Ashish Kamat: In a public forum, let me just say that first off, thank you for that kind introduction. One of my greatest pleasures has been to be part of your journey just to see everything that you've achieved. But I actually use your example to tell medical oncologists, radiation oncologists, anyone that's looking to do bladder cancer work, how you approached me and said, "Hey, can I watch TURBTs? Can I watch cystectomies?" Because that clearly gives us as a field that multidisciplinary aspect of things. And even the topic that we're going to be talking about today. When I was fellowship director at MD Anderson, I sort of instituted sending the surgical fellows, the uro-oncology fellows, to medical oncology to spend a week, two weeks with our medical oncology colleagues, spend a week with the radiation oncologist, go and see what happens on a day-to-day basis. So you were one of the first to approach me, which was great, and I use you as an example. So let's not have this be a mutual admiration session, but I want to...
Elizabeth Plimack: The point that I think is very salient to what we're about to jump into is that muscle-invasive bladder cancer is a multidisciplinary disease. It requires collaboration among all of us. And that's why, again, part of our training should be to understand what the other disciplines do because pathology, radiation oncology, medical oncology, urologic oncology, we all work together, now more than ever, I think, to really treat our patients with this disease in the best, most forward-thinking way possible. I actually think it's relevant to what we'll talk about. But we do have a lot to cover. So Ashish, we have really come a long way in the treatment of muscle-invasive bladder cancer. Platinum-based neoadjuvant therapy followed by cystectomy was the standard of care for many years. For many years, we were talking about uptake of neoadjuvant therapy. More people than we would like were going straight to surgery, skipping that step. I think we've come a long way to embed that in the treatment plan in these multidisciplinary plans really across the United States and around the world, but now we're in a new place where we are leveraging newer regimens and thinking about keeping bladders in place. So my first question for you is, how did bladder preservation after neoadjuvant therapy as a concept first come to you? And tell me a little bit about some of the places that you've been involved really advancing how we think about this new approach.
Ashish Kamat: Yeah, so this is a topic near and dear to both our hearts, and I think it's really, really critical because I would love nothing better than not to have to take out a single bladder ever again. But we clearly have to recognize that just not taking out the bladder should not come at the expense of oncologic safety from the standpoint of the patient. Because if you ask the patient what's most important to you, they want to live. They want to live with their bladder, but they want to live. And that's where, over the years, we've had this up and down ebb and flow of bladder preservation in the cisplatin era, which hasn't really been met with much success, as you know, because patients who've refused to have their bladder taken out or have been advised not to, just looking at a poorly defined clinical response in the platinum era, have had at least a 40, 50% chance of having really bad outcomes with recurrence and metastatic disease. But like you said, the new era is great because now we have not only platinum plus IO in the neoadjuvant setting, more people recognizing that you have to get this, and of course the NIAGARA protocol included patients that were cisplatin-ineligible, but now you have maybe a completely platinum-agnostic platform with EV-pembrolizumab where you have path CR rates approaching 57%, 60%.
So when you have this robust activity, it's up to us now to define whether you can clinically predict who's going to actually have that long-term, no tumor, at least no invasive tumor in the bladder, safely. And I think that's where the field essentially is looking to. Can we now, in today's day and age, with the new tools that we have, safely predict who can avoid having his or her bladder taken out? And of course, you've been part of many of these efforts that we've done through the International Bladder Cancer Group, the San Raffaele consensus meeting, workshops with the FDA, so on and so forth.
Elizabeth Plimack: So you bring up a couple of really important initiatives that really you've been a big part of, and that is gathering worldwide experts and regulatory in the same room, virtual and in person in Milan, to really say, okay, we can do this, we can give systemic neoadjuvant therapy, preserve bladders, and some of those patients are going to live long lives with their bladder in place, not needing anything else. What is the best way to do this? So tell us a little bit about how you gathered this all together and maybe quickly what the outcome of those consensus meetings has been.
Ashish Kamat: Absolutely. This was driven by patients. So as part of the International Bladder Cancer Group, which we founded about 20 years ago now, and I've had the pleasure of leading, we always reach out to BCAN, we reached out to the World Bladder Cancer Patient Coalition, the Bladder Web Cafe patients across the globe, and they have helped us drive this desire for bladder preservation safely. The next step was gathering people at a consensus meeting, and we did this first in Houston, about a hundred people gathered here in Houston in August, in the middle of summer, so no one went out, everybody put their heads together. And then we took a subgroup of this, as you know, and we had a very focused meeting in Milan with Andrea Necchi leading it at San Raffaele to essentially help further refine this definition of clinical complete response that can help drive the field. Because when... And you've been part of this. When we've talked to the FDA and EMA, clearly a lot of the pharma companies would like to use that clinical complete response or path CR as a regulatory endpoint, which is a separate topic that we need to address, but we also need to address, is it safe for our patients?
So as you mentioned, we're a global community, and we really want to affect the care of bladder cancer patients even in places where they don't have access to the latest, greatest drugs or the latest, greatest technology. In the United States, we're spoiled. We do ctDNA, we do utDNA, we have EV-pembrolizumab, we have everything. Many parts of the world, we don't have that. So the reason to get people from across the globe to come together is to say, if you have everything, this is the standard you should achieve. And if you don't have everything, like we did in Mexico and Chile and even in Morocco, you should still try to achieve that goal, lobby your regulators, try to get subsidized funds for efforts such as in India, in Tata Memorial or in Mexico City. But if you can't get that, then at least have the second-tier definition, which is still, in our opinion, medically sound, but much cheaper. So if you don't have MRI, do CT. But in some parts of the world, as you know, a PET scan is cheaper than a CT scan. So that's the reason to have this global community together.
Elizabeth Plimack: Right. I love that. And what we hear, at least tables that I'm around with international colleagues who may have limitations on what they can offer, they still want to know what the goal is, and then they are in the best place to decide what they can and can't achieve to get as close as possible to that goal. So the goal here being bladder preservation for appropriate patients after neoadjuvant therapy without surgery and without radiation. How do you approach or respond to a patient that, I'm sure you meet these folks every day, that comes to your clinic and says, "I know I have muscle-invasive bladder cancer. I really want to keep my bladder. What are my options?" How do you speak to that patient?
Ashish Kamat: Yeah, I think it's a very important question that the first thing you have to ask the patient, what matters to you? What is most important to you? And some patients will say, well, they want to have the bladder taken out. Some will say, "No, I don't want to just observe it. I would want to do something." And, "Can we do radiation therapy?" So do we need local consolidation? I think is the first question you ask the patient. Because the patient's bladder is not functioning well and he or she is waking up every hour at night anyways, then there's no point in us driving that field. But most patients want to save their bladder, and they want to do it safely. So I think the talk and the discussion that we've had with our patients has changed over the years. I still tell the patient that all the data we have so far suggests that after the best optimal neoadjuvant therapy, having the bladder removed is the only proven way, or by consolidating with radiation, the proven way of giving a long-term benefit. But in today's day and age, we have the access to data from clinical trials such as your study, Matt's study, and we also have the tools available where we can potentially offer you bladder preservation with observation on a clinical study.
I still think today our definition of clinical complete response, as we put forward in the joint manuscript that you were part of, which is negative cystoscopy, negative cytology, negative biopsies, negative MRI, not showing anything, and preferably a ctDNA that's undetectable. I think that's robust enough that we have confidence that this will help us preserve the patient's bladder safely, but I think we still haven't proven it beyond a reasonable doubt, so to speak. So I still will offer it to patients either on a clinical trial, or if you don't have a clinical trial, letting them know, "Hey, this is not standard of care. We'd have to do this off-trial, but it is still experimental." And that's how I discuss it with patients.
Elizabeth Plimack: I think that's a beautiful way to discuss it. And what you're kind of getting at, just to frame it a little bit, well, the same way, I guess, is, once we give systemic therapy, some bladders are clean. We know that because when we take them out, we don't see anything in them. But our ability to ascertain that from the outside with the bladder still in the body is limited, and so we try to triangulate that based on all of the different testing that you said, and there's a chance that we're wrong, and leaving a diseased bladder in is a risk. But I think we ask patients all the time to take risks with us, with our support, and I love the way you frame that for the patient, just saying that this is where we have the most data, this is the most sure route, but we could embark on this either as part of a trial, which requires trust in potentially the unknown, or even outside of trial given what we've learned from trials that exist, which is great. So we're about to see EV-pembrolizumab data in the cisplatin-eligible population at GU ASCO. We saw it in the cisplatin-ineligible population in ESMO with really nice response rates, as you said. How do you think this will change how we approach MIBC?
Ashish Kamat: So I really think now it's going to be a platinum-agnostic platform if you have access to the drugs. I think it's going to allow us to give a lot more patients neoadjuvant therapy, but then that whole concept of... What is this new adjuvant to? Is this new adjuvant to cystectomy as is the definition of neoadjuvant, or that's systemic therapy? I think our nomenclature is going to have to change. I think we're going to be able to offer more treatment to more patients, even those who can get platinum, with all the caveats, of course, EV, pembrolizumab and the side effects, but then we're going to have to answer the question, now, what happens when we actually give systemic therapy, document excellent response in the primary? In this case, in the bladder. Now, do we continue therapy? Do we stop therapy and do partial therapy? Do we go on maintenance with the kinder drug, which is pembrolizumab, or what do we do? I think you and I are going to have this conversation again because the field might further development.
Elizabeth Plimack: Yeah. Yeah, for sure. Well, Ashish, thank you so much for taking the time to talk about this. I think you and I could probably talk about this for many more hours, but we're really eager to see the data. GU ASCO. Eager to see you there, say hello, and more to come in this very interesting space.
Ashish Kamat: Thank you so much, Betsy. Always a pleasure.