PG: Hello, I’m Dr Petros Grivas from the University of Washington Fred Hutchinson Cancer Center in Seattle. I’m very excited today to host three amazing contributors in the field of GU oncology and have a wonderful discussion about bladder preservation. I’m here together with Dr Phil Cornford from Liverpool, UK, Dr Rob Jones from Glasgow, UK, and Dr Kurt Miller from Berlin, Germany. Welcome to all three of you.

It’s very exciting to be at ASCO 2022 live in person this year after three years, of course with safety measures. We’re also very interested in bladder preservation as a concept. Just very briefly for the audience, just to set the stage, bladder preservation is a very broad term, it has many different definitions. We are going to discuss here together today about how bladder preservation is defined, for example, there is some role in non-muscle invasive disease, for example, BCG unresponsive disease. Then we can discuss muscle-invasive bladder cancer and trimodality therapy, the role of potential immunotherapy in the future and also potentially what we call the allocation therapy. We have neoadjuvant chemotherapy and, depending on the presence of biomarkers and pathologic complete response, some patients may potentially forego cystectomy depending, of course, on the level of evidence. So let’s start in the beginning for non-muscle invasive diseases. I’ll start with you, Phil, and we saw an abstract here at ASCO 2022 about hyperthermic therapy in non-muscle invasive disease. We have not had any experience in our centre, can you tell us a little bit more about your experience in that regard?

PC: We do use hyperthermic Mitomycin; we mainly offer it to people who are considered to be a BCG failure and, of course, even that isn’t an absolute definition. But in our centre, we would give people an induction course and three more BCG at three months and if they had progression at that point we would then offer them either cystectomy if they were fit enough, or hyperthermic Mitomycin.

RJ: Can I just qualify, when you say progression, you mean recurrence or residual disease, not progression to muscle-invasive?

PC: Recurrence, not muscle, no. So if they’d got residual disease after an induction course then they would be offered hyperthermic Mitomycin.

PG: Interesting, and we saw an abstract here that showed, if I remember correctly, a 53%, is that right?

KM: Yes, it’s in that range.

RJ: At one year.

PG: One-year recurrence free survival?

RJ: Yes, so 53% were relapse-free at one year.

PG: Which is a promising rate.

PC: And it’s also not true that they all come back with high risk disease. So in our experience you will get some people who have a recurrence but actually it’s not as aggressive as the original tumour.

RJ: Phil, these data to me would suggest that you’re not really avoiding cystectomy, you’re delaying cystectomy. Is that right?

PC: Yes, I think you’re probably delaying cystectomy rather than avoiding it but there are lots of people who have a number of comorbidities. Bladder cancer patients are not all fit and healthy and you can delay it. Some of these patients are borderline for cystectomy anyway and it helps declare whether or not they would really be fit enough.

RJ: Yes, it certainly seemed to be a very well tolerated treatment from the data we saw. The other thing that was interesting about the abstract is they did actually quantify the disease-specific mortality. It was very small numbers but there were deaths from bladder cancer within the two years, I think it was about one in eight in the two-year timeframe that had died of bladder cancer. So it’s not an entirely trivial condition, is it?

PC: It isn’t, although I would say in our experience we haven’t seen that. I suspect that we are fairly careful about how we screen them before. So, of course, there are some people who just were never fit for cystectomy and who probably had a muscle-invasive disease that was undetected at the time. But there was no point being more aggressive because they weren’t fit to have anything more aggressive. But if you look at the people in the HIVEC-II study, then those people were selected out much more carefully and they didn’t see deaths within two years in that group.

PG: So a lot of data in this context and, of course, just for the audience, hyperthermic Mitomycin is still experimental in most parts and requires validation trials. But the data look interesting. In that context we have seen also other abstracts like the N-803 study, the QUILT study with BCG plus N-803. So I will start with Rob – any comments on the data we saw from Dr Chamie?

RJ: Yes. This, again, was a non-randomised study and this was again in the BCG refractory population. The novel agent here is this N-803 which is an IL-15 superagonist and that’s given intravescically but it seemingly only works if given in combination with BCG. It basically accentuates the immune response to BCG. Again, it showed promising clinical activity in terms of reducing the risk or inducing responses in persistent CIS at least. The presenters made the argument that it looked more favourable than other treatments that were available in that context.

PG: It’s interesting because as a context here we have patients with BCG unresponsive disease and we use sometimes the criteria from the International Bladder Cancer Group with adjuvant BCG therapy and depending on the time of recurrence in relation to BCG we have a definition for BCG unresponsive disease. The standard of care for those patients, ideally, is radical cystectomy and lymph node dissection, ideally. Some patients may decline it, despite counselling, or they’re not fit for it and that’s where all these treatments come to play. In the US we have the KEYNOTE-057 trial that led to the FDA approval of pembrolizumab. Of course, we have no randomised trials in this setting and, as you pointed out Rob…

RJ: Yes, but the presenter seemed relatively confident that these data would result in FDA marketing authorisation.

PG: It’s interesting.

RJ: So maybe coming our way quite soon, or at least maybe coming your way quite soon.

PG: That will be interesting to see, whether this agent, N-803, will become FDA approved or not. Kurt, any comments in that setting about…?

KM: Yes, obviously as you mentioned pembrolizumab is approved in the US but it’s not approved in Europe. So there is sometimes some discrepancy if you have no randomised trial, there’s different views on this obviously. If you look at this N-803 compound, I agree with Rob, it looks interesting to me. The results look better than if you look at, as a comparison, hyperthermia. They had after two years 71% still complete response rate which is impressive. I just can hope that they’re going to follow up with a phase III study otherwise only you will have it and we don’t.

PG: That’s a good point.

KM: So maybe that’s going to be something for the future and really bladder preserving because those patients would be otherwise going through cystectomy.

RJ: I think we shouldn’t overlook the fact that it’s also intravesical and so actually it keeps these patients in their current practice position, keeps them in urology. Certainly in the UK a massive switch of these patients from urology into oncology is going to have huge ramifications just in terms of service delivery, whatever you think about drug safety etc. So that’s also a valid point about it.

KM: And talking about intravesical, it doesn’t add toxicity, obviously, to BCG which is another argument. If you would have three times the grade 3 AEs then you would have a problem. But it doesn’t seem to be so it looks easy to me.

RJ: Although, of course, there is the problem that it has to be combined with BCG and there remains a global BCG supply problem.

KM: Yes, that’s another thing of course.

RJ: Which doesn’t seem to be shifting any time soon.

PG: There is a huge problem with BCG shortage globally, as you said, and that actually adds to the problem. The point you made is about do we need randomised trials in this BCG unresponsive disease space, high risk disease. There are differences in regulatory approval pathways between the US and Europe and there is probably a high bar in Europe.

RJ: The problem is we need to agree a standard of care as a control arm for these trials and I don’t really see that we have an agreed standard of care. I don’t think pembrolizumab is a standard of care.

PG: It’s highly variable and some people do intravesical chemotherapy in this space of BCG unresponsive disease. I would say the uptake of intravenous pembrolizumab is probably low in the US, from what I see. It’s an option but I don’t know if it’s utilised broadly. So very interesting data. We are going to move now to muscle invasive disease but really excited to see the field going forward even in the non-muscle invasive disease. We didn’t talk much about radiation therapy in non-muscle invasive disease; there is some emerging data there too.

Now, for muscle invasive disease we have the paradigm of bladder preservation defined as trimodality therapy, as maximum TURBT followed by chemotherapy and radiation. The question here I have for you, all three of you, is if you take this approach do you use neoadjuvant chemotherapy before chemoradiation? There is variability across different sites. Kurt, I will start with you this time.

KM: Obviously my background is urology and this is not only for Berlin in Germany, this combination, as you said, trimodal therapy is not really very common, to be honest. It’s probably less than 10% of patients that could be candidates for going to use it. Cystectomy is much more prevalent. But if we use it we don’t do neoadjuvant, we just do combination chemoradiation therapy. If we do cystectomy we usually go for neoadjuvant chemotherapy. So that’s the way it’s mostly done in our environment.

PG: And we do, in the University of Washington we have this approach – if you go for radical cystectomy and you’re fit for cisplatin we give neoadjuvant cisplatin-based chemotherapy, either dose-dense MVAC with growth factor or gemcitabine cisplatin. If you go for bladder preservation we do maximum TURBT followed by chemoradiation without neoadjuvant chemo.

PC: Really? So we do it differently.

PG: Okay.

PC: In Liverpool if you have muscle invasive disease and you are fit enough for an attempt at cure you have neoadjuvant chemotherapy. And at that point the oncologist will talk to you about chemoradiation afterwards. We stage them again after two cycles because we’re worried about progression on neoadjuvant chemo and if you are having a good response then we would biopsy them to see where you are up to at the end of your neoadjuvant. Then you would go in to have chemoradiation as consolidation treatment.

KM: Just a question, do you offer patients avoiding curative treatment at all? Like if you do biopsy them, no tumour, give them the option of saying, ‘Oh well, there is some risk involved, however, you might have a PT0 and you can just…’ don’t do nothing.

RJ: So this is the driving concept in a number of abstracts here is this idea that actually there are some patients where you don’t need to do anything after the chemotherapy.

KM: Yes, absolutely.

PG: And that’s a question, right?

RJ: Yes, so very much a question and actually none of the abstracts have really attempted to answer that question yet. But there are a number of studies going on on both sides of the Atlantic which are going to look at this. So, in particular, there are a couple of trials which are looking at molecularly selected patients using known predictors of cisplatinum activity particularly. The idea is that patients who then have a clinical T0, and that might be a problem here, a clinical T0 after neoadjuvant chemotherapy will then go on to not have radiotherapy but just go on to a surveillance programme. So, in other words, not just preserving the bladder but preserving an unirradiated bladder which is almost certainly a more functional bladder than an irradiated one.

PG: And that’s a very interesting concept and, as you said Rob, is being evaluated in a number of clinical trials in both Europe and the United States. We saw a trial in progress by Dr Iyer from the Alliance Group that they are doing that. They take patients with DNA repair gene alterations in one of the deleterious alterations in one of nine genes and if they achieve a clinical complete response they have the option to forego cystectomy. Of course, this is not standard of care for now, this is still research, but it’s an interesting emerging concept, as you said Rob. In that context I would like to ask you, going forward here, if you have an opportunity to have a patient in a clinical trial which markers would you look for – DNA repair genes? Anything else? We saw a study from Dr [inaudible] and the SWOG 1314 trial that looked at DNA repair genes and they had a 79% sensitivity, 59% specificity. So there’s not 100%, so are you feeling confident, is that the question?

RJ: That was for predicting the…

PG: Pathologic complete response based on the [inaudible]

RJ: The complete response. What we don’t know is how those patients actually would fare without and that’s the subject of their future trials.

PG: Of course.

PC: We just don’t know about how long this response will last for. We know in other situations that eventually… you rarely see eradication. It’s not cure, is it? So at the moment I’m still to be convinced, I suppose, is where I’m at.

RJ: But it is the same as your HIVEC, though, isn’t it?

PC: It is.

RJ: Because actually it’s not necessarily about avoiding cystectomy completely; it may be about delaying it. So actually it comes down to how carefully you can monitor these patients and whether the relapses will be intravesical. Because obviously if there’s an increase in metastatic relapses then that’s a real problem. But logically they’ve had their systemic therapy; actually, logically you wouldn’t necessarily expect to see an increase in systemic relapses.

KM: The argument would be then, for me, would you have avoided metastasis when you take the bladder out? Probably not.

RJ: Yes, absolutely.

KM: Because those guys might have micrometastases from the onset on and no matter what you do with your primary organ they will progress, even under neoadjuvant chemotherapy or whatever you do.

RJ: But we’ve all seen patients whose only ever urothelial primary has been a non-muscle invasive bladder cancer sometime previously who have then come back years later with metastases, haven’t we?

KM: Yes, I’ve seen that.

RJ: I’m with you on the logic there but there is a risk.

KM: The question for me would then be we talk about neoadjuvant treatment with chemotherapy, what is your view on all the other compounds like would anybody use checkpoint inhibitors for neoadjuvant treatment? There has been interesting phase II data but it never gained real traction.

RJ: There are ongoing randomised phase III trials that will answer those questions using the conventional algorithms, not with bladder preservation although there are post-radiotherapy IOs, there’s a Canadian and a British study, actually, where they’re randomising for and against PD-L1 antagonist post-radiation. So, if you like, adding in a fourth modality to the option. So I think we will get the answer to that question. Because you’re right, the phase II data looked really impressive.

KM: Yes, if you did proper patient selection, for example with pembrolizumab, having all these factors and PD-L1 positive and so forth, you got impressive P0, or complete pathologic responses, with those patients. That’s a small number, of course, but I’m not sure if there is a phase III looking into this – selected patients, giving checkpoints and seeing if you can avoid cystectomy.

PG: These are good questions. There are a few trials, phase II trials, looking into immunotherapy in that context. I think Dr Galsky had a trial recently looking at gemcitabine cisplatin nivolumab to see whether you can have DNA repair gene alterations correlating with clinical complete response. The challenge, as you said, is the inadequate clinical staging of bladder cancer. Maybe in the future novel imaging can help us be a little bit more accurate in the clinical staging. And I agree with you…

RJ: Or urinary and circulating biomarkers and there’s quite a lot going on looking at the ability of those, both in surveillance in these patients with cT0 patients but also in understanding whether they are actually defining T0 status.

PG: Absolutely. Definitions are needed – how do we define cT0 N0.

RJ: But we’ll get there, Kurt, with that because we’re doing it one step at a time. The first studies are going to be the chemo-induced T0s but by then we’ll have the PFS data to know whether immunotherapy genuinely helps in that setting.

KM: That’s the point. Yes, absolutely. It will take some time.

PG: It’s a good point. I totally agree with you, Kurt, we actually have eight randomised trials, phaseIII, evaluating checkpoint inhibitors in the neoadjuvant/adjuvant setting. Until those phase IIItrials fully complete and report, I’m not using checkpoint inhibitors neoadjuvantly for now. It’s experimental. But the phase II data looked promising.

RJ: And there’s the combination ADC checkpoint inhibitors, they’re already in phase III aren’t they in the neoadjuvant setting?

PG: Phase III trials.

RJ: So it may even be that cisplatinum has had its day at some point.

PG: It’s interesting to see that and we have cisplatin-based chemotherapy plus checkpoint inhibitor phase III trials or IO trials in cisplatinum fit patients. There’s a trial in the US called SWOG/NRG 1806 where we do maximum TURBT followed by concurrent chemoradiation with or without atezolizumab trying to answer the other question about checkpoint inhibitor in the context of chemoradiation which is another unanswered question. We’re about 60% accrual done so we’ll see how that accrues and there is so much data to come in the next couple of years. ctDNA is another very interesting biomarker, investigational still, but circulating tumour DNA is being incorporated into clinical trials.

PC: But it’s if it can tell you whether you’ve got micrometastatic disease or if there’s any residual in the bladder and then that would help you make decisions about what you did next, wouldn’t it?

PG: That would be very interesting.

RJ: At the moment the trials are really looking at whether you can define who needs additional adjuvant therapy. But, yes, if we then move into an era with true bladder preservation, it might help us select patients who are unsuitable for that approach.

PC: Yes.

PG: That’s right and then ongoing trials are now trying to validate circulating tumour DNA and evaluate the clinical utility it has. I have a very quick question for the three of you – if someone gets through chemoradiation therapy after maximum TURBT, and I know you’re doing neoadjuvant chemo before that, we don’t but there’s variability, do you do an interim look cystoscopy during the chemoradiation part to see whether you complete chemoradiation? Or if you have muscle invasive disease in the middle of the chemoradiation course do you go for salvage cystectomy? Or you just let them complete chemoradiation and you look at the end of it.

RJ: So the straightforward answer to that is no but I’ll be interested to see where you’re coming from here, Petros, because if you do cystoscopy, and Phil might be able to comment on this, even shortly after completion, actually it’s very difficult to define what’s going on in the bladder. So I’d imagine it would be a bit of a minefield to be in there during.

PC: I think it looks horrible. No, I would say that would look horrible and you don’t know what you’re looking at. Even if you biopsy it’s difficult to tell what you’ve got and you often get a nasty ulcer that won’t heal very well and then you look in three months and you’ve still got a nasty ulcer and you biopsy it and it’s just necrotic tissue. So we do the other thing which is neoadjuvant and will reassess them after two cycles and rescan them and if it looks like something in there then we would go and biopsy at that point. If they’ve got residual disease, and lots of it, we abandon the neoadjuvant and take their bladder out.

RJ: So where are you coming from, Petros?

PG: Actually this was a question that when we designed the SWOG/NRG 1806 there was this debate whether we should do that but we decided to not do the interim look and just look at the end of it. We do it at 18 weeks to evaluate that endpoint. Kurt, are you doing the same thing?

KM: Yes, nothing to add. It’s very hard during radiotherapy to assess the bladder endoscopically and even if you do biopsy you get a couple of complications but no real information from that.

PG: That’s what we do; we’re aligned there. What a wonderful discussion, I could stay here and discuss and learn from all three of you. The time goes by very quickly. Thank you so much, Phil, Rob and Kurt. A wonderful discussion, great to see you in person after three years.

PC: Nice to be here.

RJ: Thanks Petros.

KM: Thanks.

PG: Thank you so much and thanks to the audience for the attention. Enjoy ASCO and stay safe.