PG: Hello, I’m Petros Grivas, I’m a medical oncologist at Seattle Cancer Care Alliance, I’m an associate professor at the University of Washington and associate member of the Fred Hutchinson Cancer Research Centre. I’m thrilled today to be together with Dr Andrea Necchi, a good friend and colleague and collaborator. Dr Necchi is soon to be Associate Professor of Oncology and he’s a director of the Bladder Cancer Research Group in the Institute of Tumours in Milan, Italy. Andrea, welcome.
AN: Welcome you, a very good friend, and it’s a pleasure to be here.
PG: It’s fantastic to sit here in this amazing ASCO 2019, such interesting data and a lot of plethora of information. I would like to pick your brain a little bit, tell us what you think about, initially, non-muscle invasive bladder cancer and how the field is going in regard to novel clinical trials, especially the BCG responsive disease for non-muscle invasive.
AN: Yes, as bladder cancer experts we are all happy of living in this revolutionary time. Thanks to the event, basically, of the immunotherapy approaches in the far advanced setting. Now, as you mentioned, the good thing is that we are jumping to a totally new era and area of non-muscle invasive tumours with many trials that are targeting with earlier results the space of patients who have failed the BCG therapy and basically who are offered a radical cystectomy as the only standard of care available in Europe as well as in the United States. These trials are recruiting very well on both sides of the Atlantic and the point, and the most important point I would say, is that we are living in an exceptional time for providing patients with interesting possibilities to be included in clinical trials but also it’s a unique opportunity for us to collaborate better with urologists; it’s a unique opportunity for us to boost the multidisciplinarity around bladder cancer tumours which is, I would say, the key for success for the patient. The early data for immunotherapy are related to the KEYNOTE-057, to the pembrolizumab study, single agent study, provided to patients who had failed an adequate amount of BCG therapy and who have a high risk disease plus or minus a CIS component. The response rate, the early response rate data presented last year at the ESMO meeting and subsequently at the SUO meeting and updated at ASCO GU this year, are very promising, showing a complete response rate which is in the range of 30% which is very, very encouraging in this very hard to treat patient population who may be spared a radical cystectomy approach.
PG: It’s very interesting indeed and I agree with you, the KEYNOTE-057 trial is the first that has shown results in a phase II trial setting. Clinical complete response rate is about 40% at three months, what do you think about the durability of response? Do you think it will meet the regulatory endpoint for approval or not over time? It’s hard to say, of course.
AN: Yes, the early signal is promising. Of course a longer follow-up is needed and in particular the three month CR rate is still too short to declare the success of these kinds of studies and this kind of approach. We need probably one year or 24 months CR rate to have a better picture of the improvement that we may achieve with new therapies. But, again, we are offering something that is clearly in the right direction according to our feelings for other treating physicians, of course. And patients are very happy to receive something that is totally new, just like a little more advanced stage which is muscle invasive tumours, of course.
PG: I agree with you. I think overall the data is exciting, we have to see what happens over time in terms of the durability of response. Importantly, no patients had progression to muscle invasive or metastatic disease which is interesting. As you mentioned before, the standard of care for patients with BCG unresponsive non-muscle invasive disease is radical cystectomy, if not dissection, but many patients may be frail and too sick to get that or they refuse it. So it’s good to have options.
AN: And it’s interesting to realise that a few of these new trials, big phase III trials ongoing, randomised studies in the same clinical setting are offering patients a combination of therapies – systemic therapy on one side, immunotherapy, systemic immunotherapy, combined in many cases with intravesical BCG therapy meaning that we should work very closely with urologists because we should provide systemic therapy on one side and local therapy on the other side, meaning that probably the way that we conceive the entire bladder cancer patient management should be revisited in the light of the ongoing studies because patients may have access to different facilities in the same day to receive different kinds of treatments within the same clinical trials. It may be a big issue for many hospitals.
PG: And I think it’s an important point to underline highlight the value of multidisciplinary care, what you are doing in your centre and we are doing at our centre, to bring urologists, medical oncologists, radiation oncologists in the same room. We have this multidisciplinary clinic every Tuesday morning and we see patients with localised bladder cancer, try to come up with a consistent plan among all of us and convey that to the patient. So definitely an important need for communication and, as we have better systemic therapies, more clinical trials can actually enable us to think about multimodality therapy even in locally advanced disease. So far metastatic disease has been mainly systemic therapy with some palliation of radiation and this paradigm hasn’t changed for years. Moving forward to muscle invasive bladder cancer and it’s a very exciting time and we know that cisplatin based neoadjuvant chemotherapy is the standard of care for those who can tolerate cisplatin in the neoadjuvant setting before radical cystectomy, if not dissection. However, many patients may not be fit enough to get cisplatin because of kidney function, performance status, so on and so forth, neuropathy. And other patients may not respond. So to meet that unmet need there have been very interesting clinical trials and you have been involved in one of them, a very important trial, the PURE-01 evaluating pembrolizumab in patients with muscle invasive bladder cancer as a neoadjuvant approach in a phase II trial design. Could you talk a little bit about your trial?
AN: Yes, the strategy here is to provide patients with a short course of neoadjuvant therapy with new drugs, in this case immunotherapy, single agent immunotherapy, followed by radical cystectomy and followed by the standard of care observation of adjuvant chemotherapy. The issue here is for these patients, for patients diagnosed with a muscle invasive urothelial bladder cancer, as you mentioned, is that they have theoretically a standard of care which is a cisplatin based chemotherapy but, again, in Europe as well as in the United States, the administration of this is standard of care for a number of reasons. It’s still suboptimal, it’s still in the range of 20-25%, it’s improving to 30% but it’s a unique situation where we have a standard of care which is applied only to one-third of the patient population. This is the reason why we started first with the PURE-01 study focussing on all comers, a very critical area, of course, when you have a standard of care. But the early data supporting the fact that with single agent immunotherapy we may rescue to pathological down-staging to non-muscle invasive disease, so major response or complete response in a good proportion of patients in the range of 40-50%. The second, more important, issue is that these patients may be enriched, patients with PD-L1 expression may be enriched, with pathologic complete response meaning that the issue of biomarker here is critical. There are trials ongoing as a natural consequence of the huge amount of trials that are ongoing in the metastatic setting, trials combining chemotherapy plus IO or trials with single agent immunotherapy, cisplatin ineligible patients, comparing radical cystectomy alone. So the results of these studies are pending, of course, the study has just started recruiting patients worldwide and in particular the data from the combination therapy of chemotherapy and immunotherapy in this clinical setting are still awaited.
PG: It’s very interesting to see these combinations of chemo-immunotherapy, not only in the first line setting of metastatic disease but now moving forward to the neoadjuvant setting in phase III clinical trials. I think the results from your trial definitely support further evaluation of immunotherapy. It’s not practice changing yet but definitely supports ongoing evaluation and it’s very, very important data for the audience to look at, the PURE-01 trial. Moving to the metastatic disease setting I would like to pick your brain in terms of your opinion regarding antibody-drug conjugates which are a novel modality in metastatic disease. We have data with enfortumab vedotin, sacituzumab govitecan. How do you see these agents playing out in metastatic urothelial cancer?
AN: I see these agents very well, very well placed in the bladder cancer treatment paradigm in the near future because of, firstly, tolerability. The toxicity profile of these drugs, enfortumab vedotin, sacituzumab, was really good compared to immunotherapy or compared to FGF receptor inhibitors, for example. The early clinical data are standing in terms of objective response rate. It has been reported in both studies in the far advanced setting in very highly pre-treated patients overcoming the 30% boundaries or 40% cut-off. It’s really intriguing. Of course, caution is needed, in particular because we are still waiting for the shift from the phase II to the phase III which is always critical and the IMvigor 210 study and the atezolizumab study tells you that it may be critical for the primary endpoint achievement with these new agents. But in any case we may achieve the goal of treating unselected patients with this class of agents which is a totally opposed strategy compared to, for example, the FGF receptor targeting which are aimed to treat the 20%, 15% of patients who are molecularly selected, who heal the molecularly selected disease. So we have potentially many treatment strategies with many compounds, many active compounds. The goal in the future is to try to have prediction tools in order to orient patient counselling, to better inform patients which should rely upon the use of biomarkers. We still have to investigate further on the role of biomarkers with ADC because so far we have no data on biomarkers from this class of agent. We may further improve their results in more selected patients.
PG: It’s a great point and your point about the issue and the need for biomarkers is overall very important across different agents and, of course, in the spectrum of urothelial cancer continuum and with antibody-drug conjugates, ADCs, as you said, we don’t have any data about biomarkers yet. Do you see eventually these drugs, if they potentially get approved in metastatic disease, to maybe move forwards in the neoadjuvant setting, for example? Do you see combinations with immunotherapy or something else in the clinical trial design?
AN: Yes, I see these drugs very well in the neoadjuvant setting because of the same reason that I mentioned before because of tolerability and activity. As single agents they may be, enfortumab vedotin may be an ideal compound to use in the pre-operative space or in the next future. Already studies implying combining this class of agents with immunotherapy or with chemotherapy in the pre-operative earlier stages or even earlier stages like non-muscle invasive disease, of course. I think we will lead very soon another further wave of revolution following immunotherapy, following FGF receptor inhibitors and then we will have the ADC compounds. The problem at the end will be for the patient to give the right treatment, and you mentioned the problem of biomarkers, but the most important is that we have the problem of patient access and affordability to these new drugs worldwide. So the discrepancies and the differences between the countries and between the United States and Europe or other continents are crucial. We are all asked as investigators to sit down at the same table with patient advocates, regulators, to discuss this point because this is a huge, a very important point, perceived by the patient side.
PG: I fully agree with you and, again, it’s as we discussed before, you and me, the need for patient advocacy groups to be part of this discussion among multiple different stakeholders, policymakers, industry, academia, private practices, to provide more access to patients in those agents. Antibody-drug conjugates are not approved today but down the road may become an option in the armamentarium of metastatic urothelial cancer and we have to be prepared to provide access to many patients. A very quick, practical question – right now in Europe how do you do genomic sequencing in patients? Do you do it with metastatic urothelial cancer in all patients, selected patients?
AN: Well, in the context of academic research or within clinical trials in general we routinely offer patients next generation sequencing since the very early beginning, since they started first line therapy, I would say, or even earlier in some cases. The problem is therefore the availability of this kind of test outside of clinical trials in order to provide patients the new drugs outside of clinical trials. So this pushback to the former issue related to the access of new drugs that in some cases, for example like FGF receptor inhibitors, is conditioned by the positivity of a test so it should provide for the test first and for the drug subsequently. So it’s a very complex future. But in the research, in the clinical research area, in the academic research field, of course we are routinely offering patients this possibility because I think that in general you may offer very useful information for the patients in general to have access to new drugs or to have a deeper understanding of their disease that may be useful for other opportunities.
PG: I fully agree and there is a whole other issue that we’ll talk another time about germline mutations and whether this can have implications for genetic counselling and potential cascade testing for the broader family to prevent and screen for multiple cancers. With that I think I have to thank you, Dr Necchi, for your time.
AN: You’re welcome, thank you.
PG: Great to talk to you and looking forward for an exciting ASCO 2019 and, of course, many more data coming up in the field of urothelial cancer. Thank you.
AN: Thank you Petros.
PG: Thank you so much for your attention.