with platinum-based chemotherapy, different toxicity profile. In the past, we used to give 6 cycles of chemotherapy and then stop because if you keep giving the same treatment you get more toxicity, but the benefit plateaus. So, that raised the logical question, why are we waiting for patients to develop progression? Why don’t we just give the immune checkpoint blockade right after finishing chemotherapy? And so, that’s called switch maintenance immune checkpoint blockade.

It was studied in a randomized Phase II study, in a randomized Phase III study, both of them met their primary endpoints. The Phase III showed a survival benefit. And that’s now become a standard of care.

DR PAL: Terrific. Terrific. Well very nice, concise overview of the principle of mt.

We asked the audience this question which is a key anti-tumor mechanism of most antibody conjugates is Immune-based? Antiapoptotics? Cytotoxic? Kinase inhibition? Or I don’t know?

A lot of folks proposing that it’s an immune-based phenomenon. Can’t disagree with that entirely. There’s certainly a cytotoxic component to it.

We’re going to jump into a couple of other vignettes here again from Dr Bukovina. And then we’ll hear from Dr Ibrahim.

DR LOVE: With 5 approved lines of therapy in metastatic urothelial bladder cancer, sequencing of these therapies is a major challenge, as demonstrated in a case by Dr Bukavina.

DR BUKAVINA: Despite receiving neoadjuvant chemotherapy he still progressed, at which point he received his pembrolizumab for metastatic disease.

DR LOVE: I know he’s on the antibody drug conjugate enfortumab now and doing well….any questions about it?

DR BUKAVINA: This is a new drug, obviously. It’s supposed to deliver treatment specifically to a cancer cell.

If you can limit the toxicity while still maintaining the benefits of this drug, who are specifically the patients that we can apply this drug earlier on? Or in combination with additional drug?

What about in the primary setting, for example non-muscle-invasive bladder cancer, are there trials, potential applications of this particular drug conjugate within those patients?

DR LOVE: Like most medical oncologists, the main questions that Dr Sulfi Ibrahim has about the management of metastatic disease relates to the sequencing of the available therapies.

DR IBRAHIM: If a patient has disease progression on platinum-based therapy and has a low PD-L1 level, would you consider giving the enfortumab prior to immune checkpoint inhibitor therapy?

Secondly, what is the status of the clinical trial evaluating enfortumab and immune checkpoint inhibitor therapy in the front-line setting? And is that potentially practice changing? 

Thirdly, if you have a patient with metastatic urothelial cancer who progresses on platinum-based therapy and you have the options of immune checkpoint inhibitor therapy, enfortumab vedotin, erdafitinib, or sacituzumab govitecan, how would you sequence these agents?

DR PAL: Yeah, a lot of loaded questions there from Dr Ibrahim. But why don’t we go to that first scenario that Dr Bukovina had described. And I’m going to borrow Stephen’s Tomorrowland analogy. Ashish, I think you gave a quick node to enfortumab in your talk. Where do you see drugs like enfortumab, sacituzumab, all these antibody drug conjugates sort of playing out? Do you think we’re going to see them migrate earlier from the metastatic disease? We’ll talk a little bit about neoadjuvant data. What about non-muscle-invasive disease? Is it going to creep up all the way there?

DR KAMAT: Yes. So I think they are going to migrate early, right. Whether they’re going to come from third, second, first, neoadjuvant, all of that – I’m sure Matt will talk about.

In the non-muscle-invasive setting, if you can deliver it into the bladder, intravesically, then potentially yes, because now you’re targeting the tumor that it’s in the bladder itself. One of the concerns we had when we’re looking the EV in the Phase I study that I mentioned, was it’s a large antibody, will it actually get to the target? And the preclinical work seems to suggest that yes, it does. So, hence the Phase I study right now.

So if we can get it in, Nectin, TOPO, they’re expressed in non-muscle-invasive bladder cancer, and if you can actually get this and deliver the payload, it’s enhanced chemotherapy essentially. It’s targeted enhanced chemotherapy.

One of the advantages we have in the bladder is that you can put chemotherapy in the bladder. You can use the pretzel or you can use Jelmyto, or you can heat the chemotherapy. Or you can give targeted chemotherapy in the form of EV or SG. So, yes, I think there’s a role for it as long as the studies show that it actually hits the target and it works.

DR PAL: That’s so interesting. Stephen, is that the future for the pretzel that we’ve been referring to tonight? Is it really going to become sort of a Trojan horse, if you will, for treatments into the bladder?

DR WILLIAMS: I like that analogy, the Trojan Horse. So I think as we evolve and we understand the utility of the concentration, much as Dr Kamat just mentioned, the sustainability to treat the tumor, I think that is the next phase, or the phase that we’re I now. I’m trying to explore the vehicle, or Trojan Horse, if you will.

DR PAL: Yeah, absolutely. So maybe we’ll shift gears to you here, Matt, and we’re going to talk about some of the data related to enfortumab in the more advanced settings and perhaps some of the future horizons for it.

But Laura had asked this question around how to sort of sequence enfortumab. And Dr Ibrahim had alluded to this as well. If you see a patient, like Dr Ibrahim had brought up with perhaps low levels of PD-L1, does that influence your thinking around offering IO following chemo, would you maybe push enfortumab sooner?

DR GALSKY: PD-L1 expression doesn’t impact my decision-making in that setting, but disease burden and disease pace will sometimes. And so, if a patient has diffuse liver metastases, very symptomatic, progressing quickly on front-line platinum-based chemotherapy, sometimes I will use enfortumab vedotin second rather than going to immune checkpoint blockade.

DR PAL: And we’ll get to some of the data associated with this, but are you ever tempted to pair it with IO in the setting? Are you able to get that from payors?

DR GALSKY: Yes. So I have done that in clinical practice, thought that is not standard of care yet.

DR PAL: Yeah, I hear you. I mean some of those settings are scary. You just don’t have the luxury of time to figure out what is going to work and when.

DR GALSKY: And that’s just it. It’s that question that you don’t have to answer the question because you could give both drugs together.

DR PAL: Absolutely. Absolutely. Well said.

Well I think what we’ll do is we’ll just jump right into the next talk here, that’s going to be from you Matt. You’re going to walk us through current and future front-line management strategies for metastatic urothelial cancer. Go and take it away.

DR GALSKY: Thank you. So it’s been hard to develop drugs in this disease. And there was about a 30-year of time where there was actually no new drugs developed for the treatment of metastatic urothelial cancer. And then around 2016 this changed with immune checkpoint blockade and there were 5 immune checkpoint inhibitors approved over a very short period of time. And those were approved in the platinum-resistant metastatic setting first. Most of them were accelerated approvals, so based on Phase II studies with response rate endpoints. And those studies taught us a couple of things. One, that these drugs did not have benefit probably because they worked in everyone, but rather that when they did work, they worked really quite well. And we see patients respond with metastatic disease to immune checkpoint inhibitors, as you all know, for years sometimes.

And that, coupled with the fact that in many patients these drugs are pretty well tolerated, that led to enthusiasm about thinking about bringing these earlier in the treatment of metastatic urothelial cancer. And the logical place to do that was in a subset of patients that we consider cisplatin-ineligible.

We know that bladder is a disease of older patients. The median age of diagnosis in the United States is 76. And lots of our patients can’t get cisplatin-based chemotherapy, which we consider the first-line treatment standard. And so, there was always this unmet need, what do we do with patients who are cisplatin-ineligible, who have metastatic disease in the front-line setting. Carboplatin-based chemotherapy was the default standard. We know that carboplatin-based chemotherapy does not have as high response rates, doesn’t have as high complete radiographic response rates. So that was a logical place next to develop immune checkpoint inhibitors.

And there were 2 large Phase II studies enrolling patients with front-line metastatic urothelial cancer who were cisplatin-ineligible. Again with response rate as a primary endpoint. IMvigor210 and KEYNOTE-052, again these studies showed response rates pretty similar to what we saw int eh platinum-resistant setting, maybe a little bit higher with response rates between the 20- to 30% range. And so, accelerated approvals were achieved for both of these drugs in the front-line setting.

And there is a confusing and complicated story about the evolution of those approvals, which we could talk about maybe if there’s any questions. But the initial approvals were all comers, metastatic urothelial cancer, who were ineligible to get cisplatin.

And moving these drugs to the front-line setting then led to a series of very logical questions. And these questions were actually being asked in other solid tumors as well.

So, is there a role to give chemotherapy and immune checkpoint blockade together? Is there a role to give upfront immune checkpoint blockade to all our patients, not just patients who are cisplatin-ineligible? Should we be using PD-L1 testing to decide that? Is there a role for switch maintenance therapy? Is there a role for IO doublet therapy? So, can we give CTLA4 blockade plus PD-1 or PD-L1 blockade?

And there have been Phase III studies now, probably more Phase III studies in metastatic urothelial cancer in the past 5 years than in the past few decades.

There have been Phase III studies asking each of these questions and most of them had actually read out by this point. I’m going to take these not in order because arguably, the study that changed practice was the one that I think many of us didn’t think was the one that was going to be successful, which is the switch maintenance strategy.

So as I alluded to before, there were 2 randomized studies, a randomized Phase II study with pembrolizumab versus placebo, and a randomized Phase III study with avelumab versus best supportive care.

The Phase III study had an overall survival primary endpoint. And you can see the Kaplan-Meier curve there — significant improvement in overall survival with switch maintenance avelumab. And that has become a standard of care.

We have longer-term follow-up data from this study, greater than 2-year follow-up data from ASCO GU, and the benefit with switch maintenance avelumab has been maintained over time. So certainly reinforces that strategy.

So what about this concept of giving front-line immune checkpoint blockade plus chemotherapy or IO doublet therapy? This has been addressed in sort of parallel clinical trials. And there has been more than 1 clinical trial asking both of these questions. And we have some of those results already.

So, chemo plus immune checkpoint blockade has become a very standard strategy in other solid tumors. In lung cancer, really became a major strategy. This was addressed in 2 Phase III studies, IMvigor130 and KEYNOTE-361. You could see the survival curves here, maybe a slight benefit from combination chemo plus IO. Didn’t reach statistical significance. And so, this did not show the benefit that we thought it might show based on what was seen in other solid tumors. Hasn’t been adopted as a standard strategy.

There are studies in the neoadjuvant setting pursing that approach. I think that might be a little bit different. We could talk about that.

So how about immune checkpoint blockade as front-line treatment versus chemotherapy? Should we be giving everyone immunotherapy and not really just cisplatin-ineligible patients? So that was suggested in 3 Phase III studies. And you can see the survival curves from these 3 studies actually look very, very similar. And the phenomenon is really pretty interesting.

What you see is that initially patients do better with chemotherapy, and then over time the curves cross. And so, this probably, in retrospect, wasn’t that surprising. Chemotherapy works in a larger proportion of patients, but it works for less long. So, it’s hard for immune checkpoint blockade to catch up initially, but then over time it catches up.

And so, because of this, because of the potential for losing patients early in the survival curve, this has not been a standard strategy to give everyone immune checkpoint blockade up front.

Should we be using PD-L1 testing to make this decision? One of the challenges in addressing this is that every therapeutic antibody has been developed with a different companion diagnostic. Some of the do testing in tumor cells, some immune cells, some both. And so, when we talk about PD-L1-positive really we have to specify the test because these tests are testing completely different things. And that really is borne out when you look at the Phase III studies looking at this question.

So 3 independent Phase III studies comparing chemo with immune checkpoint blockade is upfront treatment, and these are the analyses in the PD-L1 “positive” populations. And look at the proportions of patients that these assays identify. So, based on the SP142 antibody, 24% of patients were PD-L1-positive in IMvigor130, and 60% were in DANUBE. These tests are not identifying the same patients. And that’s why the results are different. With SP142, you actually see a bit of a benefit with immune checkpoint blockade versus chemo, but you don’t with other trials.

So this has led to the label for atezolizumab to be retained. And atezolizumab right now had a front-line indication for metastatic urothelial cancer in cisplatin-ineligible patients who have high PD-L1 expression. And that is supported in part, by this data, although this is an exploratory analysis.

Is there a role for IO doublet therapy? This is where we don’t have all the answers yet. We have 1 clinical trial — I’m sorry —so we have a Phase I/II study which looked at different dose levels or different doses of nivolumab plus ipilimumab. And in this Phase II study, it does suggest the response rate with the combination is higher than what we see with single-agent PD-1 or PD-L1 blockade.

This was tested with the durvalumab/tremelimumab combination in the DANUBE study. And this study did not reach its primary endpoint. And you see a very similar phenomena to what I showed you with immune checkpoint — with PD-1 or PD-L1 blockade alone, which is the early portions of the survival curve favor chemotherapy and then later, the curves cross.

The curves cross a little bit earlier with doublet IO, and they splay a little bit further later on, but not enough to reach statistical significance. And so, that study did not reach its primary endpoint.

CheckMate 901, which is testing that combination of ipilimumab plus nivolumab, we haven’t seen the results for yet. So potentially still a role for doublet IO therapy.

So where do we go from here? How can we improve PD-1 or PD-L1 blockade further? There are 3 really logical strategies: we could move the drugs earlier. We could use combination regimens, or we can use biomarkers to identify the patients who benefit the most.

I’m going to focus on 2 combinations that are emerging as promising. One of those combinations is combining antibody drug conjugates with immune checkpoint blockade. Antibody drug conjugates are really 2 drugs, they’re an antibody targeting a specific antigen. And so, the antigen has to be the right antigen differential we express in tumor versus normal. And then the payload that’s being delivered really has to be the right payload, has to be potent. The linker has to be the right linker so that the drug doesn’t detach from the antibody and circulation and cause a bunch of side effects.

So there’s a huge amount of pharmacological science behind the construction of modern-day antibody drug conjugates.

Enfortumab vedotin, as we’ve heard, anti-Nectin with MMAE is the payload. It’s a highly potent microtubule agent. And when you give the combination of enfortumab vedotin plus pembrolizumab, in a Phase II study with acknowledging a relatively small sample size, you see response rates which are among the highest that we’ve ever seen in a combination study in metastatic urothelial cancer.

So this regimen has been moved to multiple Phase III studies in both the neoadjuvant and the metastatic setting.

How about FGFR3 mutations and targeting those in combination with immune checkpoint blockade. We know erdafitinib has a response rate of about 40% in patients with metastatic urothelial cancers harboring FGFR3 alterations. What if we give FGFR3 targeted therapy plus immune checkpoint blockade? We see response rates that look a little bit higher than what we would expect with targeting FGFR3 alone.

So these regimens are promising, and these are being moved forward as well.

So I will stop there.

DR PAL: Fantastic. You have such a marvelous way of synthesizing these complex topics in a way that’s easily digestible in 10 minutes. That was remarkable, Matt.

A really interesting question came through that I want to get your perspective on here, and that’s a patient who has node-positive disease after getting neoadjuvant chemotherapy. Obviously, a very sort of high-risk player. So what data do you apply in that setting? Is that an adjuvant nivolumab patient, or was that patient with metastatic disease from the get-go that you consider an indefinite course of avelumab for?

DR GALSKY: So a patient who has clinical N0 disease, who gets neoadjuvant chemotherapy, wo has pathological node-positive diseases, that’s an adjuvant patient. Those patients would have been eligible for CheckMate 274. That’s a great patient for adjuvant nivo.

If a patient has clinical node-positive disease to start, that’s a little bit of a different story. And that clinical disease state has sort of been lost in the shuffle. Historically, we’ve included those patients in metastatic studies, not in neoadjuvant studies, and some of the current generation of neoadjuvant studies, N1 disease — clinical N1 disease is included, but N2 and N3 disease isn’t. And so, the optimal management for clinical node-positive urothelial cancer, it has really not been defined.

I tend to give upfront systemic therapy. Longer duration of treatment. If there’s a good response, then surgical consolidation.

DR PAL: And makes perfect sense. I was just wondering, Ashish, in these cases are you ever tempted to go back to those original scans and tease out whether or not they might have truly been sort of clinical node-positive from the get-go?

DR KAMAT: Oh, yeah. No, absolutely. You always look back and look at that. The other thing I just want to highlight to the audience, I’m sure they know this, but the N1, N2, N3 has changed over the years, right. It used to be — now it’s like a single node in the pelvis, more than 1 node in the pelvis, and anything not in the true pelvis. It used to be N3 disease was actually metastatic disease. Now it’s N3 disease. So the whole disease definition is morphing as well. And some of the older studies were designed looking at N3 being N+, right. So now they’re node-positive. They used to be N+. So just keep that in mind.

DR PAL: Absolutely. Absolutely. Well said. This is something that I think the MD Anderson group has actually paved the way on. Stephen, I know you spent some time there as well. What about FDG-PET for imaging in this context? I’m leaning mainly on conventional CT. Should I be doing FDG-PET for my patients?

DR WILLIAMS: So I think not as a primary imaging. However, patients that are deemed to have a clinically aggressive T3/T4, undergoing more than, I guess, 4 cycles of gemcitabine/cisplatin, then I would lean towards getting a PET primary to proceeding with surgery. I just happen to have a patient that we did do that, PET-negative, and then comes back N+.

So, it’s an active discussion that we have at our tumor boards that we work collaboratively with MD Anderson. So I wouldn’t recommend that as a primary imaging modality. And there’s also costs that are associated with that as well. But that’s outside of our discussion.

DR PAL: Well, I have to tell you, this is one of those situations that there’s a tone of institutional variation. And just like cis/gem versus dose-dense MVAC, if I ask around the country I’m sure I’ll get a lot of unique perspectives. I’m curious to know what you’re doing in New York, Matt.

DR GALSKY: In terms of PET?

DR PAL: Yeah.

DR GALSKY: I don’t do PET routinely. I certainly think there’s a role for PET in certain patients with metastatic disease who are having some difficulty figuring out if a new lesion is actual progression or not.

For clinically localized disease, most of the time I haven’t found it helpful. I find it confusing.

DR PAL: Right. Right. No, that’s fair. A question came up here, and I’ll try to sort of paraphrase it. I mean the design of the JAVELIN-100 study was smart. As you mentioned, there were a lot of skeptics around whether or not it would yield a positive result. Is avelumab really different from the other checkpoint inhibitors? I mean you led a study that we participated in looking at pembrolizumab in that maintenance setting, because you easily swap in pembro or atezo, your choosing of checkpoint inhibitor?

DR GALSKY: Yes. So there are some differences. It’s a PD-L1 antibody instead of a PD-1 antibody. And the actual type of antibody it is, is a bit different than the others in terms of the likelihood of ADCC, which from a clinical standpoint, whether or not that actually matters. I think we don’t know that for sure. But, yes, there a differences.

Because we have randomized Phase II data with pembro, I feel comfortable using pembro in that situation. But the Phase III data, the Level I evidence is with avelumab.

DR PAL: Yeah, fair enough. And there’s key differences. Matt, maybe you can outline for the audience some of the toxicity profile differences. You mention with avelumab versus other PD-1/PD-L1 inhibitors.

DR GALSKY: So the main difference is that there can infusion reactions at a relatively more common rate with avelumab than with other PD-1 and PD-L1 inhibitor. We just don’t see that that much with other PD-1 and PD-L1 inhibitors. And avelumab causes infusion reactions. And they’re generally manageable. But that is a difference.

DR PAL: Yeah, I tend to agree with you. I see that quite frequently, in fact.

So we’re going to go into further detail around advanced bladder cancer and we’re going to begin with a question that we asked the audience, and this really just tells you how pervasive the use of chemotherapy with checkpoint inhibitors is in multiple tumor types. We’re going to ask you the question of whether or not it’s used right now in Non-small cell? Head and neck cancer? Esophageal, Cervical, Triple-negative? All of the above?

A lot of folks, maybe not so aware of the data across these tumor types, many confident that it’s used in non-small cell lung cancer and some suggesting all of the above. Certainly, there’s a role in many of these malignancies for this, what we’ll call trimodality therapy.

But we’ll go to some vignettes here from Dr Lamar and Dr Ibrahim.

DR LOVE: The potential benefit of novel approaches to the management of metastatic urothelial bladder cancer is evident with the approval of 2 antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, and 1 kinase inhibitor, erdafitinib. Dr Zanetta Lamar has a 68-year-old man who demonstrates this principle.

DR LAMAR: This is an interesting guy. He developed disease progression in his lymph nodes, and I started him enfortumab vedotin.

This patient’s performance status, despite all of his treatment, is very good. What would you consider if he progresses?

DR LOVE: How long was he on the enfortumab?

DR LAMAR: About 7 months.

DR LOVE: And how did he feel?

DR LAMAR: Overall, he actually did pretty well. He had some mild neuropathy. I had to do a dose reduction. But otherwise, he did pretty well.

DR LOVE: Any other questions?

DR LAMAR: So, in this gentleman if he had had an FGFR mutation, would you prefer to use an FGFR inhibitor over a drug like enfortumab vedotin?

DR LOVE: Dr Ibrahim also has a patient on enfortumab who previously received first-line chemotherapy and second-line anti-PD-1 treatment.

DR IBRAHIM: She’s had approximately 4 cycles of enfortumab vedotin. Her disease is responding. She has like a scaly rash on her upper extremities.

DR LOVE: How many people have you treated with enfortumab?

DR IBRAHIM: Ballpark, 5. It's been good. I don't recall a single patient who did not respond.

This is the only case where I found significant toxicity. I generally have thought of it as a well-tolerated agent that most patients respond to.

DR PAL: Yeah, I have to tell you, I’ve been impressed just as these oncologists were enfortumab activity in my clinical practice. Maybe not a 100% response rate like Dr Ibrahim had, but consistent with the published data, around 40% or so.

They bring up a good question, and I’ll put everybody on the panel a little bit on the spot, including our urologists, and ask this question. What sort of trumps here, biology or just our clinical sequencing data? So, Matt, I’ll start with you. You have this patient who has a known FGFR3 alteration, as Dr Lamar has proposed. In that setting, let’s imagine they’ve progressed through chemotherapy and a PD-1 inhibitor. In that setting, knowing that they’re FGFR3-positive, and again, you clarified the nature of the positivity for us earlier, would you go with erdafitinib or would you go with enfortumab there?

DR GALSKY: My general practice has been to go with erdafitinib in that setting, just because a patient’s been on intravenous treatment at that point for quite some time and most of the time are quite happy to take an oral medicine. And so, I would say that’s probably the main driver of that decision point for me. I find that these drugs, at least in my anecdotal experience, are pretty non-cross resistant, and so I do feel like I could go from 1 to the other in that sequence.

From a efficacy standpoint, probably doesn’t matter so much.

DR PAL: And these aren’t patients that you’re quite yet seeing in your Urology practice, Ashish and Stephen, but I can envision a Tomorrowland state, for instance, where you see a patient who’s a candidate for biomarker guided therapy, or standard sequential therapy. Any thoughts on what you might try for decision-making? Maybe I’ll start with you, Stephen.

DR WILLIAMS: Well, I think it’s premise perhaps, of training and urologic oncology in general, is focusing on the biology of the disease, rather than the sequential as a fit. There is an FGFR mutation and proceeding with an agent that can target that.

DR PAL: And I’m just curious, not one of the audience questions here, but Ashish, you walked us through some of these amazing therapies that are in development for non-muscle-invasive disease. Anything towards biomarkers for any of those, whether it’s nadofaragene, IL-15 superagonist, CG-0700?

DR KAMAT: So there’s lots of biomarker studies that have been done and currently are ongoing. But to be honest with you, none of them actually correlate with response as well as you would think based on biology. And some of it, I mean we know this from metastatic disease and muscle-invasive disease, but the problem, since you asked about non-muscle-invasive, is the tumor sample is very small, right. I mean especially in CIS, it’s cells; it’s not an actual tumor. And then to do any of our biomarker subtyping, etc, etc, is really fraught with a lot of issues.

In fact, David McConkey, when he was at Anderson, and he’s at Hopkins now, he led one of these efforts. I think 80% of samples were just not — I mean they were doing sufficient tissue —to do any sort of biomarker study. So that’s partly why even in KEYNOTE-057, the PD-L1 status didn’t correlate at all with response. So, yes, there are studies ongoing. Yes, studies have been done. But none of them have panned out to where we can pick therapies based on the biomarker.

DR PAL: That’s a great point. I guess the type of tissue is the issue there. Are you guys leaning more, therefore, on urine-based studies, cytology-based biomarkers?

DR KAMAT: That’s Tomorrowland for us.

DR PAL: Got it. Got it. No, that makes a lot of sense. There’s some really interesting scenarios here. Matt, what’s been your experience with enfortumab? The toxicities that you’ve seen with it? Anything that you would highlight in particular?

DR GALSKY: Yes, so the dermatologic toxicity, that was brought up. I mean that’s something to know about because that can be for most patients, bothersome. But for some patients, incredibly serious. There is a rate of Stevens-Johnson syndrome with enfortumab. Unfortunately, we’ve seen patients in the ICU with enfortumab. And so, it does happen. It’s a toxicity to definitely pay attention to.

DR PAL: Excellent. We’ve got a couple of more vignettes that we’re going to run through here on the next slide. Before that, a quick audience question. What would you generally recommend as second-line therapy for a patient with metastatic urothelial bladder cancer with an FGFR somatic mutation whose disease progresses when he’s receiving avelumab maintenance after first-line chemotherapy? Enfortumab? Erdafitinib? Sacituzumab? Or other?

And it looks as those most of the audience responded in the same manner as we did here, suggesting that they would go with that biology driven approach with ERDA.

We’re going to hear next from 3 folks, Dr Prakash, Dr Malik, and Dr Gupta next.

DR LOVE: Targeted treatment is now an integral part of the management of many solid tumors, particularly non-small cell lung cancer, where a number of agents are used in first-line therapy of metastatic disease and sometimes in the adjuvant setting. Dr Chris Prakash has a 58-year-old man with extensive metastatic disease to the lung, but was also found to have an FGFR somatic mutation on NGS assay.

DR LOVE: How long ago did he start the erdafitinib? And how’s he doing?

DR PRAKASH: He’s doing great. He’s been on it almost a year now.

DR LOVE: Wow.

DR PRAKASH: Yeah. So he’s tolerating it awesome. No problems whatsoever.

DR LOVE: Did he have an objective response?

DR PRAKASH: He did. He did. Resolution of lung metastases.

DR LOVE: What questions do you have?

DR PRAKASH: In patients who do take erdafitinib, how strictly do you enforce ophthalmologic exams? And is there anything easy a clinician can do in the office to monitor the visual changes?

DR LOVE: Dr Henna Malik also has a patient with metastatic disease and an FGFR mutation, an 84-year-old woman with extensive retroperitoneal adenopathy.

DR MALIK: My thoughts were to do erdafitinib. But, of course, I did think about giving enfortumab as well. So, looking at the data for both of those of how to sequence these drugs? And then of course recently approved sacituzumab, where that plays into role as well?

I decided to go ahead and use erdafitinib because I do still believe in targeted treatment, so she’s currently on it, tolerating it well. She does have episodes where she develops some mucositis and we hold treatment for a week, but her disease has decreased. Her retroperitoneal and adenopathy has decreased in size as well.

DR LOVE: The final case is from Dr Ranju Gupta, a 67-year-old man who’s received 2 consecutive antibody drug conjugates.

DR GUPTA: I gave him at that time enfortumab. 

He tolerated it quite well. I actually started him at a lower dose because his performance status is not the best and he has lots of pain issues, and I was actually able to escalate the enfortumab. So he did very well.

I just started him on sacituzumab. So he just got the first cycle 2 weeks ago. And I have given a lot of sacituzumab in breast cancer. This was my first patient in bladder cancer. 

DR PAL: Excellent cases once again. And then just really a great segue into our last talk of this evening over here, which I’ll be giving in just a moment here.

So this is actually a question that came up during some the previous talks I’ve done with Neil Love and Research To Practice, which is, what do we do in terms of these opthal evaluations for patients on erdafitinib? It’s such a different scenario, isn’t it, across institutions? I assume that a place like Mt Sinai, you’ve got ophthalmologists onsite that you can easily refer to, or am I wrong about that, Matt?

DR GALSKY: No. I mean we have a pretty close relationship, based on the emergence of these drugs and the toxicity. So, yes, it is pretty easy to get people in. But it’s a nuisance for them. So I do think a thoughtful approach to this is reasonable.

I would say that when patients get CSR, when patients get central serous retinopathy, usually they’re telling me before they see the ophthalmologist. Their vision is blurred. So the frequency of eye exams that we get, I find that patients tell me that they’re having eye toxicity before the ophthalmologist does.

DR PAL: Got it. Got it. That’s been sort of a decision point around administering erdafitinib in some of the previous sessions that I’ve done as I’d mentioned. Stephen, what about in Galveston? Are you guys able to access ophthalmologist easily? Do you envision that being a problem?

DR WILLIAMS: No, and I think institutional-dependent. So, we have a multidisciplinary team approach. It’s not a dedicated-only cancer center. Having done training at MD Anderson though, there are access, and I’m not going to put words in my colleagues’ mouth, to ophthalmologists.

But, just because you have access, once again it’s the value to the patient. And having the time, the inconvenience, those are important consideration.

DR PAL: Yeah. I’ve had perhaps similar constraints working at a tertiary cancer center. At City of Hope, we don’t have any ophthalmologists on staff. Ashish, are you in the same boat?

DR KAMAT: We do have an ophthalmology department, but you’re right. I mean they don’t do general ophthalmology. So when you have a patient like this you want to send to them, it really disrupts their flow, too, which is why you have to be very careful about it.

Let me ask you, or Matt, you a question. I hear there are apps that allow patients to monitor ocular toxicity at home. Is that something you guys have heard of and using as well?

DR PAL: I haven’t used those. Matt, yourself?

DR GALSKY: No, we haven’t either.

DR PAL: Yeah. But I do agree with Matt and his suggestion that often times patients are bringing these toxicities to your clinic well ahead of the ophthalmologic exam. So, certainly it’s good to include in your H&P with these folks, without a doubt.

There’s a lot of stuff that we could talk about here. We’re going to go through the data for sacituzumab shortly, but why don’t you, Matt, very quickly, sort of outline for use the MOA for sacituzumab. We’ve got a lot of word soup here today, with lots of new drugs. How does sacituzumab work?

DR GALSKY: Yes. So it’s an anti-TROP2 antibody, different than the antibody with enfortumab, which is against Nectin; this is TROP2. TROP2 is highly expressed on epithelial cells — well, on epithelial cancers, rather. And the payload is different. It’s SN38. It’s a topoisomerase inhibitor, like irinotecan that we give systemically for other cancers. It’s a different target, different payload, different drug.

DR PAL: Great. Thanks a lot, Matt. So that was some good level setting.

Selection and Sequencing of Therapy for Relapsed/Refractory mUBC — Sumanta Kumar Pal, MD

DR PAL: We’re going to jump into my talk now which is selection of sequencing of therapy for relapsed/refractory disease. And I think that we’ve really driven home a lot of these topics during our Q&A sessions. Hopefully, this will serve to consolidate.

So the first thing that we’re going to talk about is the EV-301 trial, which was really the pivotal trial that now has led to enfortumab’s use, much like in the settings that we’ve described so far, in that relapsed/refractory setting post-IO.

This trial included patients with histologically confirmed bladder cancer. You could have mixed cell types as well for inclusion in this study. Keep in mind here, patients had to have prior platinum-containing regimens, as well as prior immunotherapy. And patients were randomized to receive enfortumab, or any sort of preselected chemotherapy regimen, amongst those that you see there — docetaxel, paclitaxel and vinflunine. And this is a relatively common control arm that you’ll see in other studies in medical oncology in point of fact.

The primary endpoint in this study I thought was a very ambitious one of overall survival. But as it turns out, they met that end point, as you can see here, clear separation between these curves. Median OS with enfortumab was close to 13 months, with chemotherapy, 9 months, for a hazard ratio of 0.7.

And if you look at the subset analyses across various relevant subgroups here, you’re not really seeing a lot of distinctions based on demographic factors or clinical factors. Matt, for instance, had alluded to that patient with liver metastases. You see here that the activity seems to be parallel in patients with liver mets versus without liver mets. I tend to agree with him, that if you’ve got a patient with relatively high systemic disease burden, it’s reasonable to try to sequence this perhaps a little bit earlier.

You see minor distinctions based on the primary site of tumor, upper tract versus lower tract. And this is the data as it pertains to progression-free survival versus chemotherapy. Again, this was chemotherapy du jour, paclitaxel, docetaxel or vinflunine. The PFS was 5.5 months with enfortumab versus 3.7 months for the control arm.

This, as I’d mentioned before, sort of mirrors my clinical practice with the drug. And this has been really relatively consistent in the monotherapy studies of enfortumab. You see a response rate here of 40%. You do see a CR rate; point of fact, I’ve seen a handful of those in my practice with enfortumab therapy. We’ll find out soon how durable they are. I think the data there is still fairly preliminary, but it certainly trumps the response rate associated with chemotherapy.

Now in terms of toxicity, I’m really glad that many of our commentors throughout the course of the evening had gotten to some of these points. There is a rash that’s associated with enfortumab that can be bothersome. As Matt had pointed out, you’ve got to be aware that it can evolve into more severe Stevens-Johnson syndrome. So that’s something to keep in mind.

You certainly don’t see the same rates of cytopenias as you do with conventional chemotherapy, which has certainly been of benefit.

These are the adverse events of special interest here. So this details further the rates of rash, which are around 15%. You see severe cutaneous reactions in about 5% of patients, that’s inclusive of those bereft syndromes that we discussed, peripheral neuropathy that’s severe in about 5% of patients. And this has been dose-limiting in at least a handful of patients in my hands. Hyperglycemia is another one that we can certainly discuss in our Q&A session a bit later.

We talked about a little bit about this data, EV-201, looking at the patients receiving enfortumab therapy with prior PD-1 or PD-L1-based therapy. These patients were cisplatin-ineligible.  The data here suggests a response rate, I think quite impressive, 52%. Complete response rate 20%. Pretty wild. Primary progressive disease rate, only 9%. So I thought this was fairly impressive data here.

You see here progression-free survival of 5.8 months and a median overall survival of 14.7 months. And I would certainly suggest that this was a population of patients that represented an unmet need previously.

This is the KEYNOTE-A39, or EV-302 trial as more commonly called. Dr Ibrahim had asked about this in his questions earlier. Now this the trial that may actually lad to enfortumab and pembrolizumab, really supplanting front-line chemotherapy as being the standard. So, we’re really eagerly awaiting this data.

We’re going to shift gears. Matt’s already given you some brief highlights on the activity of FGFR3 directed therapies. We’ll review some of this data now.

So this is perhaps some follow-up on the pivotal trial of erdafitinib in advanced bladder cancer. This study included 101 patients receiving erdafitinib in the presence of documented FGFR3 mutations or fusions. And what we saw in the context of the study where patients got initially 1 or 2 dosing regimens of ERDA, but ultimately this standard dose of 8 mg a day. And this describes the patient population here. You can see the extent of pretreatment in these patients, 12% were chemo-naïve, 24% had gotten prior immunotherapy.

What you see in this case is a response rate that really holds steady of what was initially reported in the New England Journal paper, the response rate was 39%.

I put this, really sort of detailed slide here that highlights a couple of elements. You can see the progression-free survival highlighted, which sits at around 6 months. You can see the overall survival highlighted there. And in the forest plot you see the analyses of response by subgroups. I’d suggest that there’s really nothing that veers too far from the median in that particular case. And what you see on the lower plot in the bottom right, and I hope you have resolution enough to see this from the back of the room there, is the onset of central serous retinopathy.

So you can see that the onset tends to be fairly early on. Fewer cases emerging as time goes on. And most of the cases are in fact, Grade 1, controllable, reversible. I found that most patients, when you identify the side effect, can ultimately recover from the toxicity.

I did want to take a moment, since we’re at a urology meeting, to talk about this agent, infigratinib. This is data that we reported out a couple of years ago. Response rate here, I would say maybe slightly lower than what you see with erdafitinib, as opposed to 40%. The response rate that we saw in this Phase I expansion cohort was 25%. And again, this trial was inclusive of those individuals who had varying FGFR3 mutations. Those mutations seem to be enriched among patients with upper tract disease. And what you saw there, and again these are limited numbers here, is a 50% response rate, 13% confirmed complete response rate, but 100% disease control rate.

And those data really inspired this Phase III which is ongoing right now. This is a randomized Phase III study. I hope you’ll consider it for patients that you might see who bear FGFR3 mutations or fusions. And this is perhaps 1 reason to consider getting genomic profiling early. If not, it’s actually done in the context of this protocol. Patients are randomized in this study to infigratinib or a placebo if they bear alterations.

This is meant to be an upper tract-heavy study, but if you do have patients with lower tract disease, they could also be subjected to this randomization.

And Matt already did the heavy-lifting of describing the mechanism of action of sacituzumab. As he outlined, it’s a TROP2-directed antibody drug conjugate. TROP2 is relatively pervasively expressed in bladder cancer.

You can see some of the patient characteristics in this 113 patient study that was reported out in JCO. You can see the prior therapies that were rendered in this cohort. Patients in this series had all gotten prior chemotherapy. You can see that a smattering of individuals had gotten prior enfortumab as well in this context. And all patients in this series, prior checkpoint inhibitors.

The data that we saw in the context of this study — I’ll go back 1 slide here — suggested a response rate of 22%. So you see here that the response rate was — partial response rate, 25%. Complete response rate, 6%. I would say this is impressive data with a cumulative response rate of 31%. Not far from what we saw with the data for enfortumab.

These waterfall plots further articulate the data that was seen in this study. You can see that 77% of patients are having some degree of tumor shrinkage. The spider plots below really do allude to the fact that there are patients who have really great disease control with sacituzumab therapy.

I’ve highlighted some of the other data on this slide here. You can see the median progression-free survival in the top left at 5.4 months. You can see the median overall survival in the bottom left at 10.9 months. The duration of response is highlighted in the top right, it’s right around 7.2 months. And some of the toxicities are highlighted here.

So remember, as Matt had suggested, the payload here is SN38, which is essentially the derivative or irinotecan. So you’re going to see some toxicities that resemble irinotecan for those of you that have used it in the medical oncology setting. You’re going to see some degree of hematologic tox, with neutropenia rates and leukopenia rates as described here that can be severe and dose-limiting. You can see GI toxicities as well, with diarrhea, nausea and vomiting. Not far afield from what we’ve seen previously in the context of irinotecan.

The TROPHY-U-01 study is 1 that enrolled multiple cohorts here. We’ve seen some of the data for combo therapy recently in Cohort 3. These are patients who have progressed on prior platinum-based therapies and received a regimen of sacituzumab in combination with pembrolizumab. The primary endpoint in all of these studies was response rate.

In terms of the demographics of this population, I bring this up here really just to indicate that this was a group of patients with fairly extensive disease. You can see that patients in this cohort had a heavy burden of liver metastases. About 29% had liver mets; 32% had non-visceral metastases in this cohort. And it was a fairly extensively pretreated cohort as well.

What you see in this context is best response to prior therapy of 2% and 1% respectively. But within this cohort, with the combo, 63% of patients had tumor shrinkage. You see a response rate of 34% here, which I think is quite impressive.

I wanted to highlight some of the data that Matt’s recently presented. We have a lot of believers in targeted therapy in the audience here, something that I actually started my studies with, and medicine was HER2-directed therapies for breast cancer. The track record in urothelial cancer for HER2-directed therapy so far has been somewhat spotty. But folks like Matt are working on bringing it back.

This is some recent data that he presented at ASCO GU, looking at trastuzumab deruxtecan. And this is in combination with nivolumab.

We’re going to focus our attention at the bottom here. And I’m really going to go over this very briefly. He looked at 2 cohorts of patients, 30 patients who were described as being HER2-high, with IHC 2+ or 3+ expression. In a separate cohort, just 4 patients with IHC-low HER2 status.

What you see in that cohort of patients who are IHC 2+ or 3+ is a respectable response rate, 36.7% in that cohort. you can see that if you were 3+ positive for HER2, and again that’s sort of a gradual scale, your response rate was as high as 63%. Again, this is with limited numbers, but it really does suggest the potential for these therapies in the metastatic setting.

This waterfall plot articulates further what we see amongst patients with highly expressing HER2 with this combination. And I’ll just point out that it’s important that you bear in mind some of the unique toxicities I’d see with trastuzumab deruxtecan. One of those is pneumonitis and that was seen in a smattering of the patients who were enrolled in this study.

So, we're going to wrap up by going through some audience questions and we’ll sort of round out this presentation within the next 5 minutes or so.

First, maybe Matt I’ll just ask you to lead us out since you’ve really done a ton of work in this HER2 space. Where is that field heading? Are we going to see a resurgence of HER2-directed therapies for advanced bladder cancer?

DR GALSKY: So I think we are. I think that as a kinase that can be drugged to inhibit downstream signaling, maybe not the right disease, but as a target for antibody drug conjugates or bispecific antibodies or NK cell-directed therapies, it’s quite a good target in urothelial cancer.

There’s a drug that’s been developed in Asia that’s now been brought to the United States, RC48. It’s another HER2-directed antibody drug conjugate. It’s already been published. The response rates with that in HER2 3+ expressing tumors are about 60- to 70% as a single agent. So that’s looking quite good.

DR PAL: And tell us about the rates of HER2 expression in this population. How often are you seeing 2+, 3+ staining?

DR GALSKY: Yeah. The challenge in urothelial cancer is that the optimal way to score HER2 expression, urothelial cancer has not really been systematically evaluated. Scoring of HER2 in gastric cancer and in breast cancer, which are 2 diseases where HER2-directed therapies are standard of care. The scoring approach is completely different based on how HER2 is expressed in the heterogeneity of expression.

So, the long answer is that we don’t know. The short answer is that I see some level of HER2 expression in probably about 60% of patients.

DR PAL: Very interesting. Very interesting. And this is probably more of a medical oncology directed question as well, so Matt I’ll ask this to you. Enfortumab, sacituzumab, we’ve got this expanding lineage of therapies for advanced disease. We toyed around with this concept in renal cell carcinoma several years ago when we had only 1 or 2 TKIs. Do you see patients ultimately cycling back to these therapies over time?

DR GALSKY: Cycling back to the same?

DR PAL: For instance, if they got enfortumab a couple of treatments ago, if you will, would you perhaps offer it in the 6^th or 7^th line setting if they had a good response previously?

DR GALSKY: I think for antibody drug conjugates, that’s a particularly interesting question. Because at a high level you can think about 2 major mechanism of resistance: downregulation of the antigen or resistance to the chemotherapy moiety. And if it’s downregulation of the antigen and that’s because of intratumoral heterogeneity and you eliminate that clone or you decrease that clone, but then it starts to grow back when you stop that drug, then, sure, that would make sense. So I think it’s a reasonable thing to try as we have more of these tools in the clinic.

DR PAL: That makes sense. I’m curious about how that concept would pan out for non-muscle-invasive disease, Ashish. Maybe not in the same context; we’re not quite there yet. But could a patient presumably go to pembrolizumab and then CG0070 and then nadofaragene. Are any of those sequencing studies being looked at currently?

DR KAMAT: Yes and no, right. Because one of the things we have to remember, when you are dealing with metastatic disease there’s a shorter timeline that you’re looking at. And it’s curative or palliative. But you have a shorter timeline.

When it comes to non-muscle-invasive disease, if it’s BCG-unresponsive, because BCG is still the standard of care with a very high response rate, we’re working with a window of opportunity beyond which you could have metastatic disease. So there’s a certain finite amount of time. There’s data from our center, from Memorial, plus data presented here, that you can miss that window of opportunity.

So one of the dangers that I see is of patients cycling through endless trials of a particular therapy directed towards their bladder tumor, but then they end up with metastatic disease. And that happens even now, right. So, unless we have a true rationale for sequencing therapies, that’s a little bit of a dangerous, slippery slope for our patients.

DR PAL: Got it. Got it. So Stephen, just building on what Ashish said, are we looking at maybe a future state or Tomorrowland where there’s multiple pretzels? I love pretzels. Could there be a salted pretzel, a white chocolate pretzel and a dark chocolate pretzel, all in the bladder at the same time?

DR WILLIAMS: I think it’s an excellent point, but also it’s a point of caution and equipoise. You have to make sure that we’re trying to prevent in the muscle-invasive progressing to muscle-invasive bladder cancer and/or metastatic disease. So it has to be approached with caution.

I think it’s very intriguing, particularly with the TAR-200 device and installation of gemcitabine, as well as a number of other potential novel agents now that we have at our disposal, but it needs to be rigorously evaluated. And them ultimately, hopefully, preserving bladder-sparing options in this setting is ever more critical.

DR PAL: Matt, Stephen, Ashish, great, great conversation this evening. I want to thank everyone for attending. And certainly to get your CME credits, do fill out the surveys before you head out of the room or sign up for the program online.

Thanks again for coming out this evening, and enjoy the rest of the meeting.