The Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in MIBC - Andrea Necchi
April 28, 2020
Andrea Necchi, MD, Medical Oncologist, Department of Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy
Ewan Gibb, Ph.D., Senior Scientist & Bladder Cancer Lead at Decipher Biosciences, Inc.
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU medical oncologist and Associate Professor at Northwestern University in Chicago, Illinois. I am so excited to have here with me today Dr. Andrea Necchi, who is a physician at the National Cancer Institute in Milan, Italy, as well as Ewan Gibb, who is a Ph.D. researcher and a Senior Scientist and Bladder Cancer Lead at Decipher Biosciences. Thank you both so much for being here with me today.
Andrea Necchi: Thank you, Alicia. It is a pleasure for me and thank you UroToday for the invitation. It will be a pleasure for me to explain our research and to discuss the issues related to bladder cancer.
Alicia Morgans: Wonderful! Well, thank you. So Dr. Necchi, I wanted to talk to you about the urgent unmet need in bladder cancer. Because we know that when we are facing a patient with muscle-invasive bladder cancer who needs ultimately to have a cystectomy to hopefully cure that individual of bladder cancer, we typically use a neoadjuvant or pre-surgical treatment to try to make sure that we get rid of as much of the cancer as possible prior to that surgery.
Can you tell us a little bit about the urgent need to understand which patients will respond to that treatment and why you designed the study that you did in the first place?
Andrea Necchi: Yeah, you are right. The issue of patient selection in muscle-invasive bladder cancer to try to identify the patients who are more suited for which kind of neoadjuvant therapy is a big issue and it is a big unmet medical need that is a matter of intense clinical research throughout the world since a few years ago. We started identifying the predictors of neoadjuvant chemotherapy response and colleagues in the United States, in Europe have already published a lot and identified genomic signatures that are associated with great advantage from neoadjuvant cisplatin-based chemotherapy.
But outside of this discovery, the issue and the problems that are related to the patient side are related to the fact that neoadjuvant chemotherapy is still something that can be addressed to a proportion of patients with muscle-invasive bladder cancer and not to everyone to all-comers due to renal function test and due to limitation in performance status and so on.
So we are still struggling with the need to identify something that could be more applicable in this critical area. And of course potentially ideally less toxic than neoadjuvant chemotherapy. And this is the reason why we started and we pioneered and since two years ago the use of immunotherapy alone in this clinical setting.
The first outcome is from the early studies in this field from the PURE-01, from the ABACUS studies which tested the use of short courses of neoadjuvant immunotherapy checkpoint inhibitors before radical cystectomy provided interesting findings in terms of pathological responses, pathologic complete responses of downstaging to nonmuscle-invasive disease, found unknown radical cystectomy specimens. But the issue here as of today is still to see whether this promising response is seen at the short or medium-term actually confirm the long-term to be associated with the survival improvement or survival benefit or long term survival in this patient. This is still something for which we don't have any data and the data, of course, is awaited in the next few months.
The second point which is related to the immunotherapy as well as to chemotherapy is to try to identify which patient may benefit the most from the immunotherapy approach rather than chemotherapy approach or ideal in the future combination therapy approach that which are being tested in advanced-stage clinical trials in this space. And so with Ewan, with the CIPHER colleagues, we started investigating on the issue of biomarker selection as retrospective studies, biomarker studies within the prospective neoadjuvant therapy studies like the PURE-01.
This is the reason why we published a paper by which we applied the transcriptomic data, the RNA signature data to the population of patients in a PURE-01, and treated with pembrolizumab and radical cystectomy.
What we found was that the use of RNA signatures, the Decipher® signatures may be probably better suited than the use of gene alteration or TMB. Because of the fact that these biomarkers are also biomarkers related to chemotherapy response, so we need definitely something that may be peculiar of immunotherapy activity.
So I would like now to ask Ewan to briefly anticipate that the main findings from our signature studies and then we will discuss the potential clinical impact of these findings.
Ewan Gibb: All right, thank you! So the main finding we found actually in the study was that tumors with a basal subtype particularly basal tumors enriched with immune signatures were highly responsive to embolism, particularly in terms of outcome. So after two years, we had 11 patients who are basal claudin-low subtype who actually had zero events, which is quite striking. Conversely, in a knack cohort, looking at a sort of similar patient population, we found that basal claudin-low patients did quite poorly. So we're starting to see a subtype stratification in terms of response to treatment.
Alicia Morgans: So I think that's really important and I just want to make sure that we reiterate. When we're looking at neoadjuvant treatment for patients and we're thinking about patients who may not be particularly amenable to treatment with cisplatin, we at least based on the PURE-01 data might consider and this, of course, has to be moved into real clinical practice. Right now we have just sort of intimations from the small PURE-01 study. But we ultimately may see that we're able to use neoadjuvant immunotherapy that's of course pending the data to potentially get these patients into better shape and have better outcomes from their cystectomy. And what you are able to show with this immune signature which is related and based on the Decipher® platform, is that you may be able to identify those patients who are going to have a better outcome ultimately with neoadjuvant immunotherapy, and that actually may not identify patients who are going to respond really well to chemotherapy. Am I understanding that correctly?
Ewan Gibb: Yeah, that's absolutely correct. So in the initial study when we developed this model, it was in 2017 with Dr. Roland Seiler and Dr. Peter Black, we found that the basal subtype actually had good outcomes with the response to chemotherapy, platinum-based chemotherapy. What was interesting again, and similar to the PURE-01, we really didn't see in that initial study a good association of some type with a pathological response. And neither did we see this in the PURE-01 study. There is some indication that maybe basal tumors might be responding a little bit better in terms of pathological response but we didn't see that reached significance.
Andrea Necchi: The main findings from the disease biomarker studies are related to the fact that by with the use of a combination of molecular subtyping and immune signatures that are well described as Ewan said for example, by the claudin-low subtype, which is a mixture of basal subtype with the highest immune signature scores, it seems that this patient population is more likely to respond to single-agent immunotherapy.
As another caution, of course, we should realize that this is the only study so far for which there is such a clear association between the biomarker and the clinical outcomes. Because for example there is not an overlapping situation in the ABACUS study as well as in the other studies of combination immunotherapies like the NABUCCO study with ipilimumab and nivolumab or at the ASCO meeting in a few weeks, we will see additional data from other Spanish studies in the same clinical setting.
So the biomarker issue is still something that on the ground, it is a matter of research, but that this signal that we acquired in relation to the response at least and to the initial association with survival is very promising. And, of course, it will deserve validation and confirmation in larger cohorts and it would be interesting to apply this signature we're seeing in combination therapy studies. In studies in which immunotherapy is combined with standard chemotherapy to try to dissect the contribution of immunotherapy over standard chemotherapy in these patients.
Alicia Morgans: Absolutely, and just to reiterate, of course, immunotherapy, at least in the United States, is not considered a standard in terms of neoadjuvant treatment prior to cystectomy, which is also important to recognize. But I think that it's exciting that we are moving in the direction where that may be an option particularly for patients who may not be cisplatin candidates because we don't have a good neoadjuvant strategy for them, and certainly for patients who are really on the borderline and who may have a choice ultimately between their neoadjuvant strategy.
But just to get back to something that you had mentioned, you know, this doesn't necessarily associate with pathologic complete response, which in the neoadjuvant chemotherapy setting at least has been established in urothelial cancer to be pretty tightly associated with survival. I think in this analysis that you did, you didn't just look at pathologic complete response. You actually looked at some more distant outcomes. And I think it's important to mention those too because if this is not as tightly linked, particularly in the setting of immunotherapy to survival, which it may not be given the thought at least that immunotherapy may take time to work continuously. There are other outcomes certainly like progression-free survival that may be of more importance and you did look at that I think in this analysis didn't you?
Andrea Necchi: You raised a very, very important point. I think that this is one of the most intriguing and important point in this clinical space. Of course in this specific study, we didn't have sufficient numbers, sufficient sample size to look in the end of way more and more importantly a sufficiently longer follow-up duration to try to specifically evaluate this association and this surrogacy of by pathologic complete response over survival. Which is I would say as you mentioned the most important point in this area. There are I would say three major issues here and then we are asked to deal with when dealing with biomarker development, the definition of pathologic CR because there is no consensus, full consensus regarding the definition of pathologic CR because a few authors, for example, include the residual CIS, carcinoma in situ, residual CIS, as a pathologic response complete response.
The majority of the other authors didn't allow their residual CIS to be included as a pathologic complete response, but there is no full agreement in this regard first. Second, as you mentioned the association, the surrogacy of pathologic complete response with the outcome and in particular, on the opposite, the association, the definition of bio risk population. So a population of patients who apparently are non-responding is the pathological level by showing, for example, lymph node involvement pathologic level or pathologic PT3 or PT4, residual disease, which is the survival endpoint, which is the overall survival of this patient, over the relapse for the survival of this patient we didn't know and we are still waiting for a sufficient follow-up time sufficient follow-up duration to make such kind of analysis.
And the last point is the use of alternative endpoints to which testing new biomarkers instead of pathologic response. And I would say that in this regard and in line with FDA recommendation, for when dealing with the neoadjuvant immunotherapy, the event for survival, which is a more comprehensive endpoint compared to relapse-free survival, which includes toxicity and which includes other events that are not primarily related to disease relapse, but also related to the treatment could be a reliable endpoint to test and to see whether, and probably it's better associated with the final overall survival outcome of these patients.
So, the issue of the identification of the right endpoint for this trial is still open, and so we have a double limitation, the lack of validated biomarkers. And we are working on this and I am confident that the immune gene signatures are on the right line. And on the other side, the right endpoint to which the test is biomarkers and we still don't know which may be the best endpoint to challenge and I am then confident that in this regard, the event-free survival would be a good endpoint to test the biomarker development and to test the activity and the efficacy of medium-term of new drugs in the neoadjuvant space.
Alicia Morgans: I completely agree with you and I think time will tell and certainly more efforts at pursuing this work will tell. And along those lines, Ewan, where do you see your next investigations going? Because I think that the Decipher® platform has immense power to potentially help in this area for us to understand who will respond and who essentially is wasting his or her time in terms of getting this early therapy. And so where do you see yourselves going as investigators in terms of next steps?
Ewan Gibb: So I think in the very short term, going back to the pathological response kind of question. One thing we're very interested in doing is comparing some post-cystectomy samples to the TURBT's to better understand when a patient is not responding, like why they may not be responding. So that's one study we're undertaking.
We're also involved in a second neoadjuvant immune checkpoint plus platinum-based study with Dr. Shilpa Gupta, BLASST-1. So we're working on that study, but I think really what we're looking to do is to start to deploy the Decipher® platform into clinical trials. This is a CLIA certified test so it actually would be quite ideal to start thinking about exactly what we're doing with chemo versus immune checkpoint for example.
Alicia Morgans: I agree and I really do look forward to seeing this move forward and investigators certainly should reach out to Ewan at the Decipher Biosciences organization. I think if they have bright ideas. And Andrea I'll leave the final words with you. In terms of clinical implications, where do you see this kind of work going? What's the importance and where can it ultimately bring us in terms of our ability to better treat individuals with urothelial cancer?
Andrea Necchi: I definitely think that we should wait also for the adjuvant study results and the one of the most important studies, the IMvigor010 will be presented at the ASCO meeting. But the negative results by using adjuvant atezolizumab would be high-risk operated patients had been already anticipated by Roche.
Meaning that one of the most intriguing final words would be related to the right sequencing or treatments in these patients. We should not consider neoadjuvant space. The adjuvant space surgery or chemoradiation are separate fields, but we should look at the muscle-invasive bladder cancer as a continuum and the key would be to try to envision their right sequential strategy for the patients and it seems so far based on the data that we have so far and tomorrow maybe not necessarily the same, the neoadjuvant immunotherapy strategy followed by adjuvant chemotherapy or adjuvant new drugs could be one of the winning strategies more than the reverse. But it's only an assumption and again we should wait for more data in the post-operative space from immunotherapy to have a better sense of the overall impact we may have with new drugs and specifically with immunotherapy in the new early bladder cancer, in muscle-invasive bladder cancer.
Alicia Morgans: I look forward to those results coming out. I look forward to the work being done and I congratulate the two of you in shining a light into the black box that continues to exist around our understanding of how to best treat patients with muscle-invasive bladder cancer. I hope that that light continues to get brighter as you continue your investigations so that we can understand how to best sequence, how to best choose patients, and how to best provide a cure. I hope for more and more individuals who are facing muscle-invasive disease. Thank you so much for your time today.
Andrea Necchi: Thank you. Thank you.
Ewan Gibb: Very much.