Ashish Kamat:  Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from Houston at MD Anderson Cancer Center. It's a pleasure to be joined today by Dr. Van der Heijden from the Netherlands Cancer Institute. We've been discussing in the social media circles and in person before obviously, COVID hit, the evolution of the guidelines when it comes to advanced urothelial cancer. Recently there were updates and publications. Michiel, I know you have been very much involved in multiple different guideline panels. Honestly, it's really a pleasure to welcome you today to talk to us about the nuances of the guidelines when it comes to advanced urothelial cancer.  The stage is yours.

Michiel Van der Heijden:  Okay. Thank you, Ashish, for inviting me. It's really a pleasure to discuss the guidelines here with you. I think a lot is happening in advanced urothelial cancer. And it's almost too much for guidelines to keep up. As of course, there's always a bit of a lag time for guidelines to be made and then to be published. We are going into the guidelines as they are at the moment, and then discuss some nuanced differences between these guidelines and the data that it's based on and I hope we will also have a nice and lively discussion about these guidelines and the finer nuances in these.

So, Advanced urothelial cancer. I've always seen this a bit as a battle against the dark force. You can win sometimes some small battles, but overall, this is an enemy that is very hard to beat. However, in recent years, there have been new treatments for urothelial cancer. I think now our victories are becoming a little bit better, and I hope that in the future, there's even more hope for bladder cancer patients with advanced disease.

So the basis of our presentation today is the European Association of Urology Guidelines as they are published this year in European Urology. So, as this is a urologist association, I think it's fair to say that this guideline committee consists mostly of urologists. There are also some other specialists involved. And this is then the table of the guideline that deals with metastatic urothelial cancer. So the top part of this panel is the recommendations from the guideline panel. This is the people that were shown before and the bottom half is actually a consensus panel that has been incorporated into this guideline.

This is quite a large group of people from both EAU and ESMO that have pretty much voted on a lot of the points in the guideline and especially the points where there is some controversy. So some of this guideline is pretty straightforward. For example, for cisplatin-eligible patients, as anybody would do cisplatin-based chemotherapy is the recommended first option. However, there are a couple of points in this guideline, which I think can be debated and where there is, I think some different insights also.

One of them, and I think the main one that we'll discuss today is the guideline for patients in first-line who are ineligible to receive cisplatin. And I think the EAU and their guidelines in previous versions have been very fast in adopting a checkpoint blockade for this group of patients. At this point in this guideline, they had to, as anybody had to, select patients for a PD-L1 status. Only the PD-L1 positive patients can receive checkpoint blockade in this setting, according to guidelines. However, they still seem to recommend this treatment as the preferred option, whereas if you look at the EAU, ESMO consensus statement, it's a bit more nuanced where patients who are PD-L1 positive, have the option of either being treated with carboplatin-based chemotherapy or with a checkpoint blockade. Patients who are PD-L1 negative, I think everybody agrees to checkpoint blockade, as it currently stands, is not a good option and patients should be offered carboplatin-based chemotherapy.

This has resulted in this flow diagram, what to do with first-line metastatic urothelial cancer patients and this is based on patient characteristics. The main question that you first have to ask is if this patient is fit for cisplatin? If the patient is, then they should receive cisplatin-based chemotherapy, I think pretty much everybody can agree on that. However, if a patient is not fit for cisplatin, there are various options, one is carboplatin gemcitabine, and the other one is checkpoint blockade. And both pembrolizumab annotated in this map are registered for PD-L1 positive patients. What strikes me in this flow diagram is that performance status is given quite a big role. And in this case, I wonder if that's really supported by data. And I think that's something, Ashish that we can discuss further on, for example, a performance status of two is very different, in my opinion, if it's a disease caused by comorbidities, for example.

So if there's a patient who is otherwise cisplatin-eligible, but due to the disease has a performance status of two. In my experience, usually, checkpoint blockade is not going to do much. Whereas in this case, you might rather start with chemotherapy. And as for some PS2 patients who are otherwise cisplatin-eligible, I would still enforce cisplatin-based chemotherapy. On the other hand, if patients are weak and sometimes we refer to them as the chemotherapy ineligible patient group. So, patients who are not at all able to receive chemotherapy in my experience and what I've seen from the data so far, I think there was no strong reason or basis to think that these patients would really do well on checkpoint blockade. So let's look at the data. This is the first study done in cisplatin-ineligible first-line patients with atezolizumab already a couple of years ago.

And then this group of patient response rate was 24%. If you look at overall survival curves, these patients are doing actually quite well. And there was a bit of a discrepancy between the response rates and the rates of overall survival, for example, at one year. So it seems to me that many of these patients probably also received chemotherapy off the checkpoint blockade. So if you would just directly compare this graph to the data we have on carboplatin-based chemotherapy in this group of patients, checkpoint blockade looks much better, however, we have to keep in mind that the chemotherapy data that we see on the right is from quite a few years ago and checkpoint blockade at that time doesn't exist. So where it is attempting to directly compare these two curves, we have to realize that in the current situation, this is more a question of what is the sequence of therapy?

So we should start with chemotherapy and then proceed to IO if patients are not responding or do the reverse. And these types of questions have to be addressed in a randomized phase three trials, and several trials have been recruiting large trials with about a thousand patients, mostly with atezolizumab and pembrolizumab. And these are the KEYNOTE-361 and the IMvigor130 trials. And then these trials, first-line metastatic urothelial cancer patients were randomized between either direct checkpoint blockades, chemotherapy plus checkpoint blockade, or chemotherapy alone, which is the standard of care. Now, during the course of these trials, there was already a review by the registration authorities of these outcomes and the safety of these patients. And because of this review, without at that point, having any data available, the registration authorities, restricted the use of checkpoint blockade in these patients, in the cisplatin-ineligible population, to patients who have, who are PD-L1 positive in their tumors.

So this year, we actually got the first glimpse of the data. And this is particularly true for the IMvigor130.  This release of the data was triggered by positive interim analysis of the progression-free survival, and which was statistically significant though marginally better for chemotherapy plus checkpoint blockade.  And as this interim analysis could be done, the analysis of the other groups could be done as well. So here we see the results for overall survival of checkpoint blockade, in this case, atezolizumab versus platinum-based standard of care chemotherapy. And looking at these graphs, indeed, the checkpoint blockade looks to do better, even though at this point, this difference is not statistically significant, and these patients need to be followed for a longer period of time. We do have to keep a couple of things in mind though, when judging this data, first of all, the crossover to IO in this group of patients was still relatively small, only 20%.

And this might be a result of the time period where this study was executed. And maybe also the countries where this was done, where not always checkpoint blockade was available. Another thing I think is worthwhile to mention of this trial is that investigators had the choice to either give cisplatin or carboplatin. So even when patients were cisplatin-eligible, they could receive carboplatin-based chemotherapy. And this is a point of this trial that has been debated a lot and could have influenced the outcomes of the standards arm.   Meanwhile, there have been press releases about two other large trials, the KEYNOTE-361, which investigates in the same design pembrolizumab, and the DANUBE, which investigates avelumab, and at least also has a primary endpoint of avelumab in that PD-L1 positive population against chemotherapy. And both of these trials did not meet primary endpoints.

I think it's worthwhile to note that in a few days from now, ESMO is starting, and full data of these trials will be presented there. Another notice as said in the EAU guidelines, the performance status has a big role. However, in this trial, only 10% of patients had a performance status of two, which was allowed. In the meantime, another trial has read out, and that's the JAVELIN 100 trial in which patients who had a good response to standard first-line chemotherapy, or had stable disease were offered this trial and were randomized to either standard care, which is just basic supportive care or avelumab maintenance therapy and avelumab is an anti PD-L1 checkpoint inhibitor. This trial has actually been enrolling quite a few years ago already and had therefore already a mature follow-up by the time this was presented.

And actually, the results here were very striking. And this is something we... I think at least I didn't really expect that it would be so striking. This is the overall study population, overall survival, which has a very clear benefit for avelumab maintenance. And I think one of the reasons this study is so clear is that they selected patients basically with chemotherapy. So, the maintenance treatment was started off, the patients have a good response to chemotherapy. And that means that the patients with really bad disease, who progress fast and with chemotherapy are not in this trial. And it's a sort of a way to select the patients who would maybe do better with checkpoint blockade. And I think that's what we're seeing here, and that's possibly why this trial is positive. And some of the chemotherapy plus checkpoint blockade are a bit disappointing.

So I would like to now emphasize a bit. The ESMO guideline committee, as this is a new group of people who have been working on this for the last year. And I was part of this group as well as a disclaimer. And I think that the good thing about this group of people is that... Oh sorry, about this guideline is that we have been given the opportunity to very quickly publish our guidelines online on the ESMO websites. And this, for example, is a very recent update of the guidelines in which we incorporated the new data. So in this guideline, I think it's pretty straight forward. And I think correct on how to handle this for patients who are cisplatin-ineligible, that cisplatin-based chemotherapy is still the standard of care. And despite the fact that it's not registered in the EU yet, avelumab is recommended for patients who have not progressed on chemotherapy as per the trial designs that I just showed you.

For the cisplatin-ineligible patient, these patients can be distinguished by their PD-L1 status. So if PD-L1 is unknown or negative, a recommendation is to give carboplatin/gemcitabine followed by maintenance avelumab for tumors, which have not progressed. If PD-L1 is positive, there's also the option of starting with a checkpoint blockade. So now I would briefly like to switch to a second-line treatment. So this is the recommendations flow chart of the EAU. And despite the fact that maybe some text editing would have been appropriate here, I think this is quite a straightforward schedule where patients who receive chemotherapy can be offered checkpoint blockade, and in case of patients who have checkpoint blockade in first-line, the next line of therapy would be combination chemotherapy.

Once again, this guideline is very much on the performance status of two and higher where they also say to consider immunotherapy. Although I think the best supportive care in this patient group is also a very important option, which should be considered. The guidelines of ESMO, there was a year of date of December 2019. And once again, this guideline has incorporated some medicines that are not yet registered in the EU, although they are now registered in the United States, and these are erdafitinib and enfortumab vedotin.

And I think this is also pretty straightforward. So in patients who are platinum-refractory, checkpoint blockade is the first option. And when that's not possible, or when patients progress, enfortumab vedotin is an option and otherwise, chemotherapy could be considered. And that's mainly [inaudible] which is still registered in the EU. In patients that are platinum-refractory and have FGFR alterations, erdafitinib also becomes an option. And in patients who have started as frontline therapy, checkpoint blockades, these patients should be offered the platinum-based chemotherapy. And in patients that have had both platinum-based chemotherapy and checkpoint blockade, enfortumab vedotin is an option. And erdafitinib in the case of FGFR alterations is also an option. And once again, these drugs have not been registered yet in the EU, as phase three randomized trials are still running. So this is my review of the guidelines of advanced urothelial cancer. And I would like to now give you back to Ashish.

Ashish Kamat:  Thank you so much. That was a very concise summary of the two guidelines and the contrasting statements between the two. Thank you for doing that. I do agree with you, guidelines are fluid bodies that need the ability to be updated rapidly and the fact that you were able to do that with ESMO guidelines, with the JAVELIN data that was presented and the approval that was granted in the US is very commendable. A question that I wanted to ask you about that since we are talking about it right now. As you know, there's been a fair amount of criticism as to the study per se, but we leave that aside for the moment, because it is level one evidence. My question to you is this, do you think that in countries or regions where avelumab is not yet registered or approved, that practitioners should be looking at other IO agents after chemotherapy as maintenance?

Michiel Van der Heijden:  Well, that's a very good question. I think we generally tend to not do that. And I think a practical problem here is that these drugs will not be reimbursed. I think, based on their mode of action and what we know of these drugs, the expectation is that they will work in a similar way. However, we do like to stick with trials and that's what I think we should do. So if this is not available, patients would just be treated with... Well, I think in this case, no maintenance therapy and upon progression checkpoint blockade. I would like to make one more statement here. I think the trial in itself seemed to be very clean and well executed. However, this trial has been running over quite a few years. So I think in the standard arm, there were probably quite a few patients who are treated in places for checkpoint blockade as second-line therapy was not commonly available. So it could be that this group of patients will by now do a bit better in places where this is available.

Ashish Kamat:  Right. No, exactly. So the question then arises, in the absence of clinical trials, if these agents are not reimbursed in the EAU or EU, do you then expect as a guidelines committee to see trials being proposed that are exactly similar or comparing other drugs to avelumab? What are some of the recommendations from the guidelines committee to investigators and pharmaceutical companies, for example?

Michiel Van der Heijden:  Well, I think as a guideline committee, we don't typically recommend trials to pharmaceutical companies. But what I would say here is that first of all, there are quite a few exciting new drugs out there. For example, enfortumab vedotin is a drug that is now being tested in first-line in combination with pembrolizumab, which had very strong data in smaller studies. I think that will be a very interesting trial. There are more drugs that are currently being tested. For example, [inaudible 00:20:44].

So there are still quite a few trials that have very interesting combination therapies. And I think whenever the opportunity is there, patients should get these trials offered. With this quickly changing landscape, I think it will be quite difficult for pharmaceutical companies to repeat the JAVELIN trial as this is now becoming standard of care. And at some point these drugs will be registered in Europe, at least. And patients will get the option of this drug in the standard arm. So I think it will be very difficult to do this trial again. And I think all the new data will come from first-line combination therapies.

Ashish Kamat:  Very good point. Since you brought up the ADC and enfortumab vedotin and pembrolizumab combination study, I believe that's KEYNOTE-905. With the mechanism of action of enfortumab vedotin, do you expect this agent again, just based on mechanism and hypothesis without actual data that we know of that's mature, do you expect this agent to trickle down into earlier and earlier stages of bladder cancer treatment?

Michiel Van der Heijden:  Yeah, I can very well see that happening. I mean, the first data that we saw with enfortumab vedotin and then pembrolizumab is highly exciting. And it seems to be a drug that can be combined with all sorts of therapy, maybe even with combination immunotherapy. And it also seems to be a drug that can fairly easily be administered also in earlier settings. So I would expect that this drug will move forward into, for example, the new adjuvant space, as we have already seen some exciting results with checkpoint inhibitors in the preoperatively. And I think working with vedotin could be combined with these drugs.

Ashish Kamat:  Another question along those lines, because with EV, there's no sequencing of tumor that's acquired because Nekton is ubiquitously expressed. But if you look at agents such as erda, or even with checkpoint inhibitors, there is a request or demand sometimes to do tumor profiling, to look at the status of these various mutations, fusions, and expression levels. How much of a barrier is that to adoption of agents in your experience? Do you think agents that require complementary assays are less likely to be used? Or do you think the standard has changed so much that the sequencing of tumors is very much routine now?

Michiel Van der Heijden:  Well, I think, we have to keep in mind that you or I are at centers where sequencing is readily available. A lot of centers do not have that so easily available. And I think it will always be a bit of a barrier. We have to also keep in mind that the urothelial cancer can progress rapidly. So some patients will not be able to wait for sequencing results. So I think that will, for now, be a drawback for drugs like erdafitinib because it's much easier to advise enfortumab vedotin patients where you don't have to do any profiling then erdafitinib. Still, I think with these results, more and more patients will get sequencing done. And I think just this will still remain an option for patients, but probably after the main treatments have been done.

And I think all of this is mainly dependent on how good the drug is. If you have an enormous effect on a drug, and then people are going to be more willing to profile to see if a patient is eligible. And if the drug has a small advantage, or there is another drug that is equally effective then I think it will be more difficult. Another thing to keep in mind is that trials are now combining chemotherapy and IO in as first-line are testing these agents in combination with new action treatments. So, patients who progress on these treatments are fairly early in their disease or have already had the most common treatments. So I think that there will be more opportunities to treat with other drugs in this setting.

Ashish Kamat:  Great. And you alluded to, earlier the importance of performance status, and I wanted to ask you a practical question for our audience's sake. In patients that have performance status that are right around two and then have visceral versus non-visceral metastasis, do you have recommendations in the selection of IO versus chemo? Obviously one has a slower onset of action and another one you're trying to fight against time from a non-guideline based, again, a personal experience from your knowledge, how do you help, or how would you recommend the practitioners select between different agents if they're both valid choices with the nuances of performance status and visceral versus non-visceral metastasis?

Michiel Van der Heijden:  Yeah. So I think that's a good point. And that's something that, as I mentioned, really struck me in the EAU guidelines. I think the thought that patients with the poor performance status, especially in patients who have visceral disease or where it's based on their burden of disease, yes, it's easier to administer checkpoint inhibitors as side effects are less, but I personally have not really seen any of that type of patient response to checkpoint inhibitors.

So if a patient comes to me with, for example, liver disease and a performance status of two, but still eligible to receive cisplatin and I would see if it's possible to actually treat this patient with cisplatin-based chemotherapy, because that has the highest chance of getting their disease under control. And after we get it under control, maybe when progressing, we pick that up earlier and are still able to administer checkpoint inhibitors and give that a chance. So I'm not a big fan of really advocating checkpoint blockade for performance status two, let alone for performance status higher than two.

Ashish Kamat:  Great. Once again, I want to thank you for taking the time to have this discussion with us. In the interest of time, since we do have to wrap up, I want to give you the last word.  Any closing thoughts for our viewers and listeners?

Michiel Van der Heijden:  Well, I think this is a field that is really in motion and a lot of data is coming out. I would recommend to everybody to look at ESMO, because we just got a press release from some of these trials, that the primary endpoint is negative. However, I suspect that there's still a lot of data in these trials that is very interesting. These data have multiple arms, have multiple checkpoints, sorry, multiple endpoints.

Some of it is the intention to treat population, some in the PD-L1 population. And there is a lot to learn still from these trials, I would think. So. I would say, keep an eye on that. One other thing that I think still to mention is that there are also new combinations of IO that still can read out in the near future, especially in nivolumab. And I would recommend people to keep an eye on that because I'm personally a fan of that combination, and I hope that it will make it to a standard of care.

Ashish Kamat:  Right. Great points. Thank you. Once again, for taking the time off during your busy schedule. Stay safe and stay well.

Michiel Van der Heijden:  Thank you Ashish. It was great to discuss this with you.