Bladder cancer: Latest advances in targeted therapies and precision medicine from ESMO 2019

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Published: 30 Sep 2019
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Dr Javier Puente, Prof Maria De Santis, Dr Yohann Loriot, Dr Eva Comperat and Dr Michiel Van der Heijden

Dr Javier Puente (Hospital Clinico San Carlos, Madrid, Spain) is joined by Prof Maria De Santis (Charité Medical University Hospital, Berlin, Germany), Dr Yohann Loriot (Institut de Cancérologie Gustave Roussy, Villejuif, France), Dr Eva Comperat (Assistance Publique-Hôpitaux de Paris, Paris, France) and Dr Michiel Van der Heijden (Netherlands Cancer Institute, Amsterdam, Netherlands) to discuss the latest developments at ESMO 2019, including the use of targeted agents and the latest advances in precision medicine.

The panel discuss the use of antibody drug conjugates (ADCs) in the metastatic setting – including the use of sacituzumab govitecan in the TROPHY-U-01 trial and how these agents can be used in precision medicine.

Dr Comperat also gives an insight on how pathological changes are important to drive decisions, as diagnosis is largely tissue dependent due to a lack of validated biomarkers.

Dr De Santis also highlights the clear unmet need for cisplatin ineligible patients in the first line setting, as immunotherapy is commonly used in PDL-1 patients only.

The panel conclude by discussing the recent developments in non-muscle invasive disease.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

Using ADCs in the metastatic setting
Precision medicine and ADCs
Results from the BISCAY trial
Pathological changes and biomakers in bladder cancer
Latest data from the IMvigor-211 study
Combining enfortumab vedotin and pembrolizumab in the first-line setting
Selecting patients in the first-line setting
Updates in the neoadjuvant setting: NABUCCO trial
Recent developments in non-muscle invasive disease


JP: Hello to Barcelona in Spain and welcome to this ecancer debate educational programme. Today we have the great honour to have a great panel of experts in the treatment of urothelial carcinoma and they are going to introduce themselves.

EC: Good morning, my name is Eva Comperat. I’m a uro-pathologist in France working for the Sorbonne University and I’m very pleased to be here.

YL: I’m Dr Loriot, I’m a medical oncologist and I’m working at Gustave Roussy in Paris. I’m especially focussing on bladder cancer.

MDS: Hello, I’m Maria De Santis. I’m a medical oncologist based in Berlin in Germany and working at Charité University Hospital.

MVH: I’m Michiel Van der Heijden, I’m a medical oncologist at the Netherlands Cancer Institute in Amsterdam, the Netherlands. I also focus on the treatment of bladder cancer. I’m looking forward to a great discussion here.

JP: Thank you all of you for being here. I’m Dr Javier Puente, a medical oncologist at Hospital Clinico San Carlos in Madrid in Spain. The objective today is straight to talk a little bit about the recent advances that we have today and that have been presented during this ESMO in the treatment landscape of urothelial carcinoma. So we can start, for example, with the metastatic setting. We have several abstracts that have been presented this morning in Barcelona with new drugs. For example, first of all we can talk about the sacituzumab, these new drugs, anti-TROP-2. How did you see these results, Maria, in this context?

MDS: Sacituzumab, being an antibody-drug conjugate, is one of the most interesting developments for also urothelial cancer recently. The first data we have seen with the antibody-drug conjugates was enfortumab vedotin but today new data of the sacituzumab govitecan was presented. The important part here is that it has different properties compared to the others concerning the payload, the chemotherapy. So those ADCs have an antibody that is targeting an anti-gene, those are different, then they have a linker but then a payload. Most of the other ADCs have the MMAE as a payload but sacituzumab has a payload that is different. It delivers irinotecan, so topoisomerase-II, to the cell which is much more potent than the irinotecan. That’s why it is tolerable because it would be more toxic. This is, to me, the big difference. It has been shown today that it allows a high response rate in heavily pre-treated patients. They also showed one patient, and I thought it pretty interesting that that patient was pre-treated with four different drugs, including enfortumab vedotin, another ADC, and still had a tumour reduction of more than 70%. I think this is the really interesting difference here with the sacituzumab.

JP: What about the toxicity? Because we have observed a very high level of neutropenia with these drugs?

MDS: The conclusion of the authors was that the toxicity is manageable which certainly is true. We have been dealing with neutropenia and neutropenic fever for many, many years so we are used to dealing with that. But, of course, there is quite a high neutropenic rate and we need to consider using GCSF etc. But I think the neutropenia rate is tolerable. I would be a little bit more concerned about patients with diabetes because we have hypoglycaemia or the neuropathy rate so this can be an issue for patients with comorbidities, for example.

JP: And, looking forward, maybe there could be a problem for the combination of these drugs with other drugs in the future because this toxicity could affect the combination of these drugs together?

MDS: Well, it depends on the combination. So combining, for example, with immunotherapy should be okay because there should not be overlapping toxicity. But this was also tried out in the first line setting and we saw the data after enfortumab vedotin with pembrolizumab and here we actually did not see additional toxicity or enhanced toxicity of the combination but just the toxicity we would expect from enfortumab vedotin by itself and the pembrolizumab.

YL: And this trial raised a very exciting new question in terms of precision medicine with the ADC. It’s pretty new, actually. We know how we can select patients with targeted therapy – EGFR inhibitors, BRAF inhibitors – for ADC it’s a new field actually. If we have both drugs, maybe in coming years in a phase III trial, positive phase III trial, how we can select patients for enfortumab, sacituzumab.  So this is a question of maybe the expression, heterogeneity within the tumour, and then how we can correlate this to the activity of one drug, enfortumab or sacituzumab. It’s a very, very new thing.

JP: That’s a good point. However, we have the recent data of the BISCAY trial, the BISCAY trial is a very innovative trial trying to incorporate this biomarker in the decision of the treatment. The results are not very encouraging, it’s a little disappointing.

YL: Yes, it’s disappointing. Everybody in the audience was quite disappointed by the trial. It was a very innovative trial and it required a huge effort to conduct this trial for sure. But it was first generation, once again, of precision medicine programme because based on the DNA. Now we know in oncology that the cancer is very complex and we should probably control many parameters – the microenvironment, the clonal evolution, then the spatial longitudinal heterogeneity. So it’s disappointing but we have to move forward and maybe integrate more factors if we want to conduct such trials in the future.

JP: Definitely because I think that we have to involve more our pathologists in this, driving decisions in the future maybe. Obviously today we have only what is the kind of tumour that they have, maybe the grade or differentiations, but they don’t have any biomarker today available in this disease.

EC: This is a little bit the problem when you look as a classical pathologist on what is going on, for example in bladder, especially in bladder. The classical pathology is a little bit disarmed, I would say. We have had all these things with PD-L1 testing and so on which was not really extremely conclusive, in my opinion. Now it’s going forwards more and more towards molecular biology. On the other hand I would like to underline that we still do not have any international validated panels. We’re extremely tissue dependent and we don’t know what kind of tissue we really want to test. Do we want to test the primary, the lymph node metastases, the distant metastases? Do we want to make a liquid biopsy which is clearly not pathology anymore? So I think we really have to work hand in hand with the geneticians and MGS and all these kinds of things which are not available in a normal pathology lab, which must be clear too.

JP: In this metastatic setting, Michiel, we have recent data for a long follow-up in the IMvigor211, could you comment on that?

MVH: Yes, absolutely. First of all I want to also emphasise, going back on the previous discussion, that Yohan is describing a problem that is a fantastic problem to have. It’s only a few years ago that we only had platinum-based chemotherapy and now we have checkpoint inhibition and actually a lot of choices in the third line with response rates around 40%. This is a tremendous luxury, we are not there yet, clearly, but it’s a tremendous luxury to have this kind of choice between different new drugs, the antibody-drug conjugates but also FGFR inhibitors.

But, indeed, for the second line, of course, checkpoint inhibition is the development of already a few years ago by now. One of these randomised studies was with atezolizumab. What we did is we followed these patients and did another overall survival analysis to get some landmark analyses on overall survival and durability of response, basically. What we saw there is that actually where the curves took a while to diverge they actually seemed to at more or less the time of the primary analysis diverge. Then that difference was maintained so at the two year landmark OS point there was a 10% difference in overall survival between the checkpoint arm, in this case atezolizumab, and the chemotherapy arm.

JP: So it’s clear that there is a segment of patients that are very, very sensitive to this immunotherapy and continue alive for a long period of time. In the first line, moving to the first line, today we have the presentation of the combinations of enfortumab vedotin plus pembrolizumab. The results, I think that it is very impressive for all of us. Could you comment on this trial?

YL: Yes, it was a phase I trial, so combining enfortumab vedotin and pembrolizumab in first line in mainly cis ineligible patients. We know that these patients have a poor prognosis, chemotherapy with GemCarbo is not a good option because the median overall survival is still very poor. So we’re trying to find any way to improve the outcomes of these patients. This data, preliminary data on only 45 patients, showed a striking response rate of 70%. So the safety also is acceptable, combining seems to be feasible. The point is that we have to be sure that the duration of response, and so PFS and overall survival, are impacted by the combination. So that’s a priority of this kind of trial is just to know if we can have a long-term outcome with such a combination. I think it’s an important question regarding the data we will have during ESMO with the IMvigor 130 as well. So we have a press release stating that chemotherapy plus atezolizumab improves PFS, maybe not overall survival. But I think we have to discuss how we can be sure that the combinations impact the outcome of the patients. So overall response rate is a preliminary result but we have to follow this trial just to be sure that we have a very good outcome in terms of overall survival.

JP: Maria?

MDS: I think for the cisplatin ineligible patients in the first line there is a clear unmet need and currently we use immunotherapy in the PD-L1 positive patients. But the data still is not that great but with the combination, what we saw today, the data is really very intriguing. We were really fascinated by what we saw with regards to a reduction in tumour size by 90% etc. But what I wanted to say is that with that combination if this data are translated into PFS and OS benefit it might well be that one day we end up with a non-platinum containing first line treatment for those patients because in the IMvigor 130 it is again chemotherapy with platinum plus immunotherapy. But it would be nice, maybe, to have a non-platinum combination once that really works and maybe is better than what we have been using for the last 30 years.

JP: However, many, many oncologists are currently recruiting patients into two trials with enfortumab, the EV-201 and the 301. The first trial is after a failure of immunotherapy and the second is after chemo and immunotherapy. But today with these results I don’t know what could be the next step in the development of this drug. It’s currently focussed in the second or third line or we are putting these drugs in the first line setting.

YL: I think there are two ways. The first, probably, is in the neoadjuvant setting and especially for the patients who are not fit for neoadjuvant chemotherapy. We know that’s around 40-50% of the patients. As Maria said, we have now maybe a platinum-free regimen. So maybe this combination could be very useful in these patients and given the response we have, 30% of complete response and 70% of overall response rate. If possible, if the safety is acceptable, maybe we have to give the patients a big cocktail – chemotherapy, EV, checkpoint inhibitors and maybe it could be impactful as well.

JP: Maybe we need the helpful pathologies or biologies because when you see the data for the neo 130 there are a lot of patients that have been treated with carboplatin where they are defined as cisplatin ineligible. So at the end we have a lot of variability in the treatment of those patients in the first line setting so we need something to select properly patients in this setting.

EC: I completely agree with you. The history with biomarkers is a very long history; we really try very hard and we have tried with urine biomarkers, for example. For example, if you have a patient who has been treated in first line and who will escape it might be interesting afterwards to test as well what we missed from the primary and maybe the lymph nodes too to see whether there’s any discordance, whether there’s tumour heterogeneity and whatever and try to adapt. But this is a very wide field which is completely underexplored at the moment.

YL: It’s even much more complex with the combination because we saw that with pembrolizumab and EV, PD-L1 studies is not useful anymore. So for the future maybe you will still stay with us.

EC: Thank you.

JP: And what about the mutation of fibroblast growth factor receptor? Because it’s something that we have to think about.

EC: It’s upcoming, yes, but I think it’s not interesting for every tumour. It’s probably very interesting for the luminal tumours, especially for the papillary luminal tumours, which we might be able to discern already a little bit in the histology but this will not be the only tool. So, of course, there will still be a very big room for sequencing. But FGFR3 is not the only one, it’s a minor part of the tumours. There are all the basal, squamous tumours, for example, where we really have to find the perfect target probably. For example, also the luminal non-specified or unstable which are quite tricky tumours and which are not able to be distinguished under the microscope, for example.

JP: Any comment more on the first line? No? So we can move to another scenario. We have data in the neoadjuvant setting with the NABUCCO trial. Michiel, could you comment something about that?

MVH: Yes, we were very excited to present our first data of the NABUCCO trial which is a trial which investigates the combination of ipilimumab and nivolumab in stage 3 localised bladder cancer, or at least T3, T4 and nodal positives. So we’ve previously seen [?? 16:38] checkpoint inhibition with pembrolizumab and atezolizumab, mainly in T2 and T3 tumours, so slightly smaller tumours although still tumours with a high risk of recurrence. So we tested ipi/nivo in a very high risk group and we were really struck by what we found, that we had 46% of patients in this population had a complete remission pathologically and 58% who had non-invasive disease. So these patients had, these additional 12% of patients, had, for example, small focus of cyst or Ta, so that’s a stage that is generally seen as cured by the surgery. Moreover, we saw multiple patients who had still very clear responses in their tumour but had more of a mixed response or a partial response or a near complete remission or still some tumour foci left. So this is a very exciting result to see such extreme responses. Moreover, the treatment was feasible to give to patients preoperatively so we managed to do surgery in all of these patients, 96% of them, so all but one, in twelve weeks from the start of treatment. One patient had a delay of four weeks because of an immune toxicity.

JP: So do you think that there is a difference between the ABACUS, PURE and NABUCCO trials that could help us to select properly in the future? Because, obviously, we have three trials in the same setting with different drugs, any idea about how can we select there?

MVH: Of course these trials are goldmines for translational research. So we have tissue before treatment and tissue from the cystectomy so of course it’s going to be very important to try to see if we can select the patients that will respond. In our cohort we found an association with PD-L1; I think in the other cohorts that was found as well. But there is a lot more to investigate and I think it’s going to be very important what patient should I give this type of treatment or what patient needs chemo. Maybe there’s a group still that could use enfortumab vedotin or I go directly to surgery. So I hope there will be a future where the pathologist has a very prominent role and we know what to give our patients.

JP: We are praying a lot for that.

EC: Yes, it has become extremely complex when you look, for example, also between epithelial and the mesenchymal stroma. There are so many responses. There are so many pieces and there are so many things where you say this could be exciting and this could be exciting. But there are so many interactions which you really completely underestimate and for us, for the moment classical pathology has become clearly impossible to do everything you need in oncology. Of course, we have to rely on molecular biology, clearly, but even this will, for the moment, not be enough probably. It will take us some time to sort it out.

JP: Finally we have two minutes for commenting something about the non-muscle invasive disease. I think this is a great part of this disease because, obviously, most of these patients will be in relapse. After that we have to suffer a cystectomy. So how can you think about these new drugs that are being investigated in this setting? How do you see these results with pembrolizumab or with other drugs in this setting?

EC: I think pembrolizumab is quite interesting. There is a very huge trial, actually, ongoing in France which is called ALBAN which is with atezolizumab against BCG in high grade tumours. We do not have the results yet but I think that will be quite interesting too. I think especially immune checkpoint inhibitors will be something quite interesting because will be short of BCG in the upcoming years and therefore we have to find other ways to treat these patients, especially the T1 tumours which are quite tricky.

JP: Yohan, do you have…?

YL: Yes, I do agree. The primary data we have are pretty encouraging; it’s still immature but it’s still encouraging. There are many different phase II trials – ALBAN in France, POTOMAC investigating durvalumab with BCG. So it takes a long time for sure to get the data but if we want to unpack the disease overall in bladder cancer we should move earlier in non-muscle invasive bladder cancer for sure. So we should investigate these new drugs earlier.

JP: That’s it because obviously we have a spectrum of diseases from low grade to high grade with high risk of relapse. Those patients, if you can abort this great surgery, so I think this is great news for us. So any comment?
EC: I think also carcinoma in situ, especially non-muscle invasive tumour, plays a very important role and it’s not the same history if you have a Ta high grade tumour with carcinoma in situ or without, the same history with T1, of course. Because I think that’s really completely underestimated but clustering has shown that these are really distinct diseases with or without carcinoma in situ.

JP: Any final comments that you want?

MVH: I think it’s very exciting times for bladder cancer with lots of new developments. There’s still a lot of work to do but it’s a very exciting time to be involved in bladder cancer treatment.

JP: I fully agree with you.

YL: It’s not an orphan disease anymore.

JP: Maria?

MDS: I think we are all excited about the ADCs and more chemotherapy but I am especially excited about the precision medicine that actually was introduced for bladder cancer this year. FGFR inhibitor with erdafitinib – 40% response rate in Merkel as elected in FGFR2 and 3 mutated patients. Yohan, you are the first author of the New England Journal of Medicine paper, maybe you want to say one word on that? Because, for me, this is really big news for bladder cancer.
YL: For sure, it’s the first targeted therapy we have in the field so it’s very exciting. Now we have maybe to learn from lung cancer and melanoma, trying to follow this model and to improve how we are doing a precision medicine programme in bladder cancer.

JP: That’s it. So thank you Michiel, Maria, Yohan, Eva. Thank you for joining us and thank all of you for joining us in this ecancer debate educational initiative. Thank you so much.