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Ashish Kamat: Hello everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and joining me today are two folks who really need no introduction, Professor Matt Galsky and Neal Shore. Matt, Neal, thank you so much for joining us today. There is a lot happening in bladder cancer, and a lot of stuff that our listening audience, not just in the US but across the globe, really would like to hear from the two of you.

Today, what we'll do is tackle ADCs. Now, clearly, ADCs are more prevalent and getting more recognition in advanced bladder cancer, but Matt, if you could touch upon what's going on with ADCs in the advanced bladder cancer field and then slowly tell us where you think their role might have to play in muscle-invasive and non-invasive fields, that'd be great. And then of course, I'm going to, as always, pick on Neal for some practical nuggets and tips for our practicing urologists.

Matt, take it away.

Matthew Galsky: Sounds good, thank you.

I think maybe a lot of the listeners have seen some of this data before, so I'm going to go through it fairly quickly. But I'm really providing a high-level view of antibody-drug conjugates in urothelial cancer, where the field is right now, and a little bit of where the field's going.

Antibody-drug conjugates are comprised of three parts: there's the antigen, the payload, and the linker. All of these are important. Sometimes we focus most on the antigen that the antibody's targeting, but of course, all of these components of ADCs are important.

Enfortumab vedotin, really the first ADC approved in urothelial cancer. The target is Nectin-4, pretty ubiquitously expressed in bladder cancer. Initial studies relied on immunohistochemical testing for Nectin-4, which was expressed, overexpressed in most patients, and so that testing did not make it into the label or clinical use of enfortumab vedotin. Although there is some intriguing data about Nectin-4 amplifications that just came out suggesting that those potentially correlate better with response to EV.

There's a protease-cleavable linker, and then the payload is vedotin or MMAE. It's a microtubule agent. Enfortumab vedotin was initially approved for metastatic disease in patients who had progressed despite platinum-based chemotherapy. The next logical thing to do is combine EV with immune checkpoint blockade given that those drugs are presumably non-cross-resistant, different mechanisms of action, and different side effect profiles largely, and this data helps as well. This is data from not immune-competent models, but testing at least whether or not there was any impact of enfortumab vedotin on immune cells, on myeloid cells in these models showing that within enfortumab vedotin treatment as compared to a non-binding ADC, there was infiltration of myeloid cells with upregulation of antigen presentation machinery, potentially providing some rationale for combining EV with pembrolizumab.

Of course, that led to the combination treatment initially in single-arm studies, EV-103. These data were presented at ESMO several years ago and really made a huge splash based on the fact that the vast majority of patients with metastatic urothelial cancer responded to this treatment. Of course, the story from here was rapid development into the phase three setting with EV-302. EV-302 randomized patients to EV-pembrolizumab versus chemotherapy patients with treatment-naive metastatic disease. The regimen paper was published in the New England Journal of Medicine leading to an improvement in overall survival with a hazard ratio of 0.47. Really remarkable results, FDA approval of this regimen, and it has really become a standard first-line treatment for patients with urothelial cancer. There are toxicities associated with EV, distinct toxicities with pembrolizumab, and then a few of those overlap. Some things really to know about, and I think maybe we'll touch on these more when we have a discussion.

There is some data emerging for EV in the neoadjuvant setting, and so this is a study looking at single-agent EV and cisplatin-ineligible patients prior to cystectomy. Preliminary data from this study has been reported previously. The path CR rate with single-agent EV was 36.4% in this preliminary data set. Very intriguing data with single-agent EV given that we know that there are at least three large randomized phase three studies testing EV plus pembrolizumab in the neoadjuvant setting, both in cisplatin-eligible and cisplatin-ineligible patients. And so these studies have completed accrual, and it won't be very long until we see the results from these studies, which potentially will change the way that we treat patients with muscle-invasive bladder cancer.

Sacituzumab govitecan, another FDA-approved ADC for bladder cancer here, targets Trop-2. The payload is SN-38. This is a topoisomerase inhibitor. This was approved based on the accelerated approval pathway based on single-arm data with a response rate endpoint from the TROPHY-U-01 study of sacituzumab govitecan. In this study, in patients who had progressed despite platinum-based chemotherapy and immune checkpoint blockade with metastatic urothelial cancer, leading to a response rate of 27%, approved based on the accelerated approval pathway.

The phase three study, which is a randomized study of sacituzumab versus dealer's choice chemotherapy in patients with metastatic disease who have progressed despite prior treatment, has completed accrual. We haven't seen the results yet.

Probably the next big target for ADCs in urothelial cancer is HER2. We've known for some time that HER2 is overexpressed in urothelial cancer, and it's overexpressed at the three-plus level in a subset of patients. But at the two-plus or higher level in really a large subset of patients, the expression of HER2, the pattern, is a little bit different in bladder cancer than some other cancers like breast cancer and gastric cancer. And so the optimal way to score HER2 expression in bladder cancer is not entirely clear. This is an area of investigation.

There are a bunch of anti-HER2 antibody-drug conjugates in clinical development. I'm just going to touch on two. One of these is trastuzumab deruxtecan. This is trastuzumab linked to a topoisomerase inhibitor. This was studied in a basket study called the DESTINY-PanTumor02 study. A bunch of different baskets with different solid tumors all with HER2 overexpression, and here you see the results in patients with metastatic urothelial cancer who had progressed despite prior treatment. You could see in patients with IHC3+ expression, a response rate of 56%, so a pretty respectable response rate in patients with previously treated metastatic disease. Trastuzumab deruxtecan has been approved by the FDA based on this basket study for patients with solid tumors with HER2-3 plus overexpression. And so this is currently an available treatment in the United States for patients with metastatic urothelial cancer who have HER2 overexpression.

The other anti-HER2 ADC that's in clinical development in late-stage development is disitamab vedotin, also known as RC48. This is a different antibody. The payload is different than trastuzumab deruxtecan. In fact, the payload is the same as with enfortumab vedotin. This has been studied in a series of studies in Asia. Here you see one of those studies, a 50% response rate in patients with heavily pre-treated disease with at least two-plus HER2 overexpression. Even in patients with one-plus HER2 overexpression, you see responses with this drug. This drug has a different side effect profile than both EV and trastuzumab deruxtecan.

With drugs with similar targets, different payloads, or different payloads with similar targets, you see different side effect profiles. The side effects of ADCs depend on both the payload and the target. RC48 or disitamab vedotin is undergoing further exploration in a large international phase II study that is actively enrolling patients. This includes an arm of combination treatment with disitamab vedotin plus pembrolizumab. That was really based on data, again, from China showing that in mostly untreated patients with metastatic disease, when you give this ADC plus a PD-1 inhibitor, toripalimab, this results in a very, very high objective response rate, 71% in this study. And so we'll look to see if those results can be replicated in the current study.

We have a number of emerging data sets combining ADCs with immune checkpoint blockade. Interestingly, the studies combining ADCs with immune checkpoint blockade that have an MMAE payload seem to be resulting in higher response rates than those with other types of payloads. This might just be noise. These are small studies in slightly different lines of treatment. Or, there might be something special about MMAE in terms of the immunomodulatory effects. This is something that we need to explore further.

And so ADCs have changed the landscape. Neoadjuvant studies will potentially change things even more. HER2 is the next major ADC target. In fact, we have one recent approval now with an anti-HER2 ADC in urothelial cancer. Knowledge of the AEs associated with all of these drugs is critical because they differ a little bit with each drug, and it is important to know the side effect profile in patients that you're seeing in the clinic.

Ashish Kamat: Gosh, Matt. I mean, I don't think I've ever heard you speak that fast. I mean, you covered so much information in such a short time. I'm glad the audience will be able to go back and go through the slides and rewind because you covered a whole bunch of stuff.

If I might add one more thing: with the ADCs, obviously they're also being looked at in the intravesical setting with essentially EV phase one study already completed and reported. Of course, now they're moving into phase two, which is open and enrolling at many centers.

Neal, when you heard Matt talk about all these ADCs, I mean you've been a champion for systemic therapy and prostate, bladder. I mean, you've had classes and tried to teach urologists how to use IOs. What are some of your thoughts about the ADCs and how you think urologists might be able to adapt them into their practices?

Neal Shore: Yeah, just totally agree with you. That was a wonderful presentation of an enormous amount of content and data that Matt just beautifully went through. I mean, it shouldn't be lost on anybody that just in the last few weeks we have another tumor agnostic indication for HER2 expression. Tumor agnostic, much like the MSI high for pembrolizumab. That's always really great, so another reason for doing appropriate testing to find those patients. It's not the majority, but there are patients who can clearly benefit. I think that's a really significant advance.

As it relates to the ADCs, and Matt began with their structure, and MMAE has been the cornerstone, but there are other payloads that are coming in. They have different adverse event profiles and different efficacies. And then there's also this other notion around whether it's a cleavable or non-cleavable linker and how that can affect offsite targeting and then side effect profiles.

Another thing to be cognizant of, but as Matt really showed very elegantly, there are differences in side effects, whether it's neuropathy that we see with enfortumab vedotin. We participated in the Cohort K trial, and now that they have this truly remarkable result from the EV-302 with incredible results, we may clearly be thinking about neoadjuvant strategies, and as you bring out, even the intravesical strategies. We just signed up to do that study.

I love the idea of trying to push the field into better neoadjuvant strategies as well as bladder-sparing strategies. Clearly, we now have evidence of intensification of IO and an ADC such as EV, but you're right. There are clear side effect profiles. For example, in the checkpoint inhibitors, we see skin rash. We talk about the immune-related adverse events or the inflammatory responses wherever the lymphatics go. You can have dermatitis. You can get dermatitis as well with EV, but probably the more unique aspect to its toxicity profile is neuropathy.

I like it because, not that I want anybody to get neuropathy, but it really broadens our understanding. Both medical oncologists and urologists, there's a lot we need to do in terms of our baseline evaluation for neuropathy, strategies to mitigate the neuropathy, dose reductions, dose interruptions, and the understanding of concomitant skin rash. When you talk about sacituzumab govitecan, you can see a fair amount of GI or diarrhea and volume loss.

That's okay. I mean, we need to really just be cognizant so we can be really good stewards of this. Whether you're a uro-oncologist in an advanced bladder cancer clinic, ideally you're working hand in glove with a multidisciplinary team with your medical oncologists, and arguably your radiation oncologists if you're doing trimodal bladder-sparing strategies. I think the bottom line is, undoubtedly, if you are interested in advanced bladder cancer, not only in non-muscle invasive bladder but in neoadjuvant and trimodal bladder-sparing, the antibody-drug conjugates, they're here, as Matt brilliantly showed. They clearly work in advanced disease. They are going to work in neoadjuvant and trimodal bladder, and even potentially in NMIBC. How we use that intensification and monitor effectively the safety profiles, that's the key thing.

Ashish Kamat: Yeah, no, clearly.

Matt, the rash that you see with ADC is different, right? I mean, there's not that much of a lead to when it can actually escalate. Any practical tips? Again, we could spend a whole hour on it, but any high-level practical tips for the non-medical oncologists looking to get their feet wet in this field?

Matthew Galsky: The rashes that end up being bad rashes tend to happen early. Most rashes tend to happen early, so that's not necessarily a distinct attribute of the rashes that turn bad. But what it does suggest is that if a rash develops early, it should be taken seriously because those are the ones that tend to go on to develop worsening problems. Having a mid-level or a physician look at that rash on day eight, day 15 of cycle one, is critically important instead of just hearing from the infusion nurse that the patient reported a rash.

And then if it's available, and I know it's a luxury, trying to get dermatologists involved to co-manage as well because there are some tricks there in terms of assessment and management.

Neal Shore: But one thing I would just love to add to that is yes, it's great to get a dermatologist involved, but probably finding cardiologists these days and even neurologists. They're becoming sometimes, depending upon where you practice, as rare as dodo birds. They're very hard to find, and so I don't think that should be rate-limiting for interested uro and medical oncologists who want to use these drugs.

What we really pride ourselves on in our clinic is all the upfront education and letting the patients know you don't just reflexively go to the emergency room. Here's what you can potentially expect. Call us right away during working hours if you're really worried. Of course, there's always someone on call. But there is a really good way to, I think, really in the vast, vast overall majority of patients avoid these unnecessary ED visits where they're going to see the generalist ED doctor who's not going to really understand how to think about looking at bringing the patient in, observing them, monitoring whether or not they need to start high-dose steroids, for example, in the case of a grade three, four IRAE event, dose modification for neuropathy, dose interruption.

There's a lot of exciting opportunities here that I think the wonderful aspect is bladder cancer has just so many more tools now in our toolbox for a historically very biologically aggressive disease, both of you gentlemen know, and probably in many ways more consistently aggressive than we see even in prostate cancer. But now we have biomarkers. We have a lot of therapies to really help patients. And so availing them to all these different opportunities as well as the clinical trials and learning about how we can intensify and do it safely is one of the key messages.

Ashish Kamat: Yeah, I think safety is key, right? Because I mean, again, unless we educate our team on how to recognize these early, you're absolutely right. A lot of patients that normally in a medical oncology clinic might be treated appropriately in a surgical oncology clinic or a uro clinic will end up in the ER, and that's clearly doing them a disservice.

Do either of you gentlemen use the ophthalmologist anymore when you're putting patients on ADCs? Because I know that's in all the clinical trials and the best practices, but practically speaking, and let me ask you, Matt, I mean, do you send your patient to the ophthalmologist to do screening before you put them on, say, EV?

Matthew Galsky: Not as routinely as I do with erdafitinib, with FGFR inhibition. With FGFR inhibition routinely, with EV not routinely. If someone's had eye issues before, then I'll do it.

Neal Shore: Yeah, likewise. Exactly. Except we'll even use an optometrist because sometimes it's hard to get into the ophthalmologist, getting back to the scarcity issue.

But yes, I do that routinely for oral erdafitinib, not for using erdafitinib in the targeting releasing device that we're doing with the TAR-210 program.

Ashish Kamat: Yeah, clearly with that targeted delivery in the bladder, totally different ballgame, right?

Quick question again, do either of you gentlemen use apps or available tools on the internet to help your patients screen themselves, or do you still have them call your clinic in office? What are some of your thoughts on some of the AI generative apps that are in development for AE management?

Matthew Galsky: I haven't used any of them. I think they're potentially great ideas if we can establish that they do help patients stay safe. I tend to use either protocols that I've been involved with before that have very regimented dose toxicity modification guidelines, and then there's a really nice review paper on enfortumab-related skin toxicity that I reference all the time. I keep a copy of it on my laptop.

Ashish Kamat: Maybe we'll get that link from you to put for our readers down at the bottom as well.

Neal, any closing thoughts from you on this topic before we let both of you go?

Neal Shore: I think a program like this is really great because it really speaks to just the burgeoning of so many wonderful opportunities for intensification and personalization of care.

I think in many parallel ways to prostate, I really want to see our advanced bladder cancer clinics, whether it's urology, medical oncology, ideally multidisciplinary, recognize that there are still a tremendous amount of trials out there that need to get accrued. But even if you're not doing the trials, the newest approvals and the importance for doing further IHC as well as next-generation sequencing, particularly in muscle-invasive disease, are very, very important.

Continuing to learn, as you've asked the question and Matt ended with it, the importance of understanding the AE, the advanced adverse reaction profile. Manageable and patients will benefit from it. Hate to see patients succumb to disease and not get at least offered all the life-prolonging therapies that are now out there.

Ashish Kamat: Yeah. Great points. Again, we could talk on this forever as I normally do with you guys when we meet, but in the interest of time, we'll close this. Once again, thank you so much for taking the time, and thanks to UroToday for hosting such a valuable session.

Matthew Galsky: Thank you.

Neal Shore: Great.