EAU 2023
Treatment landscape for early-stage bladder cancer
Dr Bernadett Szabados – Queen Mary University of London, London, UK
Prof Rob Jones – The University of Glasgow, Glasgow, UK
Dr Félix Guerrero-Ramos – Hospital Universitario 12 de Octubre, Madrid, Spain
Dr Cosimo De Nunzio – Sant'Andrea Hospital, University La Sapienza, Rome, Italy
BS: Hello everybody and welcome to Milan at the European Urology Association yearly congress. My name is Bernadett Szabados, I'm a urologist from Bart’s Cancer Institute and University College London Hospital. I am together here with my co-panellists, Dr Félix Guerrero-Ramos from Madrid, Dr Cosimo De Nunzio from Rome and Professor Rob Jones from Glasgow, medical oncologist. First of all, thank you so much for coming, what a great pleasure. I wanted to kick off our discussion with non-muscle invasive bladder cancer. It’s a hugely exciting space right now with all of the new treatment options coming down. I think probably the most exciting bit is the BCG refractory setting. We’ve seen a lot of new drugs, also FDA approvals, what do you all think about all of these new drugs? Are you guys using them?
RJ: Actually, first, I’m a medical oncologist so I don’t treat this disease at the moment but I need to learn because it looks like I might be getting involved fairly soon. Félix, can you just remind me, what exactly do we mean by BCG refractory disease because the terminology causes quite a lot of confusion, I think.
FGR: As stated in the EAU guidelines and the definitions, BCG unresponsive disease is those patients who have recurrence or high-grade recurrence during the treatment with BCG after the first year after finishing BCG. But there is a subgroup of patients with an early recurrence after the first or second assessment, those are the BCG refractory and those are the patients with the worst prognosis.
RJ: To meet the definition they have to have had induction and one cycle of maintenance, is that right?
FGR: That’s for the design of the trials – you’ve had to had at least 5+2 to consider it for a clinical trial. But if you have a patient with a papillary tumour you do induction and then you have the first assessment with papillary T1 high grade, that’s BCG refractory. You don’t need to do further BCG to that patient.
RJ: And, of course, there is also that distinction between patients who have persistent CIS and patients who have papillary recurrence without CIS.
FGR: In fact, one thing important in these patients in the clinical practice is that if you have a patient with only CIS and at the three-month evaluation there’s persistent CIS, what you have to do is to continue treatment with BCG because over 60% of them will respond. The definition of the response of CIS is not at three but at six months.
RJ: So we’ve seen KEYNOTE-057, we’ve had those data for a little while but it’s in that CIS population, isn’t it?
FGR: Which is the most difficult to treat population.
RJ: So what are the implications of those data first?
CDN: We are talking on a specific group of patients which are now the only indication is if they are resistant to BCG is radical cystectomy. But radical cystectomy is an invasive treatment with so many complications and so patients normally don’t want to receive it, they are looking for alternative treatments. Now, the only alternative is a clinical trial to do a second course of BCG that sometimes, unfortunately, is not so effective. So it’s really an unmet need in bladder cancer management, the need of new treatments in BCG resistant. Probably the results of the KEYNOTE open a new era in the management of this specific group of patients.
RJ: So if we look at the CIS group first of all, that was about 40% response rate, I think. Is that good enough to forego cystectomy?
CDN: Yes, probably we need long-term data but it’s quite good because we have now another option. So, particularly if you are a young patient, so you want to spare your bladder and you have a high-grade disease or very high-grade disease, then this is a valid option.
RJ: But aren’t we just kicking the can down the road, as I’ve heard others say? Because actually most of these patients end up getting the cystectomy.
BS: I think we have also heard… we have been obviously talking about CIS but there was cohort B which was in the papillary only. Félix, what do you think about that?
FGR: We’ve seen the numbers of this cohort and its performance in this population is better. We know this, we know that these patients with only papillary disease do better than the patients with CIS. We know by the survival studies and by the clinical trials. Currently now the approval of the FDA for both pembrolizumab and intravesical nadofaragene is only for CIS BCG refractory disease but obviously data in papillary disease are better and it will also be an option for these patients.
RJ: Can I challenge on that, because I wasn’t impressed, I have to say. I wasn’t impressed. If I remember again the primary endpoint was recurrence at one year. So, remember, these are patients who by definition can’t have a response to treatment because they’ve had the papillary tumour resected. So you’re giving them pembrolizumab, in this case, in the absence of anything measurable or assessable in the bladder. And at one year 43% were recurrence free, actually, wasn’t it? So, in other words, actually have the majority recurred? What would you expect in that group of patients if you did nothing?
FGR: If you do nothing the natural history of this disease is to progress to muscle invasive.
RJ: But at a year how many of them would have relapsed? I’m asking because I can’t find anyone else who knows the answer to this question, by the way.
FGR: Over 80% of them will be recurring in the first 1-2 years. They become a patient with muscle invasive disease which now this is a life-threatening disease.
RJ: I’m a medical oncologist, I want the control arm – what’s the control arm here? If you take the bladder out, of course you’re not going to relapse in the bladder so the endpoint wouldn’t apply to the standard of care here.
FGR: You cannot randomise patients to either cystectomy or intravesical or intravenous therapy. You’ve seen that.
RJ: Yes, I get that entirely but what I’m failing to be persuaded here is actually is the pembrolizumab making any difference at all here because we don’t know what we would expect if the patients hadn’t had pembrolizumab. Again, is 43% good enough?
FGR: Yes, but also you cannot randomise to nothing versus pembrolizumab. You lead a one-arm trial.
RJ: But I need to know that it’s working before I’m going to give it to anybody.
BS: Obviously this is an extremely difficult patient population, isn’t it? But I agree with you that randomised controlled trials are going to have to come down. But we also have got new agents, intravesical agents, could you tell us about that? I think there is also new FDA approval.
FGR: Yes, the most recent FDA approval was in December 2022 with nadofaragene firadenovec with a three-month complete response rate of nearly 50%, 40-something, I don’t remember exactly.
RJ: So that’s in CIS patients?
FGR: CIS, the BCG unresponsive CIS population. It’s true that the safety profile is much more in favour of nadofaragene than for systemic therapy. It has been the second approval by the FDA, no approvals at the moment by the European Agency.
RJ: Are we going to get results in papillary only disease?
FGR: I think they have a papillary, I’m not sure. I know that other trials, like these with interleukin-15, have a papillary cohort, they will be publishing data. I don’t remember if nadofaragene has a papillary cohort. Do you think, as a urologist, if you had in your hands pembrolizumab and nadofaragene for a BCG unresponsive patient who is unfit for cystectomy, what would you use?
CDN: That’s a good question because we are very more close to intravesical treatment because it’s very close to our practice. So our experience started with BCG so we are very close to using intravesical therapy, it’s more confident for our clinic, it’s more confident with a follow-up. So we don’t need then… it’s very easy to do the installation and then to plan the cystoscopy. There are some trials trying, for example, to combine mitomycin plus BCG, so again through installation. So I agree with you, probably for a urologist intravesical installation is a more natural way to manage and to treat.
BS: Rob, what would be your ideal trial design? Would it be a three-arm study – pembro versus nadofaragene versus up-front cystectomy?
RJ: Obviously, again, your challenge there is the endpoints because then you’re really having to look at a distant control or overall survival, a core specific survival endpoint. I think that would be really, really challenging to do, just because the event rates are going to be quite low. If we did agree that, say, immunotherapy was a new standard, well, at least we can make that a control arm of future randomised trials because it gives us something to beat. But, I have to say, still my opinion is it’s quite a low hurdle to beat from what I can try and deduce from these data without really knowing what the value actually is. We’ve painted ourselves into a bit of a corner here but it maybe that if we can agree a control that would be a good way out of it.
The other thing that interests me about this whole debate is that we talk a lot about this as well as an alternative to cystectomy. For some patients, where I live where there’s lots of comorbidity and social deprivation related comorbidity, particularly in bladder cancer patients, actually there are a lot of patients for whom cystectomy actually just isn’t an option. It’s just not safe to do a cystectomy. And I know with prehabilitation you can improve that but there’s still a big group of patients where there’s a real unmet need for something because, actually, cystectomy is not an option. So actually, and I’m not sure that systemic immunotherapy is an option for them, for similar reasons, but some of these intravesical therapies may present an option for those patients.
CDN: The problem with patients where cystectomy is not an option for comorbidities or for clinical conditions is that sometimes you have to manage with the burden of the disease. Because the problem with patients with bladder cancer with multiple tumours is that if they bleed they access an emergency room for bladder irrigation. So the problem with an alternative to cystectomy, probably you can control the disease but I’m not sure that you can control the disease locally. So this is really important because we need something for bladder cancer not only to prevent the progression so the disease free survival is okay, but we want to prevent the local complications, so clot retention.
RJ: But then some of these intravesical therapies present that option.
CDN: It’s not an option if you have a large tumour, if you have multiple tumours, larger – more than 3cm. So probably the intravesical is not the best option; you have to do a TURBT, you have to do a resection, but sometimes you cannot remove…
BS: Cystectomy.
CDN: Yes, you cannot remove all the tumour so cystectomy is something that you have to propose to control local treatment, to do a salvage cystectomy.
RJ: In those patients where you do TURBT, they’re still going to relapse, aren’t they? So would you consider some of these intravesical therapies, for example, in that group of patients who can’t have a cystectomy?
CDN: It’s an option but again it depends if they can tolerate the local installation while immunotherapy intravenous is an alternative if it works long term and if you can prevent the local progression, but we don’t have the data.
RJ: I know that where I work the urologists are quite keen on device assisted intravesical chemotherapy. Is that a current standard for those patients who can’t have cystectomy?
CDN: With an intravesical device?
RJ: Yes.
CDN: The problem of the intravesical device, you need better compliance by patients because they need more cystoscopies, they need to implant the device and then for the removal of the device. Normally patients with high-grade bladder cancer, they normally undergo at least four or five flexible cystoscopies a year. So if you need more cystoscopies for treatment, it’s something that is painful…
FGR: Purely with the devices we have currently approved because we know there are several intravesical devices which are clinical trials. But with what we have currently approved, which is mainly external devices to hit chemotherapy for intravesical or whatever, if you have it stated in the guidelines, if you have a patient who is not fit or refuses cystectomy, you don’t have a clinical trial for the patient, their option will be, and this is said in the guidelines, to use any device assisted chemotherapy you can use which is, for example, what we do in our centre if the patient doesn’t complete with first or second options which are cystectomy and trials.
BS: Now, moving on, I wanted to ask you your opinions about muscle invasive bladder cancer. We have seen lots of new data, both in the neoadjuvant setting but also adjuvant setting. Félix, how do you treat a T2 muscle invasive bladder cancer patient who has got no lymph node disease on the CT scan?
FGR: First of all, all of our muscle invasive bladder cancer patients come to the MDT and there we discuss and there’s a multidisciplinary approach to discuss the treatment for the patient. It’s true that we don’t do a lot of trimodal therapy; most of our patients, if they are fit they will undergo cystectomy. We are a high volume academic centre and we also prescribe neoadjuvant chemotherapy for these patients.
CDN: In my centre, muscle invasive bladder cancer is a more linear pathway because we always discuss in the MDT. Sometimes, unfortunately, non-muscle invasive bladder cancers are not discussed in the MDT because it is very difficult to discuss all cases. While muscle invasive bladder cancer we always discuss in our MDT and radical cystectomy is an option but it depends on comorbidities, on the patient’s age. Then trimodality is another option and it’s quite frequently proposed to our patients. For me it’s still suboptimal versus radical cystectomy now in terms of OS but it’s an option that we always discuss with our patients inside the team.
BS: Rob, could you tell us about the perioperative option?
RJ: My bit is easy here because if they’re suitable for chemotherapy they all get neoadjuvant chemotherapy irrespective of whether they’re going for radiotherapy or surgery. At least, that’s what I would like. We’ve known that actually uptake of neoadjuvant chemotherapy has gradually increased without actually any new data, really. I suppose we’ve got the longer-term follow-up data. So, actually, if they’re suitable for cisplatinum which, of course, a lot of patients are not, then the commonest reason for being unsuitable is if your glomerular filtration rate is below 60ml/min, then I would recommend neoadjuvant chemotherapy to all suitable patients.
FGR: May I ask you a question? Regarding all the immunotherapy neoadjuvant trials from the point of view of a urologist, a surgeon, I’ve seen the data on the phase II trials and the pathological complete response is quite similar to chemo. But, in my opinion, I don’t know what’s your interpretation about this but in my opinion we may have an option for those patients who are not fit for cisplatin and they undergo cystectomy because you have no other option, you cannot give them carboplatin. So, in my opinion, or I foresee in the future that the role of neoadjuvant immunotherapy might be for those patients who are not fit for chemo. What do you think?
RJ: You’re right, we’ve seen some really enticing data showing high rates of pathological complete response. Remember, we’re not doing this because the patient needs a pathological complete response, you’re going to take the bladder out – that gets you a pathological complete response. That is just a marker of efficacy of the treatment. So it’s exciting and it’s interesting and it’s potent but we need to show that it’s actually doing some clinical benefit and that has not been shown yet with the immune checkpoint inhibitors in the neoadjuvant setting. There are randomised phase III trials ongoing, some of them have completed, so in that context the patients who are unsuitable for cisplatinum, there are a number of phase III trials ongoing looking at immunotherapy combinations as well as mono-agent immunotherapies. So we should hopefully get an answer to that which will be based on a truly clinical endpoint. There are other combination therapies coming through that might actually be better than cisplatinum with immunotherapy too and those trials are also ongoing. So actually we’re going to get the answer to your question. But, right now, if the patient is not suitable for cisplatinum they should not get neoadjuvant chemotherapy, they should go straight for their cystectomy if you can do one.
BS: So it looks like the near future, the next 5-10 years, are going to be extremely exciting and we will have lots to talk about. I would like to thank all of you, my co-panellists, for joining me and hopefully we will see each other soon again.
