BackTable Urology
Ep. 193 Bladder Cancer Innovations: ESMO 2024 Highlights with Dr. Andrea Apolo
Tue, 08 Oct 2024
Catch up on the latest breakthroughs in bladder cancer management. In this episode of the BackTable Urology Podcast, Dr. Bogdana Schmidt (University of Utah) speaks with Dr. Andrea Apolo, a medical oncologist at the National Cancer Institute, about recent advancements in bladder cancer treatment presented at the 2024 European Society of Medical Oncology (ESMO) Congress. --- SYNPOSIS They review pivotal trials like the NIAGARA and AMBASSADOR studies, the TAR-200 drug delivery system, the use of bladder-sparing treatment, and the role of ctDNA as a biomarker. Further, they detail the effectiveness of systemic therapies such as gemcitabine and pembrolizumab, the implications of perioperative immunotherapy, and the future role of antibody-drug conjugates. The conversation highlights the trend towards less invasive approaches while improving survival rates from bladder cancer. --- TIMESTAMPS 00:00 - Introduction 03:49 - NIAGARA Trial 09:10 - Challenges in Bladder Cancer Treatment 18:56 - AMBASSADOR Trial 25:30 - Adjuvant Immunotherapy 29:30 - Exploring Biomarkers and ctDNA 36:34 - Surgery and Less Invasive Therapies 46:31 - Future Directions in Bladder Cancer Treatment --- RESOURCES ESMO https://www.esmo.org/
This week on the Backtable Podcast.
I'm actually excited about the TAR system. The TAR 200 is with gemcitabine, but I'm excited about the whole device and the way that you can deliver it into the bladder so easily. And it delivers a slow amount of drug into the bladder. I love that. And the possibility that you can put other drugs.
active therapies in there so i'm really excited about it and i think we do need something that kind of manages the bladder right so we have these great systemic therapies but although most patients when they're responding to systemic therapies also respond within the bladder it'd be nice to have an additional intensification of treatment in the bladder potentially in the future to have bladder sparing approaches and this may be a way of doing it intensifying
treatment with these tar systems and then leaving the bladder intact.
Hello, everyone, and welcome back to the Backtable podcast, your source for all things urology. You can find all previous episodes of our podcast on Apple Podcasts, Spotify, and at backtable.com. My name is Bogdana Schmidt, and it is my pleasure to introduce Dr. Andrea Apollo.
She's a tenured senior investigator, medical oncologist, and acting deputy chief of the Geomalignancies Branch and head of the Bladder Cancer Center at the NIH. She's led numerous GU clinical trials, including one we'll be discussing today. Dr. Apollo, welcome to the Backtable podcast. Thank you so much for having me. I really appreciate it. I'm really looking forward to this conversation.
We'll be discussing highlights specifically in the bladder cancer field presented at ESMO 2024 in beautiful Barcelona. Before we get into it, I just want to point out how alive our field is right now. The meeting had over 5,000 abstracts submitted, over 600 invited speakers, but what I found fascinating was the statistics on the number of trials going on in GU right now.
In my very young urologic oncology life, this is still incredibly impressive. There are currently 351 active trials in RCC, 188 in prostate cancer, and 929 in bladder cancer. This is unbelievable.
Yeah, this is this to me, it's like a dream come true. So we've always given patients platinum based chemotherapy for bladder cancer with really not that impressive results. But, you know, we've done a lot of trials and we really struggle to do better than platinum based chemotherapy. And now we're doing this in the metastatic setting and we're bringing it to the perioperative setting.
So I think it's a really exciting time where we can actually play around with the therapies that we have in terms of designing clinical trials and find the best treatment options for patients and hopefully in the future, spare their bladder and improve their overall survival, which is really the goal.
Absolutely. And I think that goal actually is reachable. You know, when I started even just a few years ago, I used to tell patients, look, if we're still doing the same thing in bladder cancer 10 years from now, we haven't done our jobs. And even in the last few years, we've made such interesting and promising advances that I'm really hopeful we'll get there.
So I wasn't sure the best way to organize this chat. So I think maybe we should start with the most advanced, most likely to be practice changing abstract, and then spend some time on things that are interesting and thought provoking, maybe not quite prime time.
But I definitely want to get your thoughts on where you think the field is heading and what you'll be looking forward to in future meetings. So with that in mind, let's jump into the Niagara trial presented to Dr. Tom Powell's.
Yeah, so I was so excited to see the results of this study, especially after last year, we saw the really exciting results of EV plus PEMBRO in the metastatic setting. And then we saw the Checkmate 901 data, where when nivolumab was added to GEMSYS, it did better than just GEMSYS alone. And that just kind of set the stage for the perioperative trials that are
ongoing right now, and Niagara was the first one to report its outcome. And, you know, once I saw that the Checkmate 901 study was positive, that adding nivolumab actually did improve outcomes to platinum-based chemotherapy, but to cisplatinum-based chemotherapy, it didn't have as strong effect with carboplatinum. So that was...
important because we give cis-platinum-based chemotherapy for patients with muscle-invasive disease in the perioperative setting, neoadjuvant and adjuvant. So that's why I was really excited to hear the results of the Niagara. And of course, we had the press release that it was positive. So really excited to see the results of that trial.
So let's talk a little bit about the details of Niagara. So like you said, it's neoadjuvant cisplatin-based chemo with perioptervalumab addition. So these are patients who got dervalumab before and after.
One of the things that I thought was interesting here, and I want to see what you think about that, as you mentioned on it about cisplatin versus carboplatin, is patients were able to receive cisplatin with a creatinine clearance of down to 40%. Is that your typical practice? Are you seeing patients going to split dose at 40, or do you generally cut off patients at 50?
So great question. And that was one of the things that I really liked about this trial was that it was very practical and real world. And that's what I do in the real world is I go down to 40 and I split the dose. If I can make a patient cis-platinum eligible, I do. And whatever I can do to help the patient become platinum eligible is very important to me, cis-platinum eligible specifically.
So I will split the dose of cis-platinum and it's more tolerable. And that's what they did in this trial. And I really like that.
One other thing I wanted to highlight for this trial, and maybe we'll come back to that as well, is the patient population here. So we looked at patients that were T2 to T4, N0 and N1. So there were some node positive patients here. And of course, in the comparator arm, patients were randomized to get just GEMSYS and radical cystectomy, didn't get any adjuvant treatment.
Looking at this trial, if you were designing it today, what would you have included or tried to do differently? Knowing, obviously, this trial was enrolling when I was a fellow, so five years ago, so I know we didn't have a ton of the data that we have now.
But given the groupings, given the decisions that were made in the standard of care arms, if you were redesigning it, how would you do it differently now?
So great question. I think the standard of care has been the standard of care for a while until we had the approval of nivolumab in the adjuvant setting. And that just happened. It wasn't that long ago. 2021 was when that occurred. And I think that what I would have done differently had I known the activity of nivolumab and the activity of pembrolizumab.
Yes, which we'll get to in a minute.
The ambassador study that I presented at ESMO and I presented the updated 45-month follow-up data. I would have done an adaptive design where if the patients had a pathologic complete response, then maybe we don't need the adjuvant approach. But the truth is we don't really know that, right? Because if we think about this as systemic disease, then maybe they do actually have
need a little bit more therapy in the adjuvant setting, even if they achieved a pathologic complete response. But I would have designed it more adaptively. And if the patients didn't respond, I don't think I would have continued adjuvant dervalumab because would there be I don't think there would be a good rationale to continue a therapy that didn't work in the neoadjuvant setting.
Now, that's not the way it was designed. Everybody got neoadjuvant in the treatment arm and everybody got adjuvant in the treatment arm. And in the control arm, nobody got adjuvant. But I think that it was a fair design without making it multi-arms. That would have been another way of doing it, but it's already a thousand patients.
So this would have made it a lot larger where we don't give adjuvant in a different arm. And it's not an adaptive design. It's just a different arm where patients do get adjuvant and then another arm where patients don't get adjuvant. So I think a lot to learn from this trial and we yet don't have
The granularity of the data is if they did response, let's say they had a pathologic complete response, how did those patients do with adjuvant therapy versus if they didn't? How did they do with adjuvant therapy? How did they do in terms of event-free survival, which was the primary endpoint? So I think all these questions will be answered as the data is reported a little bit more and it matures.
I agree. And I do want to get back to your point. I think that's a really important point of path CR as an outcome here, because that is tricky, right? We know that even from old trials, SWOG trial, Nordic, et cetera, that when we were looking at neoadjuvant chemo in this setting, there is a PT0 rate from TUR alone, meaning no neoadjuvant treatment whatsoever, in the 12% to 15% range.
And neoadjuvant chemo gets you 25% to 38%. There is that variability of did you get a good TUR? Was it in a location where you could have truly resected all of it? And those factors are really hard to account for. But I think to me, when I think about these things, I think that the distant metastatic potential is what I worry about the most. Right. That's why we're giving the neoadjuvant chemo.
It's for the micrometastatic disease. It's to combat that. And so here the adjuvant stuff becomes really important because. PT zero, I don't know how meaningful of an endpoint it is long term. Right.
We've been using it as a surrogate for what's going on in the rest of the body. If you're downstaging, if you're responding in the bladder, which is something that we can observe and stage, although you can argue not as well as we think we can, at least that kind of gives us an idea of what's going on. And
And that's I think this study will actually help us to understand the role of pathologic complete response. And there's so many definitions of what actually is a complete response, a complete pathologic response. Do you count the carcinoma in situ? Do you count the low grade TAs? How rigid are you? Or is it just any non-muscle invasive diseases counted as a pathologic response?
I think that there's the definitions have been really variable. So it's been a hard endpoint to use. But I think we'll learn a lot from this trial.
And I think to that point, so there were in this trial, correct me if I'm wrong, about 60 something patients, 63 patients who ended up not getting a cystectomy. So figuring out the data on those patients, I think also will be informative. What do you think about that and how that factors into how we interpret the data altogether? Yeah.
I think that'll be really important because that will be our ultimate goal. So those patients that failed because they didn't get a cystectomy, if it was by choice, then it's not really a failure. I think those patients should be followed. And I don't know if they got adjuvant therapy. I think it was mixed. Some of them did get adjuvant therapy, even though they did not undergo a cystectomy.
But that may be the way that we treat patients. We treat them systemically with therapy and hopefully not remove their bladder. So in a way that failure is actually a success for patients.
If those patients remain disease-free, right? That's the important caveat because from retrospective data, we know that patients who were T0 after neoadjuvant therapy, who didn't go on to cystectomy, have a recurrence rate of up to 50%, right, if you follow them one to two years. And so obviously that's without adjuvant treatment.
But I think that's where a lot of the future will come in is how can we treat this patient? How can we pursue Protect the bladder, certainly. I mean, if we get to a point in bladder cancer that I don't have to take out bladders, I won't cry. But I want my patients to do well.
And I think figuring out which patients are going to be able to do well with their bladders intact and how do we get them there, that'll really change the game. I mean, certainly that's what we all want. That's what I would want.
Yeah, no, I completely agree. We need to learn from those patients. Yeah.
So anything else that you wanted to highlight on this? Because I think there's still quite a bit to talk about with Niagara.
Well, just that I think time will tell in terms of the rest of the outcomes of that trial and their other trials. Also, that we're awaiting their data that include platinum-based, cisplatinum-based chemotherapy in combination with with a checkpoint inhibitor, including the Energize study with nivolumab. And we also have the Keynote 866 study with pembrolizumab.
So there are additional trials that had this similar approach where they gave neoadjuvant cisplatinase-based chemotherapy with a checkpoint, and then there was an adjuvant component. So I think reading, I think the outcome of those trials will be super important. But for now, I mean, I think that we have to consider this a new standard of care. I mean, patients did so well.
They had an improvement in event-free survival, but they also had an improvement in overall survival. And that's so important for our patients because We've struggled to show an overall survival benefit in the perioperative setting. So we can be really critical about this trial, the way that they over-treated patients, but there was an overall survival benefit.
So I think, you know, we should consider including Dervalumab now in the neoadjuvant setting and in the adjuvant setting.
Now, I agree with you. I think it's hard to ignore the data, and truly an overall survival benefit is incredibly meaningful, and it's what we've been wanting for these patients for a long time. A couple of practical questions I have in this space for you. So, obviously, there's still some nuance, but as this gets more broadly adapted,
adopted, what do you think we as surgeons need to be looking out for taking care of these patients perioperatively? I say this because that duralumab they're getting before, right, oftentimes managed by the medical oncology team. But in the acute post-op setting, we Generally, hopefully, you know, our patients do great, go home on day four and everything's smooth as butter.
But knowing that they have gotten a perioperative checkpoint, do we need to be looking for other things post-op or in the acute periop period and not ignoring it, not thinking, oh, this is just nothing?
I think we're learning. I think that's a great concern to have. In this study so far, they did not report any issues with surgical outcomes or even post-surgical outcomes.
There were a couple patients who were pushed out for surgery, though. So they delayed time cystectomy. I don't know how that'll happen in the real world.
Yeah, and I think we need to understand that when the patients are getting combination therapy, the urologist and the medical oncologist need to stay really close in communications with labs because immune-related adverse events can occur at any time and often occur a little bit later. So could they occur postoperatively immediately? Of course they could.
So we don't have yet the details and the granularity of those kind of adverse events that occurred in this study, but I think that they will occur and it's important for the urologist and the medical oncologist to stay closely connected in this perioperative setting.
Yeah, I absolutely agree. I think to me, that's my main takeaway is if something doesn't look absolutely routine, my first phone calls to my medical oncologist and say, could this be immune related? What do I need to send? What other studies do you want me to get? And be thoughtful about that. With the amount of patients with variant histologies on this trial, it was up to 20%.
Are you seeing this as a positive, meaning you would extend this, basically this treatment paradigm to those patients up front, or do you want more data for that specific patient population?
So patients with variant histology often are not included in trials. So I do love the fact that they did include patients with variant histology in this study. And I treat these patients as I would regular urothelial carcinoma, unless there's a small cell component in it or a neuroendocrine, a high-grade neuroendocrine component. Then I treat them as more like a lung component.
small cell cancer with that kind of paradigm in terms of the systemic therapies that I use. But in general, patients with variant histologies, I treat them as urothelial carcinoma until we have prospective data showing that another regimen or something different would be better for these patients.
Practical question again, just because I have the expert here. What about plasma cytoid, high volume plasma cytoid? Are you scanning those patients differently? Are you surveilling them any differently or about the same? Those are the patients that I always worry about. What if they're progressing on treatment? What if I'm missing a resectability window?
Those are the patients that I get super nervous about because although they do respond well to platinum-based chemotherapy, they respond well to checkpoint inhibitors. They do have a higher rate of positive margins. They have a higher rate of recurrence. And I don't know how to better manage them with the therapies that we have right now without prospectively testing them.
But I feel like those patients... do need close surveillance and may benefit from more aggressive therapy, but I don't know what that more aggressive therapy is. I do think that they need systemic therapy. So I think going straight to surgery is not the answer.
I think they need more systemic therapy probably than other patients, but how to intensify that systemic therapy, I think we need to learn that. We don't know yet.
Excellent. Well, thank you. Again, I think this is really interesting and promising data and certainly already has the potential to be practice changing as it is. And we'll just continue to learn more and more from it. Some of the questions that we'll be looking to learn from it will actually hit on discussing a few of the other studies.
So maybe we can move on to talking about your trial, talking about Ambassador.
Yeah, sure. So the Ambassador Study, I was really excited to present the 45-month follow-up for the Ambassador Study. We had presented the 22-month follow-up at GU-ASCO, and we had a lot more data now. We're really fortunate to do a concurrent publication in the New England Journal of Medicine with the outcomes of the Ambassador Study.
So just to kind of summarize what it is, this is a phase three study randomized for patients with muscle invasive urethelial carcinoma who undergo radical surgery and they have high risk disease. And by high risk disease, This means they received neoadjuvant cisplatinibase chemotherapy and have a persistent T2 muscle invasive disease or greater.
And this includes positive margins and positive lymph nodes, which, you know, it's kind of special that we included positive margins. Or they did not receive cisplatinibase neoadjuvant therapy but have a T3 or greater muscle invasive disease or positive lymph nodes or positive margins.
So those patients were randomized and this trial was designed a while ago where there was really no treatment for these patients in the adjuvant setting, especially if they couldn't receive cisplatin and base chemotherapy, either neoadjuvant or adjuvant setting. The patients were randomized to receive pembrolizumab for one year versus observation.
with the dual primary endpoint of disease-free survival and overall survival. So we reported the outcomes of the disease-free survival and we found a doubling of the disease-free survival with adjuvant pembrolizumab. So it went from 14.2 months with observation to 29.6 months in the patients receiving pembrolizumab. So this was really exciting.
And the results just show that adjuvant pembrolizumab is effective in this setting and should be considered an option for patients that have high-risk muscle invasive disease.
Absolutely. And like you said earlier, you know, we already had nivolumab approved before. So that's two positive trials in this space. We didn't really talk about Invigor, the earlier Atizo trial that didn't meet its primary endpoint, which could be related to the Atizo, could be related to where the trials were structured.
But certainly, I think we have enough data now that adjuvant therapy in the post-cystectomy setting with nivolumab or pembrolizumab is here, right? So based on this, and obviously I know you have a little bias potentially because it's your data and you're familiar with it. So it's a good bias. If and when both drugs are approved and available in the clinic space, how will you choose between them?
So great question. I wanted to also mention that we did look at PD-L1 status because in the nivolumab 274, checkmate 274 study, it was actually the patients that were PD-L1 high did better. And although here in the United States, it's approved for all patients, regardless of PD-L1 status, in Europe, it's really only approved for patients that are PD-L1 high, the adjuvant nivolumab.
So we did look at the marker in our study, in the ambassador study, and we found that it didn't matter if you were PD-L1 positive or negative, both groups had a benefit. So I think that's important because you're not worried that you're treating somebody that's PD-L1 negative and they're not going to have a benefit.
It was really strange actually that in the patients that were PD-L1 negative, they had the largest benefit, although there was a benefit in both groups. So regardless, the point is that we don't need PD-L1 status to select the patients for treatment for adjuvant pembrolizumab. And in terms of which one I would use, I was using nivolumab for a while.
And then while my trial was ongoing, I was using pembrolizumab. Then while we were waiting to date, I was using nivolumab. And now I've gone back to using pembrolizumab. And the reason I like pembrolizumab, I like them both, to be honest. They're both pretty easy to use. The nivolumab, the trial was done every two weeks. But I use them monthly because that's an FDA-approved dosing.
And for Ambassador, we did it every three weeks. But I use the six weeks. Every six, right?
Yeah.
So it's kind of nice in the adjuvant setting to let the patients have time off coming to clinic and seeing them every six weeks in terms of dosing because that's an FDA approved dosing schedule for pembrolizumab. So I think that's a plus that you can give it every six weeks.
Is there any patient population or anything, just knowing, obviously, cross-trial comparisons are so fraught with so many problems, but is there any patient population for whom you might say, maybe nivolumab, we have slightly better data for? Or do you feel like the dosing schedule of Pembro kind of trumps things?
I think there are more similarities and differences. And from the outcomes that we have seen, I don't really see any difference. So I use pembrolizumab. I like the dosing schedule, and I'm very comfortable with it.
Excellent. And I think you and all of our, I think, medical oncology colleagues have been using pembrolizumab for its numerous indications. So I think that the comfort level certainly is really interesting. Can you comment a little bit about upper tract disease?
So the upper tract data was not as robust as what we had seen in, you know, what we had hoped, but we had seen in lower tract patients, which are predominantly bladder, and it did include some urethra, but predominantly bladder. About 20% of the patients were upper tract, and we didn't limit the enrollment of upper tract.
And we actually didn't see a difference in terms of benefit with adjuvant pembrolizumab versus observation. And I can't explain why yet. We've done a bunch of subgroup analysis to try to tease out ureter versus renal pelvis. And the truth is these numbers are so small and the confidence intervals overlap. So it's really hard to make any conclusions from the data that we have.
It is a different biology, but I would have thought that these patients... maybe perhaps would have had a great response. And right now, I think we have a lot to learn and we need to tease that data a little bit more and really do trials in upper track to better understand who are the patients that benefit. Now, that being said, given that the trial was not really designed to
select for the upper tract patients and you can't make conclusions from subgroup analysis, I give it to upper tract patients. But I tell them the data. I tell them the data and I say, do you want it? And most patients want it because they... Upper tract is scary.
We want something. We certainly all want something.
The question that I think comes up is what is the role now of adjuvant immunotherapy now that we have the Niagara data, right? So how does that fit in? I mean, if everyone's going to be getting Dervalium-AV plus Gem-Sys in the neoadjuvant setting,
And the truth is that that's not going to be the case because there's a lot of patients that, you know, refuse cisplatinum-based chemotherapy, are not eligible for cisplatinum-based chemotherapy, are not going to get any neoadjuvant chemotherapy. About, you know, half of our patients in the ambassador study got no neoadjuvant chemotherapy.
And, you know, the predominant reason was because they weren't eligible to receive it. And then there's also a group of patients that we think are not T2. And then we do the surgery and they are. And they are really high risk, higher than T2. So I think for those patients, adjuvant checkpoint inhibitor is still an important treatment option.
So I think that's where we'll kind of fit with the Niagara data that we just saw.
So now to just put a point on what you just made. So let's say you have a patient who refused cisplatin up front, not, you know, didn't get Niagara Protocol. Post-op, would you still be trying to engage in chemo or checkpoint if they're eligible but refused? Would you be trying to tackle that refusal for the second time or no?
No, that's a great question. And right now what I'm doing is I do offer them cisplatinum-based chemotherapy if they did not receive it and they were eligible. But again, if they refuse it in the neoadjuvant setting, they're probably going to refuse it in the adjuvant setting.
They have their fear of the platinum-based chemotherapy, which we try to alleviate, but a lot of patients just don't want it. But I do offer it to patients if they didn't receive it and they're eligible in the adjuvant setting, I do offer them cisplatinum-based chemotherapy. And I also offer it for upper tract patients, which, you know, we have protective data for that.
From a cup now at the NIH, this may be less of a point for you guys, but let's say a patient refuses adjuvant chemo at this point. Are you able to offer them checkpoint inhibitor in lieu of it? Oh, yes, of course. Because I know that some folks will say that they can't get insurance approval for it if they're CIS eligible. But obviously, at the NIH, this is less of an issue.
And I know there are ways to get our patients what we think is in their best interest. But even with all of this immunotherapy data, When patients didn't get cisplatin up front, we're still sort of advocating for cisplatin adjuvately because that's what we have the strongest longitudinal data for. So I'm sure that space will continue to evolve. Now, you almost led me straight to the...
to the next topic, which is how are we going to figure out how not to over-treat these patients? Because you mentioned in Niagara, right, we're having patients get dervalumab up front, then chemo, then dervalumab. Now we have ambassador and checkpoint data for just adjuvant, but we also know there are probably
Quite a few patients that are cured by surgery alone maybe don't need adjuvant or including that neoadjuvant space. So we're all talking about other markers. Is it imaging? Is it blood? Is it urine? We had the TOMBL trial presented.
What do you think about that if you want to talk about TOMBL or you want to talk about what you're doing in practice and how you're trying to answer that question for your patients now? Yeah.
It's such a great question. And I think there's a lot of effort right now ongoing to try to understand the role of biomarkers, specifically ctDNA, and how we can incorporate them prospectively and better select the patients that actually need therapy. So as medical oncologists, we intensify treatment a lot because we want to
provide the best overall outcomes for patients safely, of course, but give them the best chance. But we do over-treat patients. And I think that's why one of the reasons these adjuvant trials are so large is because we have to treat a lot of patients in order to see a benefit. And a lot of patients that we're treating, we're over-treating them, right? So not everybody needs it.
And then there's a small group of patients that may need even more that They may need intensification and just monotherapy, immunotherapy is not enough. So I think that's where the role of ctDNA comes in. And I love that there are prospective trials trying to answer that question right now, the Invigor 011.
is trying to answer that question, treating with atezolizumab, using ctDNA to treat those patients. The modern study here in the US is also asking that question, using ctDNA to decide whether you intensify the treatment or whether you do you really need the treatment, and really only treating the patients that are ctDNA positive or that convert to ctDNA positive in a randomized fashion.
So I love that. And the Tembola trial did that in a non-randomized fashion using ctDNA and seeing if they can treat the patients that are ctDNA positive or convert to positive with adjuvant atezolizumab and seeing if those patients did better. And the nice thing is that they showed that One of the things that was really interesting, I thought that they showed was that high risk.
So so we categorize patients into high risk and low risk patients. Right. And yes, the high risk patients had CT DNA, but not all of them did. And then there were some patients that were not high risk, you know, by our criteria. And they about half of them still had positive CT DNA. So, you know, we think we're good using clinical baseline characteristics in terms of how to make patient how to.
how to stratify patients into the highest risk. But we may not be capturing all the patients that are actually high risk and do need treatment in the adjuvant setting. So I really like that part of the Tembola trial and then following them and seeing they convert you know, how many of them converted with treatment, and then how did they do with the tezolizumab treatment.
So I think that this is a really important study, and more studies are going to be done that are actually randomized. So this kind of set the stage, and we have retrospective data also. So I think this kind of sets the stage for the importance of ctDNA within this perioperative study, and then what to do if you do have a positive ctDNA response. how to follow the patients, kind of what to expect.
I mean, this is all evolving right now as we speak. So I think it's really exciting to have a biomarker to work with.
Now, absolutely. And just to highlight a couple of details from Tambola. So you're absolutely right. Over 52% of their patients were CT DNA positive after cystectomy, which is a lot higher than you would think, at least certainly higher than I would have guessed.
And the wonderful thing is they were doing very serial kind of monthly measurements and 75% of patients were detected in less than four months. So you're thinking about adjuvant therapy. Generally, we start within three months, right, based on the trial. So
Using ctDNA, we would have that window to pick those patients and still have time to start them on the treatment that we would start, but potentially select out the ones that maybe didn't need it. Now, I'm looking forward to the rest of their manuscript data to see how often do you actually need to be checking.
That's a little much. We decreased that. And I liked how sensitive it was, really, of the ctDNA negative patients. Only two of the patients developed metastases. Now, of course, my hope would be that it would be zero and that it would be super sensitive and it would pick that up. And we saw that also.
In the early data presented from the InVigor 011, where they followed patients that were ctDNA negative, and they did see that some patients, although a really small percentage of patients that were ctDNA negative, did have progressive disease that was metastatic, that was not picked up.
Correct. And that was 10%. So you said, you're right, for Tombola, it was 15%. Two patients, 3%, but in the Invigor, it was up to 10% of patients. But I kind of wonder if that has to do with the sensitivity of the assays. They were doing different assays in these studies.
They were, and I think that we're only getting better. So we're only getting better. The assays are getting more sensitive. They're including methylation. They're even doing whole genome sequencing instead of whole exome sequencing now. So I think the biomarker is evolving, and we're only going to get more sensitive.
So in your perfect scenario of this perfect biomarker that I truly am optimistic it'll come. It may not be perfect right away, but we'll have something where we have nothing right now. Do you use ctDNA in your practice right now to make decisions? I do. I do.
And sometimes I struggle when I don't see anything and the patient has already undergone all the treatments. So they've already undergone neoadjuvant chemotherapy, undergone radical surgery, undergone adjuvant checkpoint, and their NAD, and then they have this positive ctDNA. I don't know what to do at that point. Do I start more systemic therapy? How do I intensify the treatment?
Do I restart checkpoint inhibitor? I mean, I think there's a lot of unanswered questions. The marker is available for us here in the US. And I think we need to learn how to use that tool a little bit better than what we know now. But I think it'll come.
Yeah, I think so too. I think the medical oncologists I work with who are phenomenal and I love them and trust them very much, but they have the same struggles that you're experiencing. They actually don't wanna check because they don't know what to do with that information.
And that would be the right thing to do, but it's hard for me not to check because I know that it's an available tool. And of course I want as much data as possible to make an informed decision for patients. But in some scenarios, we don't have the right answers to what to do with that result.
And I think the prospective data at InVigor and Modern, like you mentioned, are going to give us that data and hopefully help us figure out how to interpret this so that we have less hesitation to get the data in the first place so that we sort of know what to do with it.
So this gets me into my next question, which I wanted to ask after Niagara, and then I wanted to ask after Ambassador, and I figure I just have to ask it now. So the earlier and earlier in the system that we're introducing checkpoints, right? We hope, of course, that all of that works and our patients don't progress and don't develop metastatic disease.
And that's why we do all of it, which makes perfect sense. But now that we have really great EV PEMBRO data for metastatic disease, and I know you don't have a crystal ball to tell me for sure how using checkpoint up front will impact that data. But what do you think? Are you worried that it'll make that data look worse? Or do you hope that it'll make it look better because of a priming effect?
I don't know the answer to that, but I do tell you that initially I was, when a patient got checkpoint and they develop metastatic disease, I was moving on to EV alone, but The more I thought about it and the more I discussed it with patients, I think that there's a synergy with EV plus Pembro and I think that it's reasonable to try to intensify the treatment that they're receiving.
So even if they progressed on checkpoint, continuing checkpoint and giving the infortimavidotin with pembrolizumab in the metastatic setting. So I am doing that. I don't think it's wrong just to give EV by itself, but I don't know what the right
And whether we continue the checkpoint inhibitor or not, there is data in kidney cancer where there is no benefit to continuing a checkpoint inhibitor once a patient has progressed on it. But most of it has been done in the metastatic setting, although the most recent data with Tivolumab was done a little bit earlier.
It did have some patients that had received adjuvant therapy, but a small number. And they did not see a benefit to continuing checkpoints. So I think this is an unanswered question. All cancers behave differently, have a different biology. We know that bladder cancer is not kidney cancer. So I think we need to answer this question prospectively.
And for now, if the patient can tolerate it, I do continue the checkpoint if they develop metastatic disease with and for Tamavidotin.
Thank you. And like I said, this is something that we're all going to ask more and more as we basically have more of these patients, right? Right now, these are all patients that have just been on trial. And so we'll be following them closely. But as we start to make these decisions, hopefully we'll get some more real world. evidence in this space.
So we've spoken about the more advanced bladder cancer setting, the muscle invasive, kind of how to make these decisions. I do want to talk a little bit, just for the surgeons in the audience, about some of the more surgical trials, the Sunrise trials, starting with Sunrise. four, which was the muscle invasive trial with citralumab and TAR200.
And I think this one points a really great point on what we mentioned earlier with the patients who refuse cisplatin. In this set of patients, there are just 60-something percent of patients that enrolled on this trial We're cisplatinum eligible, but refusing cisplatinum.
I think speaking to investigator excitement potentially and wanting to get patients on trial, but also speaking to the fact that patients don't want cisplatinum. They want something newer, better, hopefully less toxic. And now that we have these newer agents, newer devices, delivery mechanisms, I think this is interesting to figure out how are we going to incorporate that into the paradigm.
Yeah, I'm actually excited about the TAR system. The TAR 200 is with gemcitabine. But I'm excited about the whole device and the way that you can deliver it into the bladder so easily. And it delivers a slow amount of drug into the bladder. I love that. And the possibility that you can put other active therapies in there. So I'm really excited about it. And I think we do need...
something that kind of manages the bladder, right? So we have these great systemic therapies, but although most patients when they're responding to systemic therapies also respond within the bladder, it'd be nice to have an additional intensification of treatment in the bladder potentially in the future to have bladder sparing approaches.
And this may be a way of doing it, intensifying treatment with these tar systems and then leaving the bladder intact potentially.
Yeah, so just to quickly introduce Sunrise for kind of the concept. So this was the muscle invasive patients who were chemo ineligible or refusing, who got TAR200 plus citrelumab versus citrelumab monotherapy. And this was in that five to three randomization that maybe we can talk about a little bit. Those patients then went on to get radical cystectomy.
And because this was phase two, we were looking at pathologic complete response patients. as the primary endpoint in these patients. And it was really, you know, I think, striking. CR in that combo arm, TAR200 plus citralumab, was 42%, which is sort of what we saw in the neoadjuvant chemo trials. Nothing went above 30%, right? So there's some neoadjuvant immunotherapy trials, but
PathCR 42% with complete response. I think it's promising, very promising.
Yeah, and I'm glad that it was randomized because, you know, someone can argue, well, they received a systemic treatment with a checkpoint. But they did have a monotherapy checkpoint arm, and the pathologic response rate was much lower. That's right. Sorry, I could have said that, but it was 23%, so half. So it's nice to see that putting the TAR200 in the bladder intensified that.
the treatment effect with almost doubling of the pathologic complete response rate. So I think I'm very excited about this data. And I think that it could be something we could potentially use in the future, along with all these systemic therapies that we are now developing in the perioperative setting.
Absolutely. And then just getting to Sunrise One, which was obviously in the non-muscle invasive space, they also showed incredibly promising results, 83% with just TAR 200 alone, which I think is really great. I'm personally, as a surgeon, a big believer in TAR. intravesical treatments for intravesical-only non-muscle invasive disease.
But looking at, there have been a couple combination trials now, right? So the Sunrise 1, looking initially with a citrelumab plus tar, and then you have data with creatostimogene in combination with PEMBRO. I think that, and then, of course, we had the PEMBRO data alone, which To me, that doesn't seem to be the primary direction that people are going.
And I think as a surgeon, we all want intravascular treatments for localized disease, one, because that's something we're comfortable with. But two, I think it more comes to the fact that we're comfortable managing those side effects, right? We know what to expect. We know kind of the worst case scenario for the patient.
And we know it's not going to necessarily be a hospital stay or, you know, stress dose steroids or anything kind of adverse immune. So as we develop more of these interesting mechanisms or delivery mechanisms, I think that we'll be able to offer our patients some new, better treatments than what we've had for them since the 70s.
Yeah, and I don't understand part of the trial. I was very excited by the results. I think that it's great that there was such a great 12-month complete response rate. I think this is the best one that we have seen.
55%, which is, you're absolutely right. The durability is where it counts, right? That 83% number, that response at any point, that's great. We're all excited. But if at three months it looks great and at six months it's all back, then that wouldn't really help the patient. That just cost him a lot of money.
But I don't understand why the combination didn't do as well as them or the monotherapy was the one that did the best, right? So that I wasn't sure if there was some antagonism or it was just the patients. These are really small numbers, right? I mean, the combination- I think it was like 50 patients versus 85 patients in the combination arm. So these are small numbers.
But, you know, why is it that the monotherapy did so well in terms of the CR rate? I think it's the endpoint that is being measured. You know, if you're measuring a local endpoint. and you're giving a local therapy, the local therapy is going to shine. But why didn't it shine when it was in combination with the checkpoint?
So I don't know if this is just a little bit of noise from the... I think they were very similar in terms of the 12-month CR rate, but I would have thought that it would have been a little bit better with the combination, and it wasn't. The TAR-200 did just as well as monotherapy in terms of the 12-month CR.
And you're right. We may see different data in longer-term follow-up. And once the noise, kind of the numbers of the patients that drop off, we might get a clearer signal with that. These are all still in the abstract phase. So we might learn more in that. But I still think it's exciting and promising. And so to get to exciting and promising, we've talked about periop immunotherapy.
We've talked about biomarkers. We've talked about better intravesical intensification treatments. You've certainly mentioned, obviously, the big lofty goal of trying to decrease the number of bladders that we remove and making sure our patients live longer that way. What do you think is going to happen in the next six months to a year?
What do you think we're going to be talking about at the next ESMO or at the next GU-ASCO? Kind of what's in the pipeline that you're looking to hear about?
So I'm excited about the antibody drug conjugates in combination with checkpoint inhibitor trials. There's three large trials, and this is, of course, because of the amazing 302 data where we saw doubling of the overall survival in patients in the first-line treatment with metastatic bladder cancer.
And there are several trials that are ongoing right now asking that question in the perioperative setting. And similar to what we saw with the cisplatinum plus checkpoint inhibitor trials, they have a neoadjuvant component and an adjuvant component.
So there's the EV304 study for patients that are cisplatinum eligible where they get EV plus PEMBRO and in the neoadjuvant setting, and then they get it in the adjuvant setting, and then there's the control arm study. that just get neoadjuvant cisplatinum-based chemotherapy and nothing in the adjuvant setting. And then we saw a little bit of data from the Volga study at ESMO.
And this was basically the safety run-in with the triplet EV, DERVA, TREMI in the neoadjuvant setting and then in the adjuvant setting. And they were really looking at clearance of ctDNA. And they found that There's a pathologic complete response rate, and there's also downstaging of the tumor, and there's clearance of the ctDNA. So that may be a good biomarker for efficacy. So more to come.
It was really small. It was like 17 patients in the lead-in. But I think exciting in that, you know, the trial is... going forward. And there's multiple arms to that study. So they only showed the safety of the triplet. There's also a doublet with EV plus Dervalumab and then Dervalumab as adjuvant. And then the weird part is that the control arm is no therapy.
But in all fairness, that's kind of what we did with our patients if they were not cisplatinum eligible. We didn't give them cisplatinum-based therapy because they can't receive it. We don't give them carboplatinum. And then we observed them in the adjuvant setting. So that's the control arm for the Volga study.
And then there's another trial also for patients that are cisplatinum ineligible, the EV303 study. And that one is EV plus PEMBRO again in the neoadjuvant setting and then in the adjuvant setting. And this is the great thing about EV plus PEMBRO is that it doesn't matter whether you are cisplatinum eligible or not. You can get this treatment. So they're, again, sandwiching it.
And they also have a monotherapy PEMBRO arm. And then they have a no therapy arm where they get no therapy in the neoadjuvant and no therapy in the adjuvant setting. So I'm excited about these trials.
I think that, you know, if we see this fantastic activity that we saw in the metastatic setting, now in the perioperative setting with no concerns about surgical outcomes, then I think this will be the new standard of care. So those are the trials that I am really waiting to hear about. the results of over the next few years.
Absolutely. Well, I think it's definitely an exciting time to be in the bladder cancer space, which is a wonderful thing for our patients and certainly an interesting thing for us. A lot to keep up with, but it's definitely promising. Well, I want to thank you for a wonderful discussion. This was so great.
I think it's so nice to be able to hear the intricacies of these data and also figure out how it is that you're applying them in your practice already in real time. I look forward to... more conversations and hopefully more progress in the field.
This was great. You asked such great questions that are really important and that we're dealing with on a daily basis. And how do we now take this data that we just saw at ESMO and apply it to our clinic? And I think we're still figuring that out. So it's fun to have these conversations. And I think the conversations will be evolving. So more to come.
Thank you so much. Thanks for having me.
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