Panel Comments on Ongoing EV-302 Trial, Patient Management Considerations in Bladder Cancer

A roundtable discussion, moderated by Vadim Koshkin, MD, of the University of California, San Francisco, focused on treatment selection for different patient populations with advanced bladder cancer, including a discussion of new data presented at ASCO 2023. Dr. Koshkin was joined by a panel that included Matthew Zibelman, MD; Cora Sternberg, MD; and Daniel Petrylak, MD.

In the next segment of the roundtable series, the panel discusses patient characteristics and treatment sequencing considerations as they relate to treatment choice for advanced bladder cancer.

Watch the next segment in this roundtable series.

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Dr. Koshkin: Now we’re waiting for the confirmatory trial, which will be EV-302. I wonder if anyone wants to comment on basically the design of that trial and what you expect from it.

Dr. Zibelman: Yes, we’re certainly eager to await that trial. Really, this is patients who in first-line metastatic disease, and they can get either cisplatin- or carboplatin-based therapy, and randomized to that mostly gemcitabine/cisplatin and gemcitabine/carboplatin versus enfortumab vedotin (EV) or pembrolizumab. Yes, that will be key to really confirm what we assume is the case with gemcitabine/carboplatin, and I really don’t know how it’s going to compare against cisplatin-based chemotherapy. I think that’s going to be hard to beat, and I don’t know that I’m convinced that EV/pembrolizumab will show at least superiority to that. I think it will be interesting, really for that patient population, how things shake out.

Dr. Sternberg: I have a feeling that, compared to platinum, it’ll be similar. The results will be similar. I don’t know the results, but I think they’ll be similar. The EV/pembrolizumab for the platinum-ineligible was already approved. It got accelerated approval by the FDA just about a month ago. People are using that now more and more frequently.

Dr. Petrylak: I think there’s several important points about this trial. It certainly was designed in a different era. In the United States, there are several sites that did not participate initially because there was no avelumab maintenance that was permitted in the study. In fact, the protocol was amended 3 months before it closed to permit avelumab maintenance. The number of patients that are going on avelumab maintenance, I think it’ll be very, very low. It’s going to be very hard to compare this to that particular standard of care. I think that this will certainly beat gemcitabine/carboplatin in comparison, but the real question is going to be going on with the cisplatin patients.

One way to look at this is are you going to see a difference in nodal disease versus visceral disease? We know that you can get durable long-term responses with cisplatin-based therapy: 10% to 15% of patients with that particular approach. Is that going to be similar with EV? Number one. Number two, is the toxicity pattern going to be similar or better? That’s, I think, where that group of patients is going to be important to interpret. Visceral disease patients, I think this is going to be the winner. I think that this will do better than gemcitabine/cisplatin. That’s just my own opinion. I don’t have data yet, but my gut feeling is it’s going to do better.

Dr. Sternberg: I’ve seen amazing results in patients with wildly metastatic peritoneal disease and other visceral disease as well. I think it’s a really good combination. But patients always eventually have toxicity, both from the immunotherapy and from the EV; one or the other or both, eventually. I can’t see staying on it forever. The fact that immunotherapy can maintain its response, even after patients have stopped, is something very positive. I have some patients who have been on other KEYNOTE trials with pembrolizumab, for example, off therapy now for 5 years, completely disease-free, who had widely metastatic disease in the liver and lung and everywhere, which is something that we never saw when we gave MVAC [methotrexate, vinblastine, doxorubicin, cisplatin] again a year later because simply we had just given MVAC. It’s been a year. Let’s give the MVAC again.

Dr. Petrylak: But that’s a great point also. Counseling patients, this is also a very difficult decision to make because I have several patients from the phase 1 trial, 1 of which was a remarkable response in a woman who had extensive liver metastases, rapid progression after having a nephrectomy for a renal pelvis tumor. She had a short response to immune therapy but then, she was on EV by itself and had a complete response, talking to her about coming off therapy, despite the fact that she had a neuropathy, was a very, very difficult conversation because the patients are afraid. They know something is working, and they’re afraid that if they come off of it that it may not work again if we re-institute it later on.

I think these are some of the important questions that we’re going to be having with these treatments. Can we give, or is it appropriate to give, immune therapy in a patient who’s had prior checkpoint therapy for adjuvant treatment after a cystectomy? Or switch maintenance therapy? What’s the duration of time that we have to wait? These are all unanswered questions, but are going to be very important to patient management.

Dr. Zibelman: Yeah. No, I agree. I think that these are going to be the questions we’re going to be grappling with at these roundtables in the years to come as we figure this out. From an anecdote standpoint, I’ve had 2 patients with great CRs [complete responses] from EV who have been off therapy. Two recently actually, who were off therapy for more than a year, and both of which within the last month who now have a little bit of progression, and so we’re going back to EV to see how it goes. I think understanding how we use these drugs, how long we need to use them for, when we can stop, is re-challenging effective is going to be really important.

Dr. Koshkin: Do you restart at the same dose as before?

Dr. Zibelman: Both had been on dose reductions for various toxicities, so I’m restarting at those, but we’ll see what happens.

Dr. Sternberg: I’ve been able to give it to a patient who was on dialysis, home dialysis, with creatinine of 8, and there was nothing in the literature though. I just made up the dosage and the schedule, and EV was tolerated at this schedule that I made up.

Dr. Zibelman: There is a cohort in the EV-103 study for low creatinine clearance that hasn’t reported yet, but we’ll get some data. I don’t know that dialysis patients are allowed. I think it was creatinine clearance 15 to 30. But we will get some data. But you’re right, it’s safe to give in a lot of these patients, which is certainly attractive about it.

Dr. Koshkin: Dan, as you pointed out about EV-302, I think the switch maintenance piece, that it was really most patients in the trial probably didn’t get it. The trial will be critiqued for that when it comes out. All the same though, I think a lot of people expect big things from this combination based on the data we’ve seen and expect big things from that trial.

Dr. Petrylak: I mean, if the hazard ratios aren’t 0.6, I don’t think it’s really going to make that much of a difference. Effectively, what you’re doing with giving pembrolizumab for a long period of time after, you are doing a form of switch maintenance with it. It’s really a similar concept. You’re using your cytotoxic treatment to reduce the tumor volume of the patient initially. But then you have a long period of time on pembrolizumab after that.

Dr. Koshkin: Yeah, that will also be fascinating data from this trial as to how long patients are actually staying out enfortumab. I would think that a lot of patients actually eventually will stop it due to toxicity reasons, as you highlighted, and continue on pembrolizumab maintenance. In our experience with the EV-103 of that combination, that’s what we did for a lot of patients, and a lot still have responses actually years later.

Dr. Petrylak: What’s the minimal effective treatment that you need of EV to prolong survival? That’s going to be a very, very important question, especially from the neuropathy and toxicity standpoint.

Dr. Koshkin: We should think about future trials to address.

Dr. Sternberg: Future trials to lower doses of therapy, and maybe give higher doses in other patients. It’s not something that the pharma companies think about as something we need to do.

Dr. Zibelman: Yeah, but pretty great that after years of not having enough therapies for bladder cancer, we’re talking about potentially de-intensification strategies for patients.

Dr. Petrylak: It may be hard to get patients on a de-intensification trial for the reasons we talked about before. They don’t want to de-intensify. But there may be other ways that we can examine this question.