ESMO 2024: Latest in bladder cancer - expert review
Dr Patrizia Giannatempo – RCCS Istituto Nazionale dei Tumori Foundation, Milan, Italy
Prof Andrea Necchi – The Vita-Salute San Raffaele University, Milan, Italy
Dr Michiel Simon Van Der Heijden – Netherlands Cancer Institute, Amsterdam, Netherlands Prof Simon Crabb – University Hospital Southampton NHS Foundation Trust, Southampton, UK
PG: Thank you, ecancer, for this kind invitation to discuss here with the excellent faculty about this round table session. I’m Patrizia Giannatempo, I’m a medical oncologist based in Milan, Istituto Nazionale dei Tumori.
AN: Hello, I’m Professor Andrea Necchi. I’m Professor of Oncology at the Vita-Salute San Raffaele University in Milan, Italy and Director of GU Oncology at Ospedale San Raffaele in Milan, Italy.
SC: My name is Professor Simon Crab. I’m Professor of Experimental Cancer Therapeutics at the University of Southampton in the UK.
MV: My name is Michiel Van Der Heijden, I’m a medical oncologist and researcher at The Netherlands Cancer Institute in Amsterdam, the Netherlands.
PG: So I think this is an exciting ESMO this year, and I think there is an important update in several trials. First of all I would like to stress that all the international guidelines are already updated with the new role of the first target therapy in metastatic urothelial carcinoma, the erdafitinib in FGFR alteration patients. I would like to start our focus on this test, I think that’s very important. I would like to ask all of you, what about, when, how and why to use this platform to test FGFR in our patients.
AN: Thank you Patrizia, it’s a hot topic for sure in the management of urothelial cancer patients. There are multiple considerations to make when dealing in everyday practice with patients with urothelial cancer. These considerations have to do with the proper timing, when we are allowed to test the tumour for this alteration, or if it is worth to test the tumour for the alteration, starting from the non-muscle-invasive or muscle-invasive or nonmetastatic disease or just prior to the need for having targeted therapy when treating metastatic patients. And here it comes, the issue of the way or the tool that we use to assess FGF receptor alteration. Is there room for using a blood test instead of using tissue, and how reliable is the tissue for these patients? How long does it take to have a test, the turnaround time for the test? So a lot of issues. I would say in my practice, I would love for every patient to have a fresh test – that is providing you with the fresh information of what is going at that point in time. So maybe liquid biopsies are pretty well positioned when dealing with the search for FGF receptor alteration. So at least for dealing with erdafitinib as a standard of care therapy in the approved level, so in metastatic patients pretreated with chemotherapy, immunotherapy pretreated patients, is it better for me to test patients with a liquid biopsy at that point in time, if they have any potential druggable alteration of that kind?
PG: Perfect.
SC: I think that’s true. One of the things that we need to be realistic about is a lot of people don’t have access to testing at the moment. We did a symposium at the beginning of this meeting. One of the questions was, ‘Do you routinely test?’ and it was 25%. So a significant proportion of people, probably dominated at this meeting by European countries, simply don’t have access to it. I think we need to be realistic that the disease has changed now, there are actionable subsets. It’s not really acceptable now to be continuing and believing that we can treat everyone as though they have the same disease; breast cancer, lung cancer, those diseases are divided up at diagnosis into therapeutic groupings that have actionable treatment options. I think we’re there with bladder cancer now, so we should be asking for this from our institutions going forward.
PG: Michiel, what about when we should perform these tests?
MV: So I think that’s a question that is mostly dependent on what the turnaround time for your testing is. So for us the testing is quite readily available and I would generally test in my last line of regular therapy, because I would be still soon enough to get the results. The unfortunate truth in bladder cancer is that a lot of patients don’t make it to that last line or don’t make it to the point where they would even be considered for erdafitinib treatment for example. So I wait until quite late. At that point I also try to estimate whether that patient will still have an opportunity to have more lines of therapy, whether trials, phase I trials, could be an option and then I would pick a much broader test. At our institute we’re in the fortunate situation where we can do a clinical-grade whole genome testing, but we also have the local limited panel, which works fine for most patients.
PG: Absolutely, and I think the important phrase in this case is the sooner we test, the best. So we have seen, just a couple of hours ago, the exciting results about the SunRISe trial. Andrea, you were the presenter. Do you want to share, how is the future of tests, FGFR in a neoadjuvant setting? We have the early results even in non-muscle-invasive bladder cancer with the two SunRISe.
AN: Yes, thank you. We have to differentiate in the way we deliver treatment between the SunRISe platform and the MoonRISe platform because actually SunRISe is a platform study that is testing TAR-200, which is a gemcitabine intravesical delivery system, which is not actually a treatment that is targeted to molecularly selected patients. Instead, we have a similar development of this kind that is using TAR-210, so it is similar intravesical delivery system, where a silicon tube is put into the bladder with a catheter, with a two-minute outpatient procedure, so very easy. This is delivering, for the first time in solid tumour, a topical therapy, an intravesical therapy, an intravesical targeted therapy. So while we have more and more robust data for TAR-200 in the SunRISe platform, the MoonRISe is obviously the beginning of the story and we have initial data for TAR-210 that has been updated lastly at the AUA this year, in particular in patients with intermediate risk bladder cancer, urothelial cancer, in which we do have a particular enrichment in FGF receptor 3 mutations of fusion, providing interesting findings with regard to the rate of responses and the rate of maintained responses in these patients. So it’s very early to say responses are x% or so or the duration is x amount, because the numbers are still small, but the point is that we are observing activity. They may replicate somehow the same story or the same destiny of the SunRISe or TAR-200 in non-muscle-invasive or even in muscle-invasive disease but in molecularly selected patients.
PG: Right. This ESMO is a neoadjuvant [7:54], there is a very important news, a very important update in this setting. Simon, should we discuss just a little bit about the NIAGARA results? Is it really a practice change trial in your opinion?
SC: I believe it is, yes. So NIAGRA, for those that haven’t seen the results yet, has shown an event free and an overall survival benefit. OS was a secondary endpoint. And at two years, that’s an absolute improvement in event free survival of 8%, and of overall survival of 7%, and that’s on top of the benefit of the chemotherapy. So I think at the moment if I had access to all options, that would be what I would recommend to patients. I think it’s a very exciting result. It was interesting they took the GFR down to 40 so that actually possibly extends patients that we might offer a conventional neoadjuvant chemotherapy approach to. And it had reasonable maturity in the data, I think it was about 3½ years, so I think we can be reasonably confident this is a real result, and, yes, I think it does change practice.
PG: Michiel?
MV: Yes, so I think NIAGRA is a great result in this setting. It’s clearly positive for EFS, it’s positive for OS, and the latter is incredibly important, because we have seen a lot of perioperative trials and they’ve always reported EFS and then much later down the line maybe they would report OS. We have here EFS and OS immediately reported. The other I thing that we sometimes tend to forget, but what I would like to remind everybody of, in bladder cancer we’re doing a lot of things with at best shaky evidence. We’ve been giving MVAC and CisGem which weren’t really tested in the original neoadjuvant trials. We had a lot of trials that had to close early due to not enough enrolment, slow enrolment, underpowered, and we didn’t really have so many clean results. This is a robust trial of 1,000 plus patients with a very clear result and I think that alone is already a great addiction to the field.
PG: Just a provocative question for all of you: what about the rate and the difference in pathological complete response? We know that the adjuvant setting is an important setting for us and the adjuvant immunotherapy has a role in urothelial carcinoma, but when we add immunotherapy to chemo in a perioperative setting, in your opinion should we see even the pathological complete response, or we just don’t care in that case?
MV: Well I think what the trial showed, and it was a little bit confusing so I would like to just explain that a bit, what happened. So pathCR was the primary endpoint, there was just a little bit of alpha spent on the pathCR, and the endpoint was to look at it six months after the last patient had surgery. Now, at that point, this analysis was done and not all of the surgery results were in. So this is the primary formal analysis and because there was so little alpha spent, and because a number of cases were still missing, it just missed that endpoint. However, in the later update, when all the cases were complete, which is the final, actual result, it actually showed a significant increase in pathCR of 10%. I think this tracks really well with EFS and also the OS. I think we are not there yet to consider pathCR a surrogate endpoint or a registrational endpoint, but I think it’s all very reassuring that actually you will do better getting the disease under control if you give the combination versus chemotherapy alone. So I think that’s a very assuring aspect. I think your question is, and that’s understandable, we also have adjuvant therapy, could we just wait until after the surgery? I think maybe less so than in the metastatic setting, but even in the preoperative setting this is bladder cancer, it can go very fast, a lot of things can happen. So patients can either progress, they can have all kinds of trouble around surgery. So I think this definitive evidence getting the immunotherapy in early together with chemotherapy, I think is useful and it makes things easier. Also I think the main question that we still have to address, how much of adjuvant IO do we need in a patient who has a pathCR or who has not responded at all, and these are academic questions we have to answer.
PG: Absolutely.
SC: One of the things I really hope we can answer form this and the other big randomised trials is, actually, is pathCR a surrogate endpoint? We’d all like it to be, but to prove that is actually quite hard. You need large randomised trials with the sort of data that we’ve seen, and it may be possible now to work that out. And if it’s not then we can put that to one side and accept that we can’t use it in that way; if it is, that’s a fantastic tool for development of this setting. So I think we may be in a position now where we can actually start to work out properly, with proper methodology, is it a surrogate endpoint and actually get to the answer.
PG: Absolutely, that is an important point. They enrolled 1,000 patients, so it’s huge, I think it is the biggest trial that we have in the adjuvant setting, so the effort was amazing, absolutely. So we have seen these results in neoadjuvant setting and we have even an update in the [13:46] trial in the adjuvant setting with the use of atezolizumab. Are you more convinced now to use atezolizumab instead of nivolumab, or do we have two strands of treated patients?
AN: Well in general in the perioperative setting I would say the big question today is how can we define success? It’s a tricky question that should involve also the patient side, patient advocates. For sure today the trial is providing survival advantage; there’s no question that it is setting a new standard of care. But if we have to think about the next step or the next move, for example when considering the difficulties in enrolling patients in classical neoadjuvant studies based on the fact that a rising number of patients are actually refusing or are very much concerned to undergo cystectomy, depending on the response, and particularly if they achieve a very deep response, classical neoadjuvant studies like NIAGARA are simply no more applicable today, simply not feasible. Meaning that for sure we do have today a new standard of care but tomorrow maybe no more applicable. Why so? Because, and here it comes the issue of a pathological response. So I think the discussion regarding surrogacy of pathological response with the outcomes are already in the past. What we need today is to provide the patients with an induction therapy that may illuminate us and them towards something different, to change the landscape, and flexibility is the way of treating the next generation of patients, depending on the way they respond, with the aim of providing more and more patients with a bladder-saving approach. This is something that today the patients are requiring and asking of us. And maybe the true success, the definition of success in this disease, will imply the use of a therapy that is as effective as possible without exposing the patient, or minimising every kind of side effect, so including chemoradiation also. There are a lot of concerns for the bladder-sparing strategy. So it’s a complex way. It’s exciting that the patients are guiding our vision and are guiding us to make the next move and this is the reason why I look at the pathological responses very carefully, because they may guide us to move the next step. In this sense, despite we do have durvalumab-gemcitabine-cisplatin as an option for the treatment, as a standard therapy option, a chemo/IO combination doesn’t seem to be well positioned in the mix for the next move.
PG: That’s a great point, really. You say that we need to define complete response not only on cystectomy.
AN: We need a complete response, yes.
PG: Exactly. We have now the possibility to test if we can have a surrogate of survival benefit with NIAGARA or the other trials that will come in the near future. But we need to understand if we can have a complete response even without the pathological response. That’s a great point, absolutely. And that’s opened the door to better… we need to have a strong biomarker. Even if we have lots of new drugs we still have no biomarker. What do you think about the ctDNA? We have already seen two hours ago the TOMBOLA trial. Do you think there is a role in the adjuvant setting for ctDNA in urothelial carcinomas?
SC: It clearly is able to predict outcomes and, yes, we’ve seen today data that’s matched by previous presentations that suggest that if you remain ctDNA negative you are likely to have an excellent outcome. It’s becoming increasingly clear that ctDNA positivity, when it occurs in follow-up, is not far off radiographic progression and one of the things that I thought we are starting to get a little clearer on is what lead time means between ctDNA positivity and radiographic progression. It appears, and it seems plausible, that the lead time varies by the risk of your disease, so if you’re high risk you’re probably going to have the two things happen relatively close together. But there may be longer lead time that we can see in patients with better risk disease. One of the things that struck me about the presentation today and previous data is that I think we need to think more carefully about what molecular relapse means. People talk about adjuvant therapy in the setting of molecular relapse, and obviously we’ve got the IMvigor011 trial ongoing. I’m not sure it really is adjuvant therapy. There’s a molecular relapse and yet at the same time it’s probably going to behave differently as a disease setting than obvious metastatic disease. So I think the question about how you treat that, do you consider it as adjuvant, treat it in an adjuvant way potentially with immunotherapy, or do you view it as just early metastatic disease, and would you therefore want to go to EV-pembrolizumab? We are still getting to grips with what this all means, I think.
AN: There is an underlying issue, as he has mentioned already, of accessibility of the test. Because in the case of [19:32] and the Danish colleagues’ study, they made their own test, they did a good job, they set the benchmark for this, but in general when dealing with the commercial platforms like [19:48] test and so on, there is a big issue of accessibility to these tools. So they are available in the United States, for example, and not available nor reimbursed in the European countries. So a very high potential but the applicability today in the daily practice outside of trials is still very much limited.
PG: Yes, that’s important. Michail, we have almost two, three tests available for ctDNA, which is the best? We don’t know. When we think about adjuvant setting and we think about neoadjuvant setting we have to think about adverse events. Do you think that the adverse events that we risk when we treat patients in this area, in this setting, is affordable? in that the trial that we have already seen in ESMO, so for the SunRISe and for the NIAGARA, can we accept this kind of toxicity or do we think it’s too much for them? What’s your comment?
MV: I think in NIAGARA what we’ve observed and what I also personally experienced is that a lot of the IO toxicity, which would be the added toxicity, falls into the background compared to the chemotherapy toxicity. So, yes, there is IO toxicity and the toxicity can be life-altering. It can be hypothyroidism, which does mean you are stuck to a tablet a day every day for the rest of your life, but it can be also worse with diabetes or adrenal insufficiency, fortunately not super-high percentages with this treatment. But in general this therapy is well tolerated I think and we also tend to forget the toxicity of cisplatin. I mean if cisplatin would be developed today, I don’t know if it would even make it to the clinic, and we’ve learnt to deal with that over time. I think that IO combined with chemo is not a huge problem. I think the next step is going to be EV-pembrolizumab, clearly has some other toxicities to manage, I wouldn’t say worse but other toxicities to manage. But we have to see this in the context of the types of treatments we’re giving and I think we should just focus on educating ourselves how to deal with it. I think in the beginning of using EV-pembrolizumab there were a couple of toxicities that we got nervous with, but we actually already learned to deal with it, at least the doctors or physicians who administer quite a bit of EV. I think it’s already much better than in the beginning so this is a bit of a learning process, but nothing to be scared of.
PG: What about, because in the SunRISe-4 trial you include patients even fit for cisplatinum but they refuse to receive cisplatinum. So you had experience with NIAGARA and you have experience with SunRISe, and if you have the same population, so cisplatinum-eligible patients, and in future we have a positive trial, even the final result at SunRISe, which in terms of toxicity is the treatment that you’d choose for these patients?
AN: Well, patients are driving the steps and guiding us, illuminating us to make the next move. So in principle we lack a consensus about how to best define the cutoffs for safety boundaries. For example, each one of the trials that tested newer therapies, even ADC or IO, in the perioperative setting, like neoadjuvant setting, have provided a few cases of grade 5 events. So how many patients are we allowed, or can we conceive, to lose due to toxicity in a curative setting? We don’t know, we don’t have any benchmarks, and we need consensus on this,5 so we need guidance on this. We need the patient to be on board with us, saying, ‘OK, doctor, you are on the right lines,’ or ‘40% grade 3/4 events are not tolerable, there is a standard of care, there is surgery law, so please be careful.’ We don’t have this kind of guidance and it is very important. So in general, I would consider safety on the same level as efficacy and it’s key for the efficacy in the long-run for any kind of newer therapies that we are providing before surgery in particular, but also in the adjuvant setting in these particular patients. So it’s a difficult task, it’s a difficult scenario because we lack important information and important guidance also from established guidelines, so a consensus of experts. But hearing from the patients, for sure, safety is a big argument to convince the patient to move towards a certain direction as compared to another one.
PG: Yeah. So, thank you all for this insightful discussion and we covered I think the most important topics of this ESMO. Thank you to everyone.
