A roundtable discussion, moderated by Peter O’Donnell, MD, discussed the advanced urothelial treatment landscape, as well as recent trial data from ESMO 2023. Dr. O’Donnell was joined by Terence Friedlander, MD; Matthew Galsky, MD; and Jonathan Rosenberg, MD.
In the next segment of the roundtable series, the panel discusses the “buzz” around the EV-302 study, which showed improved progression-free and overall survival in patients receiving enfortumab vedotin plus pembrolizumab.
Dr. O’Donnell: Why don’t we dive into the ESMO data. It’s hard not to start with what I think was the most eye-catching data from the meeting, the EV-302 data, looking at EV [enfortumab vedotin] plus pembrolizumab. Terry, I’ll start with you. What were just your initial impressions of that data set?
Dr. Friedlander: Yeah, there’s a lot of buzz about this trial, because there was a press release about it for about a month before, a little less. That the study was positive for both its primary endpoints of OS [overall survival] and PFS [progression-free survival]. I think that got a lot of us excited. We really wanted to see the data. I think in my mind, I was trying to understand, is this going to be an incremental benefit? Was this going to show maybe a 3-month overall survival benefit compared to standard chemotherapy? That was 1 big question. Or was this going to be more impressive? What was the PFS going to look like? Were we generating these long-term durable responses or were we just sort of splitting the curves apart a little bit? But at the end of the day, most of the patients were going to progress. I was really looking at the OS and the PFS, and obviously, their response rates are really important.
As well as the toxicity. We had a lot of data from the EV-103 trial, which actually, a lot of us have been investigators on, that seem to suggest that this might be more transformative. That was what I was really looking for when the data came out. I would say the other piece that I was concerned about before the study was presented was what type of therapy did the control arm get? The control arm in that study was platinum-based chemotherapy, but avelumab maintenance wasn’t mandated, at least at the beginning of the trial. In my head, I was asking, “Is this going to be a study of chemotherapy EV with immunotherapy just against chemotherapy or would the control arm really be getting immunotherapy as well?”
When the data came out, I remember watching the presentation and just thinking that on each of those metrics, OS, PFS, response rate, toxicity, and then the value of the control arm or the aptness of the control arm, it just really met all the boxes we were hoping for.
The control arm 30% of patients got maintenance avelumab and actually 60% of the patients ended up getting a checkpoint inhibitor at some point. As Matt just said, a lot of patients don’t get to the second line or beyond. We have this really steep attrition of patients. It was reassuring to see that giving the EV/pembrolizumab early seems to really help patients. I think it was just an apt comparison. I think there’s more to say about the study, but that was my initial takeaway. It really was, I think transformative.
I don’t know about you guys, but it’s the only presentation I’ve ever been to where there was a standing ovation given as soon as the data was shown. I’ve never seen that. It really reflects, I think, the idea that finally we’ve found a regimen that actually performs better perhaps than standard platinum chemotherapy. We really haven’t seen that ever in urothelial cancer. That’s really, I think, a transformative moment.
Dr. O’Donnell: I had a physical reaction to seeing the data and I wasn’t even in the room. I’m with you on that. Matt, just initial impressions of that dataset?
Dr. Galsky: Yeah, I agree with those comments, and I think it’s important to recognize that within the span of 10 minutes, however long the presentations were, back-to-back presentations in the same meeting showing an improvement in outcomes compared to platinum-based chemotherapy when this hasn’t been shown in 30-plus years. There just happened to be 2 studies that read out at the same time, same meeting, same session, and it’s really quite remarkable.
I think to the points about it being transformative, whatever adjective you want to use, I think this is not an incremental benefit. We’re used to seeing incremental benefits, and there’s nothing wrong with that. That’s how we make progress in this disease at times. But it’s clear when something is different. I think the other presentation that I can remember recently where there’s been this reaction has been with MSI-high colon cancer or rectal cancer showing pathological complete responses in the vast majority of patients. You know when it’s transformative data, when the whole room reacts in that way.
Dr. O’Donnell: Jonathan, you said something interesting that maybe I’d ask you to comment on here, is that you actually found the data to be quite consistent with previous data for EV or EV/pembrolizumab. Can you comment on that?
Dr. Rosenberg: Across the trials of the phase 1, the phase 2, the phase 3, and then the combination phase 1 and 2, we’ve essentially seen the same performance of the drug in bladder cancer. In the phase 1, 2, and 3, the response rate and the overall survival were all almost spot on. In the phase 1/2 in EV/pembrolizumab, again, same exact response rate as we saw in the phase 3 data. Enfortumab vedotin induces rapid responses in patients, and pembrolizumab seems to accentuate that. We almost have the best of both worlds from EV-302 in many ways, where we get the rapid disease control that you get with enfortumab, probably augmented by pembrolizumab. But we get the durability that we’ve been hoping for in a clinical trial that immune checkpoint blockade yields, but often as monotherapy at much lower levels.
I think the long-term data from these trials of the combination of checkpoint and an ADC [antibody-drug conjugates] really suggests that there’s going to be a group of patients, maybe not the 5% to 10% that we’ve historically seen with platinum, maybe 30% to 40% of patients who might have durable remissions. Whether or not that means that they’re cured, we don’t know. Cure is a tough word in oncology. The only way if a patient’s cured is if they die of something else in old age, and that’s great. But we haven’t seen anything like this before in metastatic disease. I think this is the best possible place to be before we’re going to get to something that actually cures patients, as Terry said.