The Future of Adjuvant and Neoadjuvant Therapy for Patients with Muscle-Invasive Bladder Cancer - Tracy Rose
March 21, 2022
Tracy L. Rose, MD, Assistant Professor of Medicine, Division of Oncology, The University of North Carolina at Chapel Hill and Lineberger Comprehensive Cancer Center
Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center
Sam Chang: Hello, I'm honored today to have actually Dr. Tracy Rose from University of North Carolina. She's an assistant professor there in medical oncology and leads their clinical trials group and has led a lot of important trials focusing on treatments for advanced bladder cancer. My name is Sam Chang. I'm a urologist in Nashville, Tennessee and work at Vanderbilt. And Dr. Rose is actually going to be giving a talk at this year's geo ASCO, focusing on neoadjuvant and adjuvant therapies for bladder cancer. And so what are some of the highlights I guess ... We'll start sequentially from the neoadjuvant aspects, some of the highlights that you're going to be speaking about this year's meeting.
Tracy Rose: Great. Thank you. It's lovely to speak with you today. So the perioperative space in muscle-invasive bladder cancer is actually really exciting right now. There's a lot going on, and there's been a lot recently, we have this paradigm of cisplatin based combination chemotherapy for eligible patients prior to radical cystectomy, which has been the standard of care for a while now. And there's a huge number of recent studies and then upcoming studies that have the potential to change that paradigm, which is really exciting.
So first off, even within just the cisplatin based combination chemotherapy, we've had the historical studies, but also several studies looking at dose intensity and dose density of treatment that have boosted pathologic response and outcomes in the muscle-invasive bladder cancer space. And then, I think very exciting is we've seen the advent of immunotherapy in the metastatic setting and that is now moving into the perioperative setting to see if we can actually improve outcomes.
And so there's been a number of studies, including one we did at UNC looking at combination chemotherapy with immune checkpoint inhibition for neoadjuvant therapy. So essentially, adding a checkpoint inhibitor to standard of care cisplatin based combination chemotherapy. And those studies have all been actually pretty consistent and their results and pretty promising in boosting some of the pathologic response rates that we see. So it has yet to actually translate into a randomized trial that has read out yet, but there's several based on this data that are ongoing. And so there's a real potential that we can actually see improvements in pathologic response, which may translate to improvements in disease rate and overall survival potentially in muscle-invasive based bladder cancer.
Sam Chang: So in the specific regimen that you all reported on, I think that was a JCO article looking at chemotherapy. It was gemcitabine cisplatin, correct?
Tracy Rose: Correct. Yep.
Sam Chang: Combined with pembrolizumab. Tell me about the sequencing and the dosing in that at trial.
Tracy Rose: Yeah. So our study gave pembrolizumab concurrently with gemcitabine and split dose cisplatin, which is actually the only study out of the group that's been reported that used the cisplatin split dosing. And we were actually very pleased to see pretty good pathologic response rates of 56% and good pathologic CR rates as well with the split dosing of cisplatin. There's actually not that much new adjuvant data with split dosing cisplatin anyway.
Sam Chang: Anyway. Right.
Tracy Rose: And then a lot of the other studies used full dose cisplatin. Some of them gave the pembrolizumab on day eight. We gave pembrolizumab on day one, but really throughout all the studies that are all single arms relatively small patients, our patient sample size, ours had 39, but the results are pretty consistent, which is I think when you put all the studies together, really compelling for boosting these pathologic response rates.
Sam Chang: And did you all see any differences in terms of toxicity or morbidity or delay in cystectomy or anything like that?
Tracy Rose: So we had the expected ... our study actually had a pretty low rate of immune related adverse events. If you look across all the studies that have been reported, there's the expected rare immune-related adverse event, but very few patients actually had any delay to cystectomy or we had no patients that didn't end up getting a cystectomy due to adverse events. We had an expected amount of myelosuppression, acute kidney injuries, et cetera, which we see from cisplatin.
Sam Chang: See from ...
Tracy Rose: Yeah.
Sam Chang: From the chemotherapy that they normally get from a neoadjuvant setting. And I think an important part or corollary to that is I think and I hope the surgeons are doing a better job. I'm sure they are at Chapel Hill. And I think more so even in practice that we're starting to see a better relationship in terms of having these muscle-invasive bladder cancer patients consult with medical oncologists to at least sitter neoadjuvant therapies. And now, we have exciting possible additions to the neoadjuvant regimen. So there's still patients though that either don't respond as well as we want to neoadjuvant chemotherapy who don't get neoadjuvant chemotherapy that we see and then undergo cystectomy. And then there are clearly some I think more recent data that really shows some promise for additional therapies afterwards. So tell us some of the highlights in terms of the adjuvant setting.
Tracy Rose: Yeah. So I mean, I think this question applies both to these patients that can't get cisplatin chemotherapy before and to those who have high risk pathology after cystectomy, but we have seen a lot of data come out recently in the adjuvant setting for muscle-invasive bladder cancer. So the big New England journal paper looking at adjuvant, nivolumab, which showed a disease free survival benefit for higher risk patients. So those who got neoadjuvant chemotherapy and have persistent muscle-invasive bladder cancer or those who did not but have T3 plus or node positive disease. And so the nivolumab is now FDA approved.
There was a sister study looking at atezolizumab in that setting that did not meet their primary endpoint, but what came out of that study was some really interesting data looking at circulating tumor DNA, essentially looking for known mutations in the cancer. And if they're president postoperatively, I think cycle one and cycle three during adjuvant therapy and actually they demonstrated that it looked like there may be a benefit to adjuvant, the tocilizumab and the patients that had positive CT DNA. And so really, getting down to this personalized medicine approach. And so I think that there's a lot to be done, both in figuring out who exactly needs the adjuvant therapy and looking at how we can use CT DNA to our advantage in those patients so we're not overtreating people, but were given people effective therapy.
Sam Chang: So from a urologist standpoint, we're not that bright as a category of individuals, as you know, and I love the folks and we've talked about earlier how respective the surgeons are at Chapel Hill, but all joking aside, it was somewhat confusing to us as we saw the data regarding, and this has been somewhat the case with some of the immunotherapy regimens, some show an advantage we think in phase two and then phase three, the statistical differences, the primary outcomes aren't reached. And so the tocilizumab and the pembrolizumab data and the adjuvant setting initially was confusing at least to me.
But then, as you described and talked about further digging into actually what's going on with those patients, clearly it seems like the patients that didn't have circulating tumor DNA, and tell me if I'm wrong, after surgery, they didn't seem to get a benefit from atezolizumab, which makes sense. You think that compared to someone who didn't have any cells versus those that do, you've probably done a pretty good job if the bladder's out and they don't have circulating tumor DNA, they're probably going to be okay, probably. So in looking at the nivolumab data, I don't know if this has happened, have they also further teased in to see if there were actually differences in terms of their data? Were they a higher enriched population with more circulating tumor DNA patients or do we not know that?
So I don't know that we know the answer to this, and one may say that nivolumab has a sort of blanket approval for the patients that fit. And so it may be less important to them to really figure out which patients would benefit. I think it's a question that absolutely needs to be answered. And there's one other study with pembrolizumab, the AMBASSADOR study done through the cooperative group that I think will not only shed some light on the somewhat conflicting results we get from the two studies, but also hopefully look at CT DNA and validate some of the things we've seen from the atezolizumab trial.
Sam Chang: And so from a medical oncologist standpoint, is there a sense that they are innately different in terms of their efficacy or that there probably isn't that much difference than it was populations of patients, et cetera? What's the scoop there?
Tracy Rose: Yeah. So I don't know the-
Sam Chang: I don't want to get you in trouble, but I just wondered if-
Tracy Rose: I don't know that we really know the answer to this. We have seen differences in the metastatic setting with slight differences in trial design that people have used to explain why the Pembrolizumab study and the second line setting was positive and the Atezolizumab study wasn't. Similarly, we talk about different patient populations, CT DNA things with Atezolizumab versus Nivolumab. If we get enough of these, we may start to think that maybe there is truly a drug specific difference here, but I just don't know that we know. If you look at the broader Atezolizumab data in bladder cancer in general, it looks somewhat comparable to the other drugs. But, it is starting to feel like a little bit of a pattern, but I think it's still an unanswered question. Yeah.
Sam Chang: And, do you think there's a sense that there may be a difference between the PD1 as a category versus PDL1, or it's still too early as well?
Tracy Rose: I think same answer. I mean, it is that the PD1 drugs have been meeting their endpoints, and I guess the PDL1, not so much. But, I think it's probably too early. I mean, Atezolizumab clearly has activity, I think it's just figuring out exactly which patients is the million dollar question for all of our drugs that benefit from one versus another.
Sam Chang: In that same setting that we've talked about, the adjuvant setting, obviously we've got the positive data regarding what we discussed about with Nivolumab. In those patients that have not seen or received any type of chemotherapy, currently, how do the medical oncologists determine ... There's FDA approval for Nivolumab, but for the individuals who have never received platinum-based chemotherapy, who would be eligible? It's, I think, easy when they're not eligible to receive platinum, but what about in those patients who are healthier or younger that had perhaps microscopic nodal disease? We think there would be an advantage for platinum-based therapy. How are oncologists now weighing their next steps? Is it now slam dunk Nivolumab? Is it, depends on the situation? Is it, well, they've never seen platinum-based chemotherapy, we would go there. What's the thought process you go through?
Tracy Rose: Yeah. So, for the bladder patients, if for some reason they just skipped neoadjuvant Cisplatin, and they're eligible for Cisplatin, typically I still recommend that. The overall response rates to Cisplatin are just higher than those for immunotherapy. And so, there's some rationale to me that it may more effective. It's very tempting for some of the very, very high risk people to put them on the metastatic paradigm, actually, and give chemo followed by immunotherapy, but we really don't have any data yet to support that. And then, if they're not Cisplatin eligible, but potentially Carboplatin eligible, we really don't have level one evidence for adjuvant Carboplatin. So, those people, I have that Nevolumab discussion. I'll tell you, though, I've been turned down several times by patients who are Cisplatin eligible but want Nevolumab. Because from a patient perspective, it's more tolerable-
Sam Chang: The tolerability, sure.
Tracy Rose: And they like it. So, clearly this is patient-centered. So, that's part of the decision making. I think the interesting conversation comes with some of the upper tracked patients who many of whom don't get neoadjuvant chemo and then are not eligible for Cisplatin but we have the level one evidence from the POUT trial. And, approval for Nivolumab that included some of those patients. Although, if you look at the subgroup analysis of the upper tract, it's a little bit less impressive. So, that's a very hard discussion with patients, I think, because they favor the immunotherapy many times for tolerability reasons. But, I tend to favor GemCarbo for some of those patients, but even that subgroup analysis is not positive. So, that's a really interesting disease setting, I think, right now, really ripe for clinical trials.
Sam Chang: Right. And so, along those lines, do you innately feel that in those upper track patients, as we switch gears a little bit from cystectomy now to upper tract. They've undergone a nephrectomy, they have high risk features. The POUT data would suggest that some platinum, either cist- or carbo-, would show a benefit. And I think it would be easy in terms of if they're platinum eligible, they get Cisplatin. How do you make that decision between GemCarbo versus now going on an immunotherapy for a period of time?
Tracy Rose: Yeah, I mean, I don't think we know this answer. I mean, I do think that there's some suggestion that immunotherapy may be less effective for the upper tract patients. There was actually a very tiny neoadjuvant study even for upper tract that looked at only Pembrolizumab and didn't look all that good. And so, if they're chemo eligible, I tend to favor that. But really, I think there's a big split. We don't know what to do with these patients. I introduce both. And again, a lot of times the patients will favor immunotherapy.
Sam Chang: I see. And so, we've talked about some exciting neoadjuvant findings, it's exciting adjuvant findings that really have opened opportunities as well as many questions for our patients. So, there's got to be trials going on now in the perioperative setting. What are some that excite you, that you're going to highlight, hopefully, at this year's meeting?
Tracy Rose: Yeah. So, I mean, I think one drug that we haven't talked about is Enfortumab Vedotin, which has really changed the metastatic management, and can be given to patients with impaired renal function. And so, there's actually a huge number of studies looking at this drug, one of which is going to be presented as a neoadjuvant cohort, each of looking at Enfortumab before cystectomy at ASCO GU this year. And I think that there's all sorts of variations, EV Pembro versus chemotherapy, EV Pembro versus EV, et cetera. And, I think that drug will be really interesting to see how people tolerate it, if it can improve pathologic response. And, there's even studies being designed in the adjuvant setting looking at that. I think the Cisplatin ineligible neoadjuvant space is a really interesting space too, with lots of studies, an immunotherapy going on. We've seen lots of single arm studies that look surprisingly promising in terms of pathologic response. And, will that move into a standard of care in the future?
Sam Chang: Care. Right. So, I think clearly then there's a better acceptance, like I said, in terms of surgeons understanding the probable beneficial role of neoadjuvant therapy. And now, it's like anything in terms of trying to make it better, and then balancing that with the tolerability profile of these additional medications. Anything exciting, then, that you see in the adjuvant setting as well, similar types of combinations?
Tracy Rose: Yeah. So, I mean, there's studies going on, are being designed, looking at some of our targeted therapies, too. So, some of the FGFR3 inhibitors, which may be applicable to our upper tract conversation. Looking at Enfortumab certainly may be beneficial in the adjuvant setting. I think it's going to be really tough as some of these neoadjuvant studies read out that have an adjuvant component, knowing whether doing things neoadjuvant is important, or whether we can just do adjuvant immunotherapy. And so, I also anticipate in a few years, we may be left with some questions based on the current design of all the studies going on.
Sam Chang: Right. Because I think just as importantly, clearly we want to maximize the beneficial treatments that we have, but we definitely don't want to maximize them at the cost of perhaps over treating some of these patients. And so, what you just said, of which really made the difference, would it have been enough just to do adjuvant versus the combination. Those are going to be the difficult questions that I think our medical oncologist colleagues are going to have to help us with, because we obviously would like to know also upfront who really would benefit from any type of therapy, even cystectomy versus trimodal therapy and that type of thing. You guys have always been, you guys being the researchers and clinicians at University of North Carolina, have always been at the forefront of studies and clinical trials. Are there certain ones that you, or certain ideas or concepts that you all are evaluating yourselves now and are excited in?
Tracy Rose: Yeah. Well, that Cisplatin ineligible space is really a nice window of opportunity, I think, to have patients who have this TURBT, bladder cancer resection, and then end up having a cystectomy. And there's some period of time there. So, for example, we have a study right now that looks at Pembrolizumab in that setting, which has good safety data already published in combination with one of the HDAC inhibitors Entinostat, which Billy Kim, who works at UNC with me, and one of my colleagues, has some really great data, pre-clinically looking at Entinostat as synergistic with Pembrolizumab, essentially inducing this anti-tumor immune response. And so, we're actually giving patients either Pembrolizumab alone or Pembrolizumab plus Entinostat in this window of opportunity and doing really translational endpoints of looking at, do neoantigens increase or decrease, can you actually get this anti-tumor immune response?
And so, I think that disease setting, in general, is really ripe for some of these studies. And, instead of doing a thousand people trial in the metastatic setting, randomizing looking for clinical activity, we're actually going to get pre- and post-tissue, give patients the chance to get active treatment. So, I think it's a really nice disease state to do these kinds of studies also with potential patient benefit.
Sam Chang: And to be able to then, like you say, be able to hopefully then those predictive changes in terms of, organ confined changes, being able, then, if that translates to ultimate disease-free survival, recurrence free survival, metastatic-free, would be incredibly beneficial. Because then being able to then determine upfront would be great.
Tracy Rose: Yeah.
Sam Chang: Well, Tracy, thank you so much for spending some time with us, and it's a conversation that honestly wouldn't have been a very long conversation a decade ago. And, thank you so much and look forward to your presentation.
Tracy Rose: Thank you very much.