Enrique Grande: Hi, Ashish, good to see you.
Ashish Kamat: So congratulations on your ESMO presentation, it was excellent, and we're all looking forward to diving deeper into some of the data that you presented. So take it away with DISCUS.
Enrique Grande: Well, thank you so much, Ashish, and hi everybody. Well, I had the privilege to present at ESMO the results of the DISCUS trial. The DISCUS was an academic phase II randomized trial that compared head-to-head three versus six cycles of platinum-based chemotherapy upfront, and before maintenance avelumab in first-line urothelial cancer. And I think it is important to know where we are coming from. Today, enfortumab vedotin and pembrolizumab is the standard of care in first-line, no doubt about that, it doubles the efficacy compared to chemotherapy in the first-line in terms of responses, PFS and overall survival. However, in most of the countries, particularly because of access issues and reimbursement issues, well, we are still not able to offer enfortumab vedotin to all of our patients, and still today, platinum-based chemotherapy is still used in the majority of the countries. Well, we know that avelumab as a maintenance treatment in patients who had a benefit response, or at least stable disease, with platinum induction chemotherapy, well, it is impacting in the overall survival and it was the former standard of care in this scenario.
So the thing is, traditionally, we were considering that the more cycles of chemotherapy were translated into longer overall survival, more responses, longer progression-free survival. That is what we thought that it happened, we tried to squeeze chemotherapy until toxicity or until our patients were extremely exhausted about that. So the question behind the design of the DISCUS trial is, how much should we squeeze the chemotherapy? Is this enough, three cycles, or do we need to go up to six cycles of a platinum-based chemotherapy?
All right, so this is the design of the DISCUS trial. The DISCUS trial was a prospective phase II international randomized trial that compared head-to-head the standard of care, six cycles of platinum-based chemotherapy, gemcitabine plus cisplatin or gemcitabine-carboplatin, that was the treatment choice by the investigator, followed by avelumab maintenance for up to two years. And I think it is relevant to highlight the limit of the timelines we are offering for avelumab, since in the JAVELIN Bladder 100, the pivotal trial that gave the approval to avelumab, the treatment could be given until progression or until unacceptable toxicity. So we are here limiting the amount of treatment with avelumab.
In the comparator arm, experimental arm, we were using just three cycles of upfront chemotherapy, once again, platinum-based chemotherapy according to the investigator's choice, gem-carbo or gem-cis, according to what investigators decided it was the best for the patient, followed by avelumab maintenance, once again, up to two years. The patients were stratified according to two factors, the presence of liver metastasis and also the chemotherapy the investigators decided it was the best for the patients, carboplatin or cisplatin. Patients were first-line metastatic urothelial carcinoma, eligible to receive at least carboplatin to be treated for the metastatic setting, and their ECOG performance status should be good, zero, one or maybe two at maximum.
It is important to highlight the primary endpoints that were decided here. There were two co-primary endpoints, the most important one, it was the quality of life, and quality of life measured from the baseline to the cycle seven day one. So that means after the patients finished the total amount of pre-planned cycles of chemotherapy in the standard arm, what we were using in the past, versus the equivalent time in the control arm where only three cycles of chemotherapy were delivered. The second co-primary endpoint was overall survival, but the statistical alpha allocation was very small.
This is the consort diagram, and I think this is extremely important for daily practice, and this is extremely important to understand the results and what we can really expect from avelumab as a maintenance treatment in the intention to treat population. Take a look at these figures, because I think it is relevant. The end sample size of the DISCUS trial was 267 patients, so this is a very robust phase II randomized trials. Patients who were randomized to a standard control arm, six cycles of platinum-based chemotherapy, and the end sample size was 134 patients. In the experimental arm, 133 patients received only three cycles of platinum-based chemotherapy.
But take a look at this, because this is what it really matters in daily practice. Only 69 patients in the control arm, those patients who were randomized to six cycles of platinum chemotherapy, only 69 of them, so that means around 56% only of the patients reached the maintenance avelumab part. Why is that? Well, it is because of progression during chemotherapy, or because of toxicity during chemotherapy, or because of early progression just after the induction of chemotherapy with platinum.
In the experimental arm, where those patients were randomized to receive only three cycles of platinum-based chemotherapy, up to 96 patients received avelumab maintenance, so that means 74% of the patients. Why it is important? Well, it is important because the less number of cycles you can give to the patients, the more patients will be able to receive avelumab maintenance. So the shorter time on chemotherapy, the more patients will benefit from the long-term efficacy of the immune checkpoint inhibitors as a maintenance therapy. This is important, because the median survival that we had at DISCUS, it is dramatically less than the median survival we saw in the pivotal registration trial, in which patients were selected biased, because only those patients with a clinical benefit after induction chemotherapy were recruited in the pivotal trial.
Take a look at the main outcomes, take a look at the primary endpoints of the DISCUS trial. For the first time, with a primary endpoint of quality of life in a randomized prospective trial, we can say that three cycles only of platinum-based chemotherapy, followed by avelumab maintenance, is impacting significantly in a better quality of life of the patients versus those patients who were randomized to receive six cycles of upfront chemotherapy. And this is not only a matter of one specific time point, but it is maintained in the different time points after cycle number five, six, seven and later cycles.
In addition, this impact in the better quality of life is translated into less efficacy. Well, take a look at the hazard ratio for progression-free survival, 1.05. Take a look at the hazard ratio for overall survival, 1.15. Take a look at the median progression-free survival, eight months in the three cycles arm versus nine months. Take a look at the median survival, exactly the same, 18.9 months for both arms. We can't say that this is non-inferiority, because the trial is not powerful enough to demonstrate non-inferiority of three versus six cycles. But definitely, from a clinical perspective, this is easy to see that there is no major differences in the efficacy that we can expect.
And what about the responses? Because in the past, traditionally, we thought that the more cycles of chemotherapy were translated into higher and deep responses in the CT scan. Well, as you can see here, in the best overall response by investigators, 61% versus 59% of responses, no minor difference in terms of responses. And particularly relevant is the progression disease rate as best response, 6% in the three cycles arm, in the experimental arm, versus 10% in the six cycle arm, so that means that definitely it seems there is no detrimental activity.
So the thing is, and these are the conclusions of the DISCUS trial, the thing is that three cycles of chemotherapy seems to have a better quality of life without detrimental efficacy. The PFS is very similar, eight months versus nine months, with a hazard ratio of 1.05. Median survival is exactly the same, 18.9 months. So this is what we can really expect of avelumab maintenance in the intention to treat population. This is far from the 24 months that we saw in the pivotal trial. When we are considering the intention to treat population, 18.9 months is what we can really expect from that.
So three cycles was not superior to six cycles, we cannot claim for a non-inferiority, but at least it doesn't look like different. More patients in the three cycles arm reached to avelumab, so maybe the shorter chemotherapy cycles, the more patients will benefit from the maintenance strategy. And probably the most important key learning from the DISCUS trial is that we can do de-escalation trial in first-line metastatic urothelial carcinoma, not only for chemotherapy, but also from the new antibody-drug conjugates agents that we have. So the thing is, if the new standard of care is enfortumab vedotin and pembrolizumab, that is given forever or until progression or until toxicity, can we diminish, can we reduce the number of cycles of EV-pembro without losing efficacy? Well, this is the key learnings from the DISCUS trial. Thank you so much, Ashish.
Ashish Kamat: Thank you so much, Enrique. That's really important and impactful work, and as we all tend to do, when we focus on the patient-reported outcomes, that really gives us insights that sometimes you can't glean when you're focusing on the standard endpoints that we look at. But with that in mind, and again, congratulations on incorporating that endpoint, share with me a little bit your insight into how you think this would translate into real-world application of this three versus six cycles, just given the fact that for decades, we've all believed that more cisplatinum at least, or more chemo is better and you want to push the patient to get the maximal response, how do you think this is going to fit in with the current paradigm?
Enrique Grande: Well, honestly and humbly, I would say that DISCUS trial is practice-changing wherever enfortumab vedotin and pembrolizumab is not available. From now on, it doesn't really looks like necessary to squeeze the chemotherapy, to go up to four, five, six cycles of chemotherapy, because with only three cycles, you can get exactly the same efficacy, or similar efficacy, but with a better quality of life, so this is practice-changing.
Ashish Kamat: No, definitely. Again, and speaking of practice patterns and access, we all know EV-pembro has a lot of access issues, cost, et cetera. What about the CheckMate data that came out at the same time as EV and it got lost in the noise, how would you factor that, gem-cis-nivo, along with this paradigm, the three plus avelumab?
Enrique Grande: That's a great question. CheckMate 901 is showing that the triplet, gem-cis-nivo, is impacting overall survival versus gem-cis. I have two concerns with this triplet. The first one, gem-cis-nivo is only for patients eligible to receive cisplatin, so these are the best patients. So the best patients, the best in terms of less comorbidities, younger age, et cetera, should receive the best medication, and the best medication is enfortumab vedotin-pembro, this is the first one.
If you don't have access to EV-pembro, and if you have only the opportunity to offer to your patients the triplet versus gem-cis followed by avelumab, if you take a look in deep at the progression-free survival hazard ratio and shape of the course of the progression-free survival, you can perfectly see that there is no clear synergism in the first part of the PFS score. What it means? It means that when you are offering for a combo platinum-based chemotherapy, gem-cis, plus nivolumab, you are looking for some synergism. It perfectly seems that the benefit of the triplet is because of the maintenance nivolumab. I don't really see the need to add nivolumab on top of gem-cis. This is true, that you have a little bit more responses, but this is not translated into better progression-free survival. I think the benefit is because of the maintenance nivolumab. We definitely need a head-to-head comparison of gem-cis-nivo versus gem-cis followed by avelumab maintenance in this scenario, Ashish.
Ashish Kamat: Yeah, no, and again, Enrique, this is really, like you said, something that is truly applicable to the global community, because it can be used not only in places where patients want to avoid certain toxicities, which you've been a champion of helping patients with, but clearly across the globe where there's access issues. So again, congratulations on the presentation, congratulations on the trial, and look forward to hearing many much more from you.
Enrique Grande: Thank you, Ashish.