David Aggen: Thanks, Tian. It's so nice to see you and so exciting to be here at ASCO 2026 with all the advances that are happening in genitourinary cancer. And excited to talk to you today a little bit about how the landscape is changing for bladder cancer patients.
Tian Zhang: Yeah, great. So let's start there. So bladder cancer landscape really changing quite a lot for metastatic disease as well as now in the perioperative neoadjuvant space. Tell us a little bit about your current practice patterns and what things look like in Memorial.
David Aggen: So honestly, I think we're at a transformative moment in bladder cancer where we now have data from EV-302 with 3 1/2 years of follow-up that at 3 1/2 years about 42% of patients are alive. In patients who have radiographic CRs with EV and pembrolizumab in the metastatic setting, 83% are alive at 3 1/2 years. And if you compare that where we were at before with platinum and immunotherapy as maintenance, we're really in a different space now. And I think the question in our clinic now is not cisplatin eligibility, but who is ineligible for enfortumab vedotin and pembrolizumab? Clearly in the metastatic space, EV-302 has set a high benchmark for what we're going to do next for patients in the metastatic setting. And building on that, we now have data for perioperative EV plus pembrolizumab from EV-303 or KEYNOTE-905 and EV-304 or KEYNOTE-B15 where we see clear benefits to giving neoadjuvant and potentially adjuvant EV plus pembrolizumab for patients.
So really when I'm approaching a patient, either an MIBC or in the metastatic setting, I'm doing that calculation. Is this somebody who has a contraindication of those therapies or is this the right first move? I think where the challenge is going to be now is with all of this data supporting the use of ADC plus IO, what we do in patients with refractory disease. And so we're just starting now, I think, to understand how we handle sequencing, which is a new problem for bladder cancer. And fortunately now we have a lot of tools at our disposal to try to treat patients when EV plus pembro is too toxic or ineffective. I do think the other big challenge though is once we move beyond EV pembrolizumab in the metastatic setting, when we look at real world data sets, the overall survival numbers are pretty sobering. The median overall survival for most patients when you get beyond EV plus pembrolizumab is around a year. And so I think those sequencing decisions are really going to become critical for us as we're treating patients with bladder cancer.
Tian Zhang: I know this is a topic we share and an interest that is really going to plague the field right now as we treat more patients with EV and pembrolizumab. What are your current takes? Are patients going to be resistant to the NECTIN-4 targeting or are they going to be resistant to the payload? What are your thoughts?
David Aggen: Well, I wish it would be so straightforward that there's one mechanism, but it's going to be quite nuanced. We have some data we're presenting here at ASCO 2026 looking at paired biopsies from patients before they got EV plus pembrolizumab and at the time of progression on EV plus pembrolizumab to understand patterns of expression of the target of enfortumab NECTIN-4. And what we found is quite interesting actually. In patients who have primary resistance, where there's progression of cancer within the first six months on therapy, there's a tendency that we see a decrease in the expression of membranous NECTIN-4 and an increase in cytoplasmic expression of the target. And so it may be that in some patients, a mechanism of resistance is loss of the target. That being said, there's some patients who have acquired resistance, who have late resistance to EV plus pembrolizumab who progress beyond six months where we actually see differing patterns.
There's some patients where NECTIN-4 actually goes up. And so my suspicion is that we're going to have some patients that are clearly resistant because they've lost the target of the ADC and we're going to have other patients who are resistant because of payload resistance where giving more MME or mortaxel-based chemotherapy after pembro is really the wrong choice. So the onus is really on us now to understand the biomarkers that are going to drive those treatment decisions. At the moment, we really only have the choice of an FGFR3 inhibitor or in patients who have HER2 overexpression using those personalized therapy options, but I think we need to be more nuanced.
Well, I think what's emerging is when we get beyond EV pembrolizumab, patients are going on to platinum-based chemo or a trial with another ADC usually with a topoisomerase payload. And my sense is that patients who get those topoisomerase payloads are really going to only have one chance at it. So really picking the right target with that payload's going to be critical to give patients the best outcomes. And there's several studies that are looking at topo ADCs to try and understand what might be next and might be better than platinum-based chemotherapy for patients.
Tian Zhang: And to that point, a couple are reading out here at ASCO, so we'll look forward to seeing those results of newer NECTIN-4 ADCs but delivering topoisomerase inhibitors. And in refractory disease, we certainly need more options for these patients. To your point, median survival of the year is not great. So how can we sequence better options for those patients? You also in your poster also are thinking about other targets and other ADC targets that arise after EV pembrolizumab.
David Aggen: Yeah, so definitely. I want to be clear that there's definitely some patients after EV pembrolizumab that still have membranous NECTIN-4 expression, and we're seeing clinical data here at ASCO. Dr. Gopa Iyer is presenting an abstract on a NECTIN-4 targeted ADC with a topoisomerase payload with encouraging objective response rate around 40% in all comers and an EV exposed patients, about 35% of patients are responding. In patients though who have those post-progression biopsies on EV pembrolizumab, we do see that the majority of tumors retain TROP-2 expression and a subset also have HER2 expression. And so we might have multiple ways to try and target these refractory cancers with different antigenic targets in the cancer. And I think we're just at the beginning of understanding that.
With so many patients getting EV pembrolizumab now and muscle-invasive disease, we're going to have a lot more paired biopsies to understand not just the antigen landscape in these post-treatment biopsies, but also I think what the biologic mechanisms are that are driving those changes in NECTIN-4 expression. I think there's some really intriguing data coming out of UCSF and other places to try to see if there's ways that we can actually upregulate NECTIN-4 and maintain responses. But nonetheless, I do think there's going to be emerging patterns where other ADC targets are present on the tumors and getting biopsies at the time of progression to understand what's going to be best for a patient will be really critical when it's feasible.
Tian Zhang: Yeah. It's really important to characterize disease progression. We have also some circulating tumor cell data here that will show we can actually see some proteomic expression of HER2 in EV pembrolizumab refractory disease. So I think the more we have, the more we need to learn and absolutely your work is going to help us figure those things out. Last little bit, tell us a bit about ECLIPSE-EV and your work there and the investigator initiated trial that you've run for the last few years.
David Aggen: Well, it's kind of you to bring it up and really appreciate that you've been a co-investigator on the study with us. So the EV-ECLIPSE trial is looking at slightly different patient population, patients who have lymph node involvement and have evidence of muscle-invasive bladder cancer with the goal of seeing if with an effective systemic therapy we can downstage those patients and have them proceed to consolidative surgery. It's a question that's coming up now when you have a regimen in the metastatic setting with enfortumab and pembrolizumab with a 45% radiographic response rate, should we be doing consolidative surgery in those patients? And so the goal of EV-ECLIPSE is to give six cycles of neoadjuvant EV plus pembrolizumab with imaging along the way to make sure you're headed in the right direction and in patients with responses proceed to consolidative surgery, patients then continue pembrolizumab to complete one year of therapy. The primary endpoint of the study is looking at pathologic downstaging and clearance of cancer in the lymph nodes and we're really looking forward to presenting this data and also biomarker data to understand who the exceptional responders are to these therapies.
I think where all of this is headed and where we want to get in muscle-invasive bladder cancer is figuring out the composite biomarker that's going to allow patients to safely go to bladder sparing. I think we're not there yet in standard of care practice, but I'm hopeful data from EV-ECLIPSE and from other prospective studies is going to give us that information. The other thing that I think will be interesting from EV-ECLIPSE is we recently heard a press release about the VOLGA study with EV plus durvalumab followed by surgery and then durvalumab as adjuvant therapy. And the key distinction in VOLGA is that there is not an adjuvant ADC component. And I think we're really struggling as a field to say, how much does adjuvant therapy matter? And I think EV-ECLIPSE is going to give some additional data to help lend to that possibility and perhaps in patients with locally advanced disease, we should be giving more neoadjuvant EV plus pembro because we may not have a shot at giving more adjuvant ADC.
Tian Zhang: Well, it's critically important work and congratulations on all the work that you're presenting here at ASCO and any last takeaways for the UroToday audience.
David Aggen: I think we're at really a transformative moment in bladder cancer where we have a lot of ways to track patients' response to cancer with ctDNA, with novel biomarkers, with other circulating biomarkers. And the onus is really on us now, not just to develop better therapies that build on the EV pembrolizumab backbone or newer therapies in the frontline setting, but to really figure out how we're going to best incorporate these biomarkers to give patients the best outcomes. I think it's really motivating and exciting to see everybody at ASCO and all the innovation that's happening for bladder cancer. I think four years ago we were having a very different discussion about outcomes in the metastatic setting. It's the most exciting time.
Tian Zhang: Absolutely. Thank you so much, David.
David Aggen: Thank you.