Optimizing Treatment Decisions in Muscle-Invasive Bladder Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist and co-director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Shilpa Gupta, a Genitourinary Medical Oncologist here at Cleveland Clinic. She was previously a guest on this podcast to discuss the use of enfortumab vedotin and pembrolizumab for urothelial cancer, and that episode is still available for you to listen to. She's here today to discuss personalizing treatments for patients with muscle invasive bladder cancer. So welcome back.

Shilpa Gupta, MD: Thank you, Dr. Shepard, for having me back, and really excited to talk about the latest developments.

Dale Shepard, MD, PhD: Sure. So, give us a little idea what you do here at Cleveland Clinic?

Shilpa Gupta, MD: So I'm a GU medical oncologist, as you said. So, I see patients with all GU cancers, including kidney, prostate, bladder, testicular cancers. And I do a lot of research, including clinical trial and translational research.

Dale Shepard, MD, PhD: Excellent. We're going to focus on bladder cancer today. And so, we're going to look at some phase three data about perioperative use of treatments that may be a little bit different than what people may be used to in the past. And we're also going to talk about ctDNA-guided adjuvant immunotherapy. So, maybe as a backdrop, a lot of people listening in may not be as familiar with newer things. How has bladder cancer management changed over the last few years in terms of what we used to do and how we think about that now?

Shilpa Gupta, MD: Yeah, so that's a really great point. And last when we talked about the enfortumab vedotin pembrolizumab data, that was in the context of metastatic disease when we had the pivotal trial EV-302, where Dale, for over four decades or five decades, all we had was cisplatin for this disease, for advanced disease. And once patients progressed on it, there was nothing available. Then we got immunotherapy approvals back in 2016, 2017, which moved the field forward, but again, that works only in 20% patients. And then when we saw the frontline regimen, there were a lot of attempts to combine immunotherapy with platinum chemotherapy, and it was not better than platinum chemotherapy alone. And it was only when the EV pembrolizumab was able to beat the platinums in the frontline setting and became the global standard. That's when we last spoke a couple of years ago. And now we are seeing the same regimen actually make headway in the localized setting, muscle invasive bladder cancer where in bladder cancer, when we view it, we typically view it as in two buckets.

One is patients who are eligible to receive cisplatin and undergo radical cystectomy. And those patients have to have creatine clearance above 60, no neuropathy, no heart failure issues. ECOG performance status has to be great and things like that. And a lot of our bladder cancer patients, it's a disease of older patients or it used to be at least median age 71. These patients have a lot of comorbidities like diabetes, CKD, hearing loss. So, they cannot get cisplatin. And for these patients who were historically cisplatin ineligible, we did not have any perioperative therapy. They underwent upfront cystectomy and their outcomes were inevitably poor, because they would recur soon after or later because lack of any perioperative treatment. And then we would actually treat them in metastatic setting. And then there's the bucket of cisplatin eligible patients for whom there's data that giving them cisplatin-based chemotherapy prior to surgery, improved outcomes compared to surgery alone.

So now what we saw that EV-pembro talking about that first, the pivotal trial, KEYNOTE-905, that looked at the cisplatin ineligible patients who are either cisplatin ineligible or refused chemotherapy. They received EV/Pembro for three cycles prior to cystectomy versus nothing. And then after cystectomy, they continued six more cycles. And the control arm continued as is, and some of them got adjuvant immunotherapy if they were candidates off protocol. And this is the first time we've seen in this setting, the pathologic complete responses of 57 to 60%, which is like unheard of even with cisplatin. And this is the first time we've seen tremendous improvements in overall survival and event-free survival, like hazard ratio being in the range of 0.4 to 0.5. And this is really moving the needle forward, because over 60% patients are cisplatin ineligible.

Dale Shepard, MD, PhD: And so I guess just from a treatment standpoint, historically there was an issue with people getting preoperative chemotherapy. Do you think with a shift toward immunotherapies that that might change?

Shilpa Gupta, MD: Yeah, I think that's a lot of people are chemophobic or have all these myths about chemo. And I think we have to be careful, because drugs like enfortumab vedotin, even though it's a new ADC, it is a chemo pretty much.

Dale Shepard, MD, PhD: Sure.

Shilpa Gupta, MD: People lose hair with that and have these toxicities, which are unique. But I think it's, given the results we are seeing, I think it's certainly more attractive to patients.

Dale Shepard, MD, PhD: And then you talked about the data with cisplatin ineligible. Tell us a little bit about that sort of, as we think about cisplatin eligible, what do we know?

Shilpa Gupta, MD: Yeah. So that's really, I think, where the field has now moved. We don't care about cisplatin eligibility in metastatic setting, given EV/Pembro is good for everybody. And now more recently, we saw data from the B15 trial where the EV/Pembro four cycles were compared to GemCis four cycles, patients underwent radical cystectomy. And then the EV/Pembro group continued five more cycles adjuvantly, regardless of path CRs. And in the control group, if they were eligible for adjuvant immunotherapy, they could get it off protocol. And again, we saw similar pathologic complete responses of 57% to 60% and also improvement in event-free survival and overall survival data is still not mature, but that's what we are seeing.

So, this tells us this regimen is the regimen for every patient. And whether three cycles is enough or four, that's really, it was based on the logistics rather than any science. And given the pathologic CRs are similar in both three versus four in the two trials, I think as long as patients get some EV/Pembro before surgery, we expect good outcomes.

Dale Shepard, MD, PhD: As you mentioned, EV really is chemo in many ways. Are there patients still, despite the data that chemo might make more sense than EV?

Shilpa Gupta, MD: I think yes, there are some patients. For example, EV does have unique toxicities of bad peripheral neuropathy, diabetes. And I mean, even though cisplatin causes peripheral neuropathy, it's just different. We've never really seen patients get bad neuropathy with three to four cycles of cisplatin, as you know, but with this, we can. So I think those patients who are baseline really have ongoing peripheral neuropathy, we wouldn't give them cis either, but I think we have to be more cautious with this. But for the most part, I would think that if somebody is a candidate for cystectomy and is in good shape, whether the cystine eligible also includes performance status, too, so I think they can easily get the regimen. But big question now facing us is, if they have such great pathologic CRs, do we need to give them more adjuvant? Because the toxicities do build up.

And only 50% patients, for example, completed the perioperative regimen in the cisplatin eligible group, and only two thirds of patients made it to adjuvant therapy in the cisplatin ineligible group. So, I think the bigger question is how do we select these patients who may not need any further therapy? And in this trial, it's a package, neoadjuvant, surgery, adjuvant, but the field is also moving towards ctDNA to help us guide that.

Dale Shepard, MD, PhD: Yep. And we're going to talk about that as the next topic, but just really quickly on this perioperative approach with EV and Pembro, one of the things, and quite honestly, I remember seeing patients that just went straight to surgery. And even though they probably should have gotten neoadjuvant, the urologist was the first person they saw and they went straight to surgery. And there's always this sort of like, "Well, I was afraid if I give chemo, then they wouldn't get to surgery." How much of that really is a concern with the EV?

Shilpa Gupta, MD: No, you're so right, Dale. I mean, the neoadjuvant therapy is still only 40% utilized in the country like the U.S. where we should be seeing all these patients. And that phobia about delay to care has been shattered with a lot of studies. But I think with this, especially in the, I think academic places, people will be aware we need to just have more information out there so that this regimen is being offered in the community. Because as you know, GemCis is the standard people are used to. We also have GemCis durvalumab as the new great upgrade from GemCis and community docs are aware of that. But this is a regimen unique to this cancer. So I think that it's important for people or urologists to refer every patient to a medical oncologist.

Dale Shepard, MD, PhD: Excellent. So you kind of alluded to this here a couple of minutes ago, much like we talk about new ways to treat, then I think it seems like equally important of who not to treat and when not to treat. And that brings us to the ctDNA topic. So, tell us a little bit about how ctDNA is being used to try to select who might need further treatment. Let's start really basic. What is ctDNA, and how are we envisioning that might be helpful?

Shilpa Gupta, MD: Yeah. So ctDNA is really just circulating tumor DNA detecting molecular level or molecular residual disease. And we've seen that in several cancers in clinical trials, but in bladder cancer, it's basically the assay we use is the Natera assay, which is a tumor informed assay. Not to say that there are not other assays out there, but this was the one that has studied. And we had a trial called IMvigor010 where muscle invasive bladder cancer patients, whether or not they got neoadjuvant therapy, if they had high-risk pathologic residual disease at the time of cystectomy, they were randomized to atezolizumab versus observation. And that was a flat out negative trial. There was no difference in event-free survival or overall survival. But the investigators from that study took on this humongous task. They went back and looked at which patients actually derived benefit from atezolizumab based on the ctDNA test that they had had.

And they found that those who had positive ctDNA at surgery or after that, they actually derived improvement in survival with atezolizumab. So then they launched this pivotal study called IMvigor011 in a prospective setting. Whoever has had a surgery or cystectomy, if within 12 months they converted from ctDNA negative to positive or they had ctDNA positive to begin with, they were randomized to atezolizumab versus placebo. So only ctDNA positive patients and rest were just being watched. And this study showed improvement in overall survival and event-free survival. So really that has now informed us that if ctDNA is positive, somebody will benefit from adjuvant immunotherapy. If they're negative, their outcomes are really good no matter what you do.

So, I think that is really important to now with these more effective therapies like EV/Pembro, are we going to over-treat everybody or can this be used? And there's no trial looking at that in those studies, but I think the field is moving towards trying to use this as a complementary tool.

Dale Shepard, MD, PhD: And I guess as we think about ctDNA as a biomarker, and so not to get into like semantics, but I guess when you think about adjuvant therapy, traditionally adjuvant therapy is something you start very quickly after surgery. And so, in this particular approach, it was any ctDNA positivity within a year. And so, how much of this is do we think truly making adjuvant decisions? How much of it is early treatment of disease that's recurring? And I mean, ultimately it doesn't matter, but I mean, just from a mindset, we may potentially be starting what we call adjuvant therapy like nine months after surgery.

Shilpa Gupta, MD: Right. No, you're absolutely right. We are historically used to 12 weeks. And after that the window is out and there's no benefit. And that's what we tell our patients when they're coming for adjuvant treatment that now it's too late. Let's just watch you.

Dale Shepard, MD, PhD: That happens a lot. You see somebody at four months, you're like, "Eh, too late."

Shilpa Gupta, MD: Exactly. And now with this approach, it's pretty much, I think we are seeing it's probably early micrometastatic disease. That's what we are catching. And in our clinic, because we have this tool available as a standard and for immune monitoring as well as monitoring patients post-surgery, I've actually been able to ... I don't act on a positive ctDNA, but when I do see a negative to positive and I move the scanner, we've been able to sometimes see a very micrometastatic deposit. So in this, I think it's what we are seeing is targeting the micrometastatic disease before it shows up on the scan.

Dale Shepard, MD, PhD: That was a question I was going to ask is how you're using the ctDNA data if you're actually pulling the trigger and treating with the ctDNA positivity, or are you still waiting for radiographic progression?

Shilpa Gupta, MD: So, right now atezolizumab based on the ctDNA is not yet approved. Once it is approved in the adjuvant setting based on that, I think that will become our approach. Right now what we are doing is for patients who have undergone a surgery and are on adjuvant immunotherapy, and we are monitoring their ctDNA just for information purposes. And if that ever becomes detectable or rises, then we are moving the scan up to rule out metastatic disease, but we are not acting just on that without radiographic evidence. And in our metastatic patients, because we have this tool available to monitor, we are just monitoring when we start our therapies, their ctDNA decrease. So I would say these are still not as a decision-making tool, but just helping us reassure us.

Dale Shepard, MD, PhD: As someone who used to treat prostate cancer and have all of the discussions about the small increases in PSA, what's the patient perspective on this? When they see these numbers and then they see a number go up and they're like, "But why aren't we going to do something?" I'm like, "What's the patient acceptances and anxiety?"

Shilpa Gupta, MD: It's like the new PSA for bladder cancer. And I've actually had many patients send an in basket that, "Oh, we got our ctDNA report," which we didn't even have in Epic. And they sent me the report and then it's a whole new question, "Oh, it was negative, has become positive what to do." So, I think it does create a little bit of anxiety on the patient end and we just have to do the scans and then have this whole discussion that it's way too early to treat just based on this. Now in breast cancer, they're doing some studies based on ctDNA. We are not there yet.

Dale Shepard, MD, PhD: So, we've discussed kind of two approaches, right? So one is everybody gets perioperative, like some EV/Pembro upfront, surgery, everyone gets treated afterward. We've talked about this approach of using ctDNA as a marker, treating people when you need to, if you will. You think two, three years down the road, how are decisions going to be made?

Shilpa Gupta, MD: I think it will be a lot of, it will be also on bladder preservation. Dale, I mean, surgery is such a morbid procedure. And if we are seeing such high pathologic responses and we can use good biomarkers like MRI, ctDNA, urine DNA to confirm that somebody has a clinical complete response to, let's say EV/Pembro, what can we do to save their bladder? I think that's where the field will head because a lot of patients are already questioning after the surgery like, "If there was no cancer in my bladder, why do I need more treatment?" So I think that will be our next goal to preserve as many bladders as possible.

Dale Shepard, MD, PhD: What are we learning so far about ctDNA sort of at the end of neoadjuvant therapy? So you can kind of do a biopsy maybe and get an idea of response, but are we going to be able to use ctDNA to try to do that bladder sparing?

Shilpa Gupta, MD: Yeah. I think the ctDNA for what we are seeing is more of like a distant systemic disease kind of a marker. And those who have positive ctDNA at the end of neoadjuvant, they really do poorly, regardless of what they get compared to those who have clearance. But in that setting, actually urine tumor DNA is really emerging as a better biomarker because of the bladder in place and that can detect whether there's localized disease or not. So it's not ready for primetime yet, but that's what is being looked into.

Dale Shepard, MD, PhD: Perfect. So two pretty interesting areas of bladder cancer research. They're going to change the way we're thinking about the disease. So appreciate you coming, giving your insights.

Shilpa Gupta, MD: Thank you, Dale. Appreciate it. Thanks for having me.

Dale Shepard, MD, PhD: Absolutely. To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. For more podcast episodes, visit our website, clevelandclinic.org/canceradvancespodcast. Subscribe on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Thank you for listening. Please join us again soon.