EV-302 Patient-Reported Outcomes

Shilpa Gupta, MD, from the Cleveland Clinic in Cleveland, Ohio, shares her findings on patient-reported outcomes from the EV-302 clinical trial with Amanda Nizam, MD.

Drs. Gupta and Nizam discuss the unique aspects of the trial, highlighting the impact of enfortumab vedotin and pembrolizumab on progression-free survival and overall survival in metastatic urothelial carcinoma.

1:01: Summary of the landmark EV-302 trial.

5:28: Subgroup analysis based on cisplatin eligibility.

7:33: Discussion on the transient decline in EORTC QLQ-C30 scores at week 3.

8:50: Additional information gleaned from patient-reported outcomes after the completion of treatment and through disease progression.

9:54: How to more comprehensively capture patient-reported outcomes in areas that affect quality of life, such as treatment-related toxicities.

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Dr. Nizam: Hello, I’m Dr. Amanda Nizam. I’m a genitourinary medical oncologist at Cleveland Clinic, and I’m joined by Dr. Shilpa Gupta, also at Cleveland Clinic, who’s the director of the genitourinary oncology program at our institution. And she’s going to discuss her abstract that she presented at ASCO 2024 about the EV-302 clinical trial E-PRO collection. Welcome, Dr. Gupta.

Dr. Gupta: Thank you, Dr Nizam.

Dr. Nizam: So we’ll start out, if you could tell me a little bit about the study. So EV-302, obviously, was a landmark trial in metastatic UC, and led to the approval of enfortumab vedotin and pembrolizumab in the front-line setting for locally advanced and metastatic urothelial carcinoma. However, this study incorporated patient-reported outcomes. So I wanted to see if you could tell us a little bit about that, and describe your presentation at ASCO 2024.

Dr. Gupta: Yeah, sure. As you know, Amanda, the EV/pembro doubled both the progression-free survival and overall survival compared to platinum chemotherapy. And this time at ASCO we reported the patient-reported outcomes, and this was a unique way of collecting the patient-reported outcomes, because not only did we collect the PROs at baseline and then weekly for 12 weeks, which constituted to four cycles of each arm. But then, patients also continued to fill out the EPROs every three weeks, even beyond progression and through survival follow-up. So even when they were on subsequent therapy. So that is a unique aspect, and I want to just highlight here that as you know, in the control arm, the platinum chemotherapy had a maximum of 6 cycles of treatment, and maintenance immunotherapy was not mandated. So that was pretty much the treatment duration. But in the experimental arm with EV/pembro, pembrolizumab was up to 35 cycles, and there was really no end date for EV. So treatment continued until disease progression or intolerable side effects.

And another unique aspect in this study was, there was a PRO key secondary end point. So the time to pain progression and the change from baseline in the Brief Pain Inventory, worst pain at week 26 were allocated alpha, and that was a pre-specified secondary end point. And there were other secondary end points which were descriptive and not adjusted for multiplicity. And we saw that regarding compliance, it was around 70% or higher through week 17 in the chemotherapy arm, and week 29 in EV/pembro arm. Which as you know, Amanda, you participated in this study so significantly, that patients had fewer touch points with the clinical team on the chemo arms. They were just coming for the scans or they were getting treated elsewhere. But in the EV/pembro arm, they were here pretty much every week getting treated. So that explains that the compliance was worse maybe in the chemo arm because of this reason.

And also, when people progress on a treatment, they’re less motivated to fill out the EPROs. And we’ve always had to remind them, and it’s a lot of burden on the patient. But regardless, I thought this was really important to bring out.

And the time to pain progression really was not statistically significantly different in both arms. And the change in the worst pain was also, the clinically meaningful threshold was not met. But I think what is highlighted here is that two-thirds of patients did not have pain at baseline. I think we wanted to look at this population as a whole, but we also wanted to look at the patients who had moderate to severe pain at baseline, likely from their disease burden. And there we found that the change in the worst pain on the Brief Pain Inventory was, greater improvements were seen with EV/pembro.

And just want to highlight here, that the two questionnaires we used were the EORTC QLQ-C30 for the quality of life data, which included cancer related symptoms function and the global health status, and the Brief Pain Inventory, which is historic pain score, not cancer specific, but that was what was used. So we saw that in patients when we selected one-third of those population which had moderate to severe pain, they had more improvement with EV/pembro. And also in the global health status, we found that patients in the chemo arm had a transient worsening from week 1 to week 17, which then resulted to baseline at week 20. And EV/pembro, they had a transient worsening at week three, but then it returned to baseline earlier at week 4, and remained there.

Again, when we looked at the moderate to severe pain at baseline, patients in the EV/pembro arm had a clinically meaningful improvement in the EORTC QLQ-C30 score, where in the past, 10-point change has been considered clinically meaningful.

So we also looked at the subgroups based on cisplatin eligibility. And when we looked at both these subgroups, we found that patients who got EV/pembro, when we compared that to cisplatin chemotherapy, the differences were significant compared to when we compared to the gem/carbo. And that is not surprising, because we know that patients who get gem/carbo or are cisplatin ineligible are more frail to begin with, and cisplatin is not as easy to tolerate as gem/carbo.

But what we can say is that EV/pembro performed pretty consistently in both the groups. And then when we looked at the EORTC QLQ-C30 functioning domains, which was the role functioning, physical social functioning, and the global health status, and the cognitive and emotional functioning, all those parameters across the domains favored EV/pembro.

And in conclusion, patients who got EV/pembro, besides getting the endpoints of the efficacy and safety met, we saw that they did not have any detriment to the global health status quality of life, pain, or functioning. Especially patients who have moderate to severe pain at baseline, they saw clinically meaningful improvements in their worst pain and global health status quality of life. The more important aspect of this study was that the patients voiced throughout the treatment journey, not just during active treatment, but also at progression subsequent therapies, it provided us a long time of their voices. And this will help us design better trials. As you know, these tools that we use today are over 30, 40 years old, and really not relevant to our current treatments, but this is the best we have, and they’re not perfect. But I think overall, the PRO data complements the clinical efficacy that we have seen before with this regimen.

Dr. Nizam: Yeah. And I had a quick question about that transient dip in the EORTC QLQ-C30 scores at week 3, in that both the cisplatin-eligible and cisplatin-ineligible patients, but then a return to baseline at week 4. Have you explored the potential reasons for this transient decline?

Dr. Gupta: Yeah. I think it’s, we also tried to do a deeper dive into this, and it could be that when you’re starting this new regimen with, EV/pembro is a newer regimen, and it’s not clear why this was such a transient dip early on and then got better. But in the chemo, it’s possible that patients are getting steroids throughout. Maybe they don’t have that early dip, but after EV/pembro, that first cycle, some patients start getting side effects. Probably that explains it, because it was so transient and then comes up, which means that maybe they were starting to respond to treatment. And with the chemo, you would think, because they are kind of getting steroids during chemo, that didn’t really manifest as a one-time dip. But yeah, that was also an interesting finding.

Dr. Nizam: And in terms of long-term quality of life, so one of the very commendable aspects about study was that you followed patients even after completion of treatment and through disease progression. So have you gleaned anything from the patient-reported outcomes? Obviously, we know the compliance was a little bit lower, as we expected, but have you gleaned anything from the data that you’ve seen for the PRO data following disease progression and when they’re on subsequent treatments?

Dr. Gupta: Yeah. We haven’t taken that deeper look yet, because the pre-specified was week 26. That’s kind of what we presented. But I think it’ll be very important to see that long-term. Especially if some people… You know that EV/pembro can be toxic in a lot of patients, especially with the neuropathy and rash. And I think it’s reassuring to see that despite those kind of unique and significant toxicities, the PRO was not worse. But long-term, certainly will be important to take a deeper dive once we have more data.

Dr. Nizam: Very good. And one other important aspect you bring up with PRO related research. So obviously, the questionnaires used in this trial and other trials tend to capture global cancer related symptoms, rather than treatment-related toxicities that may affect quality of life. As you know with EV/pembro, we see a lot of neuropathy, which can impact quality of life. So building upon the findings of these studies, what are some ways we can more comprehensively assess patient-reported outcomes? Specifically in locally advanced and metastatic urothelial cancer treatments, and especially as novel systemic therapies advanced to earlier disease settings?

Dr. Gupta: Yeah. That’s a great point, Amanda. And I think the tools are certainly outdated, right? Because we are not really capturing the treatment related toxicities, there’s no way for us to distinguish based on the current questions, because they’re pretty vague and general questions. So I think one way to do it is to come up with more kind of a novel PRO assessment tools, and validate them for our patients. For example, a lot of these questions, if they ask, “Are you feeling sick.?, in the olden days with the chemo, that question may be relevant, but not with really immunotherapy and other agents. So I think for, let’s say, these novel therapies, like you just said, there should be treatment tailored questionnaires. Like patients who are getting FGFR3 inhibitor really don’t get neuropathy, but they get a lot of other really, really bad toxicities. And immunotherapy, while well tolerated, can cause really significant adverse events too. So I think we just need to put more work into developing new tools as we are developing novel therapies, for sure. Especially when these intense therapies move early on.

Dr. Nizam: Very good. Very good. Well, thank you so much for joining us, Dr. Gupta, and we look forward to future analyses from this study.

Dr. Gupta: Thank you so much.