Ashish Kamat: Hello everyone, and welcome again to UROToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology at MD Anderson Cancer Center. And as always, it's a distinct pleasure to welcome to our forum, Professor Matt Galsky and Neal Shore. And I want to thank both of you again for taking the time. Really, having you both on for our Bladder Cancer Center of Excellence is so educational for folks, not just in the US but across the globe, who really can't otherwise access the latest and greatest information.

So Matt, you're going to teach us about immunotherapy for bladder cancer, focusing more on advanced disease. And then Neal, I'm going to pick your brain on the earlier stages of disease, and practical tips for our colleagues across the globe that want to adopt this in their practice. If that works for both of you, Matt, take it away.

Matt Galsky: Sounds good, and thanks for having me. So I'm going to talk a little bit about immunotherapy for bladder cancer, and provide some updates. I'm going to run through the material pretty quickly. But in 2023 at the ESMO meeting, things really changed for the treatment of advanced bladder cancer in terms of the role of immunotherapy, specifically immune checkpoint blockade. But prior to ESMO 2023, in the years leading up to that, there were a series of Phase III studies in the metastatic urothelial cancer setting that taught us some really important lessons. And I think it's important to recognize that there were probably more Phase III trials done in this space within about a five-year period of time than there had been in the past couple of decades. So lots of important lessons here, and I think we're still learning from these studies. Essentially, the lessons that we learned were that single-agent immune checkpoint blockade for metastatic urothelial cancer is probably not an ideal strategy. It's hard to define a population of patients for whom that's the best approach. When those drugs work, they work really, really well. But it's hard to determine beforehand which patients are going to be the ones who benefit the most.

Early second-line treatment does seem to work well, and that's the switch maintenance strategy. So starting with platinum-based chemotherapy, switching immediately to immune checkpoint blockade after four to eight cycles of platinum-based chemotherapy was a strategy that worked pretty well and led to an improvement in survival. It became a new standard treatment for several years until ESMO 2023.

Combining CTLA-4 blockade and PD-L1 blockade, the jury's still out a little bit. The data that's come in from Phase III trials so far does not support a dual immune checkpoint blockade strategy in urothelial cancer. There's still one study that we're waiting for the primary analysis. And then combination platinum-based chemotherapy plus immune checkpoint blockade as an overall strategy just hasn't really worked that well. And this was a bit of a head-scratcher because this is a strategy that's worked in virtually every other solid tumor where it's been tried. You take the chemotherapy that's been used for several years, you add immune checkpoint blockade to it, and improve survival. And we didn't see that with platinum-based chemotherapy and immune checkpoint blockade. There were a bunch of potential reasons for that. One of the reasons that was both practical and scientific is that the prior trials in IMvigor130 and KEYNOTE-361 that combined platinum-based chemotherapy and immune checkpoint blockade used either cis or carboplatin, depending on what a patient was eligible for. So it was mixed populations of patients. There is data suggesting that cisplatin might have specific immunomodulatory effects versus carboplatin. If that data is true, then perhaps adding immune checkpoint blockade just to cisplatin-based chemotherapy would be the ideal strategy. And we have a Phase III study that tested that, CheckMate-901. You can see the schema here on this slide. And this study showed an improvement in overall survival and has now been approved by the FDA as first-line treatment for metastatic urothelial cancer. This was presented at ESMO 2023 and subsequently published in the New England Journal of Medicine.

The other study, here's the progression-free survival data. Again, a benefit with adding immune checkpoint blockade to gemcitabine plus cisplatin. And you can see the response rate data, and you have almost doubling of the complete clinical response rate. So not only a higher frequency of responses but an increased depth of responses.

And here's the adverse event profile. And what you see when you combine chemotherapy and immune checkpoint blockade is not necessarily synergistic toxicity, but you see the individual side effects of both of those components of the regimen. So the other study presented at ESMO 2023, of course, is EV-302. These studies were presented back to back, so I think it's important to take a step back and realize what happened at that meeting, from a medical oncology standpoint or just from an oncology standpoint. So two back-to-back presentations, the first presentations to improve outcomes compared to platinum-based chemotherapy as front-line treatment for metastatic urothelial cancer in 30 plus years. Presented back to back in the same meeting, both published in the New England Journal of Medicine, both now approved by the FDA. So EV-302 compared enfortumab vedotin plus pembrolizumab. So antibody drug conjugate plus PD-1 blockade, versus platinum-based chemotherapy. This was an all-comer trial rather than CheckMate-901. So patients on the chemotherapy arm could get gem-cis or gem-carbo. Here's the baseline characteristics. Pretty typical for a front-line metastatic urothelial cancer trial in this day and age.

And here you see the primary endpoint, overall survival, marked improvement, hazard ratio of 0.7. If you break out the patients who are cisplatin-eligible or cisplatin-ineligible, it doesn't matter. The effect size is almost identical. EV plus pembro versus platinum-based chemotherapy, response rate very high with this regimen. You can see here, an overall response rate of 67% with EV plus pembro, and a complete clinical response rate of almost 30%.

And here you see the adverse event profile, and the adverse event profile is different with EV/pembro versus chemotherapy. There are distinct side effects with EV, distinct side effects with pembro, and those are mostly non-overlapping with what you see with chemotherapy. So with EV plus pembro, a rash is something that we look out for, peripheral neuropathy, itching. Immune-related side effects, hyperglycemia, etc.

The traditional paradigm in oncology is first you test something in the advanced setting and then move it earlier. And immune checkpoint blockade has, of course, been moved earlier. It's been moved to the non-muscle invasive setting. We're going to hear more about that later. It's been moved to the adjuvant setting in muscle-invasive bladder cancer. And now we have three Phase III trials that tested adjuvant immune checkpoint blockade. All of these were designed quite similarly. So high-risk patients after radical surgery with muscle-invasive urothelial cancer. You could read the eligibility criteria for the trials here. They were virtually identical in these three studies.

Here's the IMvigor010 study, which did not meet its primary endpoints.

And here is the CheckMate-274 study, which did meet its primary endpoint of an improvement in disease-free survival in both the intent-to-treat population and in patients with high PD-L1 expression.

Here's the overall survival data. This is interim data presented for the first time at EAU this past year, showing a similar effect on overall survival, which is a secondary endpoint, as has been seen with disease-free survival.

And here's the AMBASSADOR study, an Alliance study, NCI-supported study, with pembrolizumab in this setting. Also meeting its co-primary endpoint of disease-free survival, not yet showing a survival benefit, but the data is not yet mature.

So how can we improve on this? Well, one way is trying to define which patients need adjuvant therapy, because we know that many patients are cured with surgery alone. Circulating tumor DNA is a prime candidate for that, particularly tumor-informed ctDNA testing. We know in the IMvigor010 study with adjuvant atezolizumab, that if you retrospectively look at patients who had detectable ctDNA after surgery, they seem to be the patients who derived benefit from adjuvant immune checkpoint blockade, not the patients with undetectable ctDNA. So that is being prospectively validated in the IMvigor011 study, which is shown here.

And we're taking a slightly different approach in the United States within the US Cooperative group system. This is the MODERN study, and this study is enrolling patients after cystectomy. Depending on if their ctDNA is detectable or undetectable, they're randomized to an escalation strategy or a de-escalation strategy.

So of course, immune checkpoint blockade can be associated with side effects, and the side effects really can mimic autoimmune diseases of virtually any organ. So just a few take-home points about immune-related toxicities.

One is that there are some typical time courses for the emergence of different organ system involvement, but these side effects can really happen at any time, so it requires vigilance.

The first step is to determine the severity of the toxicity. And this is graded based on reproducible scales that have been used in the context of clinical trials developed by the NCI.

And then to act upon that, and there are several resources to inform the management of immune-related side effects. ASCO as most, it's the NCCN. All of these produce really great detailed publications in terms of managing toxicity.

This is a very general management scheme. If symptoms are mild, we usually continue treatment but watch really closely. If symptoms are getting more severe, then we hold treatment and we think about steroids. More severe than that, stop treatment, start steroids. And then more severe than that, stop treatment and don't restart treatment and start steroids or other immunosuppressive therapies.

And again, ASCO guidelines, really detailed information. First, define the side effect, perform a diagnostic workup, grade the severity, and then identify the treatment, and inform whether or not it is going to be safe to re-challenge that patient with treatment.

So immune checkpoint blockade clearly has changed the landscape, and things are moving earlier and earlier, and we're going to talk about that a little bit more.

Ashish Kamat: Thanks so much, Matt. You covered the locally advanced and advanced disease spaces really, really well. And I think it's really great that you highlighted that any society that the audience wants to look at, whether it's CITC or ASCO, has defined guidelines and recommendations on how to manage toxicity. Which is something that we, when I say we, I mean Neal and I now, need to really hammer home to our trainees and our colleagues about moving this into earlier phases.

Neal, with the success that we've seen in the advanced stages of disease, right, we haven't seen that truly replicated in the earlier stages of disease yet. I mean, again, pembro approved, KEYNOTE-057, good results, good durability, but not a home run. And you've, of course, been involved with that as well as with the other trials, POTOMAC and CREST, and others using IO with BCG. What are some of your thoughts on how this is moving and where it might land in the urologist's office, other than for advanced disease?

Neal Shore: Well, I appreciate the question, Ashish. And you're right, the KEYNOTE-057, which you were a key leader on, was a very important study that really heralded the first time we were able to get across the finish line and regulatory approval for BCG-unresponsive CIS for patients receiving pembrolizumab. And just this week in Lancet Oncology, we have another follow-up paper, demonstrating even better results for patients with papillary disease, high-grade papillary disease, BCG-unresponsive, just came out this week. So we are making real progress. And that's in the BCG-unresponsive NMIBC. And as you mentioned, there is the CREST, the POTOMAC, the Merck 676 Phase III trials that are looking at IO respectively, sasanlimab in the Pfizer study, durvalumab in the AstraZeneca study, and pembrolizumab in the Merck 676.

So this is all in BCG-naive after induction, and just IO alone with induction BCG, and potentially in combination with maintenance. So none of these three very important trials have read out. They're getting close. I think the bottom line for your question for me is, and as Matt did a great job of illustrating, is the importance of the multidisciplinary team. The guidelines are there. They're not that complicated, actually. But one of the things that's really important that I would add to Matt's slide content is having the ability to be in contact with your medical subspecialists. And this is true for medical oncologists as well as for urologists, to have a dermatologist you can work with, a gastroenterologist, an endocrinologist, a pulmonologist. And there's no weakness in getting that multidisciplinary team really fortified. But in NMIBC right now, all of the IO drugs are traditionally given intravenously. There undoubtedly will be a movement towards administering them subcutaneously. The sasanlimab in CREST is delivered subcutaneously. Nivolumab is getting a lot more advanced in subcutaneous administration in other solid tumors, melanoma, kidney cancer.

The advantage of subcutaneous administration is there's just greater throughput in the clinic. Both for urology practices that may not have peripheral IV access, easy performance, but even in medical oncology offices, where you can get greater throughput. We live in this era, globally, of a person-power, physician shortage, and an expanding population. I mean, bladder cancer, prostate cancer, kidney cancer, are typically diseases of the elderly. And there's that graying of the world effect with a shortage of clinicians. So throughput is super important. I mean, the era of town and gown is over. It's time for everybody to work better together. And so make sure that patients get optimized therapy. And I think that's really the take-home.

The other really important theme of Matt's presentation is, we're seeing these incredible advances of IO in metastatic disease. It's only a matter of time that we continue to move it more proximally into bladder-sparing, neoadjuvant, and in NMIBC. So urologists and medical oncologists who are busy in the community all need to be very familiar with this data so we can optimize patient care.

Ashish Kamat: Great points, Neal. Especially the town and gown, I got to remember that one. Just to clarify again, the toxicity profile does not change with the subcutaneous route of administration. It is much easier for the patient and the clinician though, and the throughput. That is the point you're trying to make, which I really appreciate. What do you think about the adoption of IO therapy when it's subcutaneous, simply because it's subcutaneous? Do you have any words of wisdom, both you, Matt and Neal, to our practicing urologist, other than what you already mentioned, just moving from IV to sub-Q?

Neal Shore: Well, you make a really important point, if it's okay for me to go first, Matt. I have not seen a difference in my own personal experience of sub-Q versus intravenous administration of IO therapies. And so, this requires dedication and a real significant interest from the team effect, not just from the physician, but your nurse support team, your physician assistants, your nurse practitioners, etc., who really are familiar with all these autoimmune-like syndromes that can develop, or essentially an inflammatory response wherever the lymphatic system goes, or essentially an itis in any part of the body. But as Matt showed very nicely, you halt drug if it's grade two or higher, and then you make a decision at some point to add high-dose steroids. There are some other medications, depending upon the adverse event. And then bring in, if you need to, a medical subspecialist.

Matt Galsky: And I would just add that, as Neal pointed out, the guidelines for management of immune-related toxicity are not complicated. In fact, they're well-written and easy to follow. What is complicated is recognizing sometimes that someone has an immune-related adverse event, and that requires vigilance. And it comes back to what we were taught in med school, which is patients don't read the textbooks. And so no one's going to come in and tell you that they have immune-related colitis. They might not even tell you that they're moving their bowels five times a day, whereas they used to move their bowels once every other day. It takes extracting that information in taking a good history.

Neal Shore: I love that. You're absolutely right. It's vigilance. And as we say, advanced cancer care is not a dalliance; it's not for a dabbler. You have to be really in it. And I think if you want to call yourself a center of excellence, whether you're in a tertiary center, academia, or in the community, you've got to step up. And I think now is the time, given this just burgeoning of wonderful, fascinating combination therapies. As you point out, the 901, the 302, some great data was presented at AUA 2024 by Guru Sonpavde on the lymph node metastasis patients in the 901 arm, how remarkably well they did. So it's the proverbial embarrassment of riches, but there's no free lunch not to throw in too many hackneyed expressions. You have to be able to recognize and talk to patients very carefully, the team approach, to let them tell you if something's early on going awry.

Ashish Kamat: Great points, guys. Two more quick questions, if I might indulge both of you. Number one, Matt, you shared a lot of data, and of course you presented a lot of data, and Tom Powles has too, on the importance of tumor-informed circulating DNA. For the practicing clinician out there, is it ready for prime time? Do you recommend getting it on all patients? If not, which patients would you select?

Matt Galsky: We're in one of those unusual times with this technology that we've been in with some other technologies, where a clinician can order the technology and get the results back. These are commercially available assays. And I think the danger is that we put the cart before the horse and don't establish clinical utility. So yes, I think it's reasonable to order. It would be probably silly to think that if you order it, it's not going to be incorporated, at least in part, in your decision-making. But I would certainly encourage everyone to try and get these clinical trials done that are meant to determine clinical utility. Because if we don't establish clinical utility now, then we'll never be able to do it.

Ashish Kamat: Agree with you 100%. And Neal, closing question to you, because I think I know Matt's bias, I've seen him present this, but I want to ask you as a fellow urologist. When we've taken care of a patient, put them through neoadjuvant chemotherapy, done their radical cystectomy, and their pathology comes back unfavorable, I tend to want to believe the data presented, in which Matt also summarized now, with the CheckMate and the AMBASSADOR, and recommend to patients that they consider adjuvant IO. What's your sense there? How do you counsel patients?

Neal Shore: Yeah. I present the data and I tell them that you could. These are clearly the patients who have a greater risk for recurrence, and they have to be stratified appropriately. And based upon AMBASSADOR and 274, I tell them a year of IO therapy has clearly been demonstrated to be beneficial. There's more mature data from the 274 than there is on the AMBASSADOR, but I think that'll be forthcoming. Fortunately, as Matt pointed out, it's really only 10 to 15% of patients that will get the grade 3/4 IRAEs. The other 85 to 90%, it's extremely well tolerated. And if we can reduce their recurrence, and effectively augment cure with the surgical approach, that's what we're aiming for. So that we don't go down that cascade of metastatic disease. So I'm pretty aggressive and have been pretty aggressive in offering adjuvant IO therapy. Who knows? Maybe at some point, in addition to the wonderful trials that Matt's running regarding ctDNA, but also, maybe there's ultimately a role for artificial intelligence, and letting us discern who would benefit and who would not.

Ashish Kamat: Thanks so much, guys. In the interest of time, I'm going to wrap it up, but again, this is great. Thank you so much for taking the time.

Matt Galsky: Thank you.

Neal Shore: Thanks.