MG: Hello from ASCO GU 2019 in San Francisco to this ecancer expert discussion. We have a great panel of experts in bladder cancer today. I’m Matt Galsky, I’m a medical oncologist in New York. We have Dr Ananya Choudhury from the UK, Dr Andrea Necchi from Italy and Dr Joaquim Bellmunt from Spain. Today we’re going to talk a little bit about the abstracts that have been presented today and contextualise that information with the evolving landscape of treatment for urothelial cancer. So one of the first abstracts that I wanted to talk about is something that as a medical oncologist I haven’t really appreciated, I don’t think, that much over the years which is this issue of local recurrence after treatment with cystectomy for muscle invasive bladder cancer. My general sense is that systemic recurrence, systemic relapse, is the major problem but I think that we’ve seen some compelling data, observational data, that maybe we’ve underestimated the impact of local recurrence. So today we heard an abstract which was a retrospective look at a subset of patients who were enrolled on a randomised study in Egypt looking at the potential role for chemoradiation as adjuvant treatment in this patient population. Dr Choudhury, what did you think of that abstract?
AC: I thought it was a very interesting abstract. Professor Zaghloul and his team have previously presented data suggesting that there is a role for adjuvant radiotherapy without any radiosensitisation in high risk patients who have aggressive features post-cystectomy. This abstract that was presented today suggests that rather than radiotherapy alone there may actually be a role for adjuvant chemotherapy sandwiched either side of a relatively low dose of radiotherapy to the pelvis. What the abstract showed was that patients who were randomised to receive the combination of chemotherapy radiotherapy chemotherapy did better than patients who were treated with radiotherapy alone. It’s an interesting study, I think the numbers are small and the data that was presented today is a subgroup analysis because the data presented today showed results in patients who had urothelial cancer whereas a majority of patients in Egypt actually present with squamous cell carcinoma. There were differences in the way the patients would be treated compared to how they’re treated in the UK and Europe and the US whereas these patients did not get neoadjuvant chemotherapy and we would normally give patients neoadjuvant chemotherapy before they proceeded to any radical treatment. But I do think it potentially strengthens the hypothesis for looking at a study to see if there is merit in giving adjuvant treatment post-cystectomy. There have been a number of studies attempted around the world; at the moment there is a study open in Europe, there’s two studies open in Europe, one in France and one in Belgium, and there’s a study open in India, but the US tried to open a study and failed to recruit. What would be interesting, actually, would be to see what other colleagues thought about this data and whether it compelled them to revisit the question.
MG: Dr Bellmunt, your impression of the data? The patient population was restricted to patients less than 70 which that and the issue of potential differences in urothelial cancer in the US versus Egypt, we think about squamous cell cancers being potentially different, do you think there’s a difference in the urothelial cancers they’re seeing there as well?
JB: I think at the time that this trial was designed squamous cell carcinoma was the most frequent histology and they were concerned for local recurrence because squamous tend to have much more frequent local recurrence. This is why they randomised radiation therapy versus radiation plus chemotherapy because, as has been asked during the presentation, why neoadjuvant chemotherapy was not given, why they did not randomise chemotherapy versus chemoradiation therapy that would have been what we believe is the rationale in urothelial cancer outside Egypt. But we know that the pathology has changed in Egypt, they are no longer seeing squamous cell carcinoma because of this parasite that was producing this type of tumour. Then what they have done is just this post-hoc analysis in patients with urothelial cancer with all these limitations. But it’s a good point because it’s restricted to urothelial patients having non-squamous histology and it’s information that is relevant in terms of radiation therapy might prevent recurrence. It’s something that we have forgotten and maybe it’s being rescued now, this concept.
AC: I guess as a clinical oncologist I’d be keen to promote bladder preservation as the first line of treatment for appropriate patients rather than go looking at patients post-cystectomy. The question that you asked about whether these patients are genetically different is really interesting. I’m not aware of a lot of data out there comparing the same histology related to the ethnicity of the patients but we know certainly in other cancers that the outcomes of different cancers and their treatments do differ from country to country, even when it seems that the treatment they’re getting is the same.
AN: I think overall that this data allows once again the need for a multidisciplinary collaboration in these patients, these patients with local or locally advanced disease. Mainly the need to open the door also for the multidisciplinary collaboration between medical oncologists and radiation oncologists and other urologists outside the of the UK in managing properly this patient population.
MG: Absolutely, and I think we’re seeing more of that; each year at these meetings I think we’re seeing more of that. Dr Necchi, you’ve been a leader in the development of immune checkpoint blockade in the clinically localised muscle invasive setting and today we heard updated results moving immune checkpoint blockade even earlier to the non-muscle invasive disease setting in BCG unresponsive patients. Do you think there is an unmet need there and what’s your take on the data that was presented today?
AN: Yes, Arjun Balar basically presented data that are in line with those already presented last year at the ESMO meeting and also at the SUO meeting showing that there is an interesting rate of complete responses that is pretty much in line with the rate of CR obtained in a bit more advanced disease like muscle invasive disease, 40%. In particular this response seems to be sustained over time because the trial is reaching the most important endpoint of complete response at three months or sustained response at six months or even beyond this time period. So at least in the proportion of patients for whom the data have been presented, so the patients with T1 disease plus CIS, the early data with single agent activity, with single agent drug, are promising, pending the results of biomarkers that may guide us in being more able to select patients more properly to achieve even higher results in terms of CR and maintain CR over time. But they are interesting and I liked the fact that probably in the next future patients with early high risk disease may be considered all those who have a non-muscle invasive high risk disease and early muscle invasive disease to be considered altogether for clinical trials.
MG: Dr Bellmunt, the follow-up study that we heard about today from the pembrolizumab presentation is moving treatment even earlier and so this might be one of the only datasets in the BCG unresponsive setting, single arm study. Do you think this is practice changing?
JB: I think the data, as Andrea has mentioned, is compelling. So that 40% complete responses in patients that have CIS, that means those patients tend to progress and are candidates for cystectomy, that’s really striking. This is at three months so the most important thing is how these responses are durable. Some data was presented that some patients are still maintaining this complete response at nine months and this is really interesting data. But still this is a part of the whole trial so there are three cohorts. The cohort that was already presented at ASCO is an update and it’s reassuring, meaning that there is strong rationale for investing with immunotherapy in this setting. So it looks like if we are moving earlier and earlier immunotherapy is working much better initially. Obviously we need to be really, really happy and patients need to get this under consideration for the future because no-one wants to get rid of the bladder, right? So the side effects, quality of life. So if this is a treatment paradigm shift then it’s going to change the life of a lot of patients.
MG: And toxicity concerns in this patient population, given what you saw today and assuming that these treatments become commercially available for this disease population in the future, you feel comfortable giving them in this disease state?
JB: Well I believe that the profile is similar as what has been observed in second line so there is no unexpected side effects that are of concern. Obviously all the time experience in giving these agents is crucial and we are all learning on how to manage side effects. If you early recognise a potential life-threatening side effect you are able just to block that and then not create grade 5 side effects, those grade 5 we are seeing in the very beginning when we didn’t know that these agents could produce pneumonitis or severe colitis and so on.
MG: It does seem like over time these datasets, the risk for those severe events seems to be getting lower and lower. Dr Choudhury?
AC: I was going to say on that point that although the data is incredibly interesting and compelling I think the follow-up is short. So I think it’s important not just to work out what the complete response rate is long term but also to get a bit of an idea about what the chronic long-term effects may be with immunotherapy in this group of patients. Because these patients, in lots of ways, are going to live a full and long life compared to a lot of the patients that we’ve been treating in the metastatic setting. So I think that becomes a real important part of the discussion.
MG: What’s the role for radiation in these patients currently and is there another opportunity to bring in radiation, given what we know about the potential for radiation to combine with immune checkpoint blockade?
AC: The role of radiation in this group of patients is very interesting and is almost having a little bit of a rebirth. There has been increasing interest in whether radiation, especially with radiosensitisation, could be useful in non-muscle invasive high risk cancer. It could be possible to treat these patients with radiotherapy combined with radiosensitisation; the data that we use not to treat these patients comes from a very old study with old radiotherapy techniques and without radiosensitisation where radiotherapy was shown to be as good as BCG in controlling the disease but no better. The other thing that we don’t know is we don’t know whether it works on a different group of patients. It may be that the patients who respond to BCG are not the patients who would respond to radiotherapy. It would be very interesting to develop almost a multi-arm trial, maybe a bit like STAMPEDE in prostate cancer, whereby we could test a number of different treatment options for these patients in one go in an efficient way. Because we have the patient numbers and there is a need to try different combinations of treatments.
MG: So there’s one such study going on in the United States like that although it’s a multi-arm study but less of a multi-stage study. But one of the arms in that study is a combination of immune checkpoint blockade and radiation in the BCG unresponsive disease state and lower dose radiation. So it’s certainly something to watch.
AC: Yes, I think that will be very interesting.
JB: There was also an interesting poster regarding the BCG response and the tumour mutational burden that was by a group from Brazil. So it looks like as more tumour mutational burden you have you are more likely to respond to BCG. But those are patients that initially received BCG so who knows in this like refractory still TMB is there. So there may be synergistic effects with the BCG and radiation therapy and immunotherapy.
AC: Absolutely and we are beginning to learn what the potential synergies could be with radiotherapy and immunotherapy. So there will be a number of studies that will report over the next year or two that will give us an indication as to the safety profile of combining radiotherapy with immunotherapy and also give us some tantalising results as to whether there is a response as well.
AN: Of course the possibility to have a new drug that is active in the CIS component may be critically important in order to expand the role of radiotherapy also in this population that was always considered as not eligible for or as not more suited for a radiotherapy approach.
MG: We’ve been hearing more and more at these meetings about antibody drug conjugates and today we heard an update of a phase II trial, single arm trial, with sacituzumab govitecan, an antibody drug conjugate that has shown activity in triple negative breast cancer as well. Dr Necchi, what’s your take on that data and what’s the landscape of ADCs in urothelial cancer? Where’s the place for them in our treatment?
AN: The data are compelling because we are dealing with a response rate in a pre-treated population that is over the expected proportion of 20-25%, we are reaching 30%. Of course the data are very early, very early in their development, because we are dealing still with a few patients, with 4-5 patients. But overall it’s nice to see that we may have a form of vedotin, sacituzumab, on the other side as presented today that may be available for all comers, for unselected patients on one side. On the other side we may have a similar activity in a more select, molecularly selected, patients like those that are suited for targeted therapy like FGF receptor targeting. So the landscape will be probably driven by the biomarker, by the biomarker selection, on one side. Patients with biomarker driven disease may be probably more suited for a targeted therapy approach first but the possibility to have a rescue with a more than active compound that may be available for all comers, it may be a good option for those who cannot receive or who fail targeted therapy for their tumour or cannot receive it because they don’t have any mutation. On top of that there is immunotherapy, of course, and so we are opening the door to combinations and combinations just behind the corner with these compounds, including antibody drug conjugates with immunotherapy. There is a plethora of phase I/II trials that are ongoing or in plan in every clinical stage, I would say, at this stage except for the early stage disease. So the data are early anticipated and are awaited. Basically it all depends, or mostly will depend, on the biomarker selection.
MG: Dr Bellmunt, it’s conceivable that we’ll have approvals for FGFR inhibitors and ADCs around the same time. So you have a patient with an FGFR3 mutation, which drug do you choose?
JB: That’s a good question. I think that both these drugs have received this breakthrough designation by the FDA and maybe it’s not going to be one before the other, they might be competing. So enfortumab vedotin has these antibodies against nectin-4 that has high expression in bladder cancer so you don’t need to screen the patient. The second compound presented today is against Trop-2, it’s also highly expressed in bladder cancer and the response rate for enfortumab is 40%, for this one today it’s 31%. Still a lot needs to be learned – what is the impact of immunotherapy before receiving these agents, there is limited data. For targeted therapies we have a lot now under development, FGFR3 inhibitors or pan-FGFR inhiibtors. Erdafitinib has this 35-40% response rate in selected patients that have mutations or translocations so you need to select from the whole patient population, sometimes it’s in between 20-25% of patients having FGFR3 alterations, genomic alterations, the most frequently described to be a driving potential response to these compounds is the mutation and translocations. Then for those who are selected we still probably don’t have the good biomarker because even selecting these patients for translocations and mutations still we only see 35-40% responses, so we are going down. So we’ll see. I think that now more trials need to be generated because all these compounds combined with immunotherapy, as you have mentioned, probably are going to expand the way that we treat patients and the patients are going to derive benefit from all these sequential… not sequential, who knows what is best? Should we start with an FGFR inhibitor or one of these antibody drug conjugates?
MG: So you brought up an important point about the response rates maybe creeping down a little bit as the sample sizes increase. We’ve seen response rates in the 20-30% range dating back a couple of decades with cytotoxic chemotherapy, is your gut feeling based on seeing the data, based on seeing durations of response? Do you think these drugs are different?
JB: Probably those are a bit different. So the median duration of response for erdafitinib, and those patients have received two or three lines of therapy, is 5.4 months so it’s more than what you expect to see with second line chemotherapy that is 4.5. So it’s a bit longer but it’s not as long as you would like to see and maybe immunotherapy or combining antibody drug conjugates plus immunotherapy we are going to see long-term response. So yes, targeted therapies we have the experience with lung cancer, so some patients deriving a nice response but those response are limited. At some point the tumour likely develops newer mutations and progresses on the treatment.
AN: I think it would be very good for us to accumulate data, and they will, presumably, accumulate data in the next future, regarding the likelihood of response to get benefit also to chemotherapy or an antibody drug conjugate in patients who are molecularly selected according to FGF receptor alteration. There may be some signal that may suggest that this patient population not only are predicted poor responders to immunotherapy but may be poor responders also to chemotherapy or to other drugs. This information will be critical in order to be able for us to select the right strategy and the right sequence to discuss with these patients.
AC: I think, though, we should have a little note of caution about the robustness of the biomarkers that we’re using to stratify the patients. I think we have had our fingers burned in the past where we’ve assumed that we have a robust predictive biomarker; we’ve used it to enrich a population or even used it to direct treatment within a clinical trial and we’ve had a negative result. We’ve also shown that a lot of these agents actually work in patients who would be biomarker negative. So before we jump straight in with stratifying the patients with the biomarkers that we should just make sure that we have not only a robust methodology behind the biomarker but we’re sure that the biomarker is predictive not prognostic.
MG: Excellent point. We heard an update of the RANGE study today, a study which explored the role of antiangiogenic treatment combined with chemotherapy in the post-platinum setting. We don’t have many randomised phase III studies in this disease that have met their primary endpoint and here we have a study that met its primary endpoint that thus far hasn’t had a significant impact on clinical practice. What’s your impression, why do you think that is?
JB: Yes, we all know that the RANGE trial was positive as per trial design, that was progression free survival based on the investigator assessment. The endpoint was met but the point is this endpoint was statistically significant, the other question is is this clinically relevant because it was one month and a half improvement in PFS then linked to that the overall survival was negative. The presentation of today has been very relevant because we all learn from negative trials. What they have done is they have gone back and analysed their PK, their prognostic factors of all these patients. In fact, if you optimise the dose in these patients you get an overall survival benefit and this has been shown in gastric cancer and colorectal cancer, other cancers, with ramucirumab. I think that that presentation that linked the PK, so the levels of the ramucirumab, with the prognostic factors, meaning that if you have several adverse prognostic factors maybe the metabolism of the drug changes and this may lead not to the sufficient amount of activity for this drug. It was a really nice analysis despite this is retrospective but maybe in the future, despite what you have mentioned, we have no perfect biomarkers. But we need to start stratifying patients based on prognostic factors, predictive factors and genomic correlates and so on because maybe we will be able to select this specific subgroup of patients that derive benefit despite the drug being not positive for the whole patient population.
AN: Joaquim, do you think that this data may be able to rescue the interest towards the antiangiogenesis targeting in these patients based on the landscape of new drugs that are coming in the ground of therapeutic possibilities in urothelial cancer? What is your impression regarding the possibility to still use a drug like ramucirumab in this patient population combined with chemotherapy?
JB: I think that despite all these antiangiogenic trials adding an antiangiogenic drug have been negative, we need to hear about CLCP trial in first line that I have heard news that probably are not satisfactory the results. But because there are subsets of patients, and you have experience with pazopanib, seeing some patients with outstanding responses, long-lasting. I have a sunitinib trial, I remember patients having long-term responses and you have also experienced with antiangiogenic that specific patients derive benefit from specific agents. So it might be that the next step, if the company is willing just to invest in bladder, is just probably select patients, monitor the thresholds, the Cmax of the drug and so on, this might be the future, personalised medicine. So the medicines are not useful for all patients.
MG: So still maybe uro (urothelial cancer). So with that we’re going to complete our discussion. Thank you for joining this ecancer expert panel.
