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Alicia Morgans: Hi. I'm so excited to be here today with Brenda Martone, who is a nurse practitioner at Northwestern University. And we're going to be talking through a case study—a patient case of a patient who was treated with the EV-302 regimen. Thank you so much for being here with me today, Brenda.

Brenda Martone: Thanks, Alicia. I really appreciate the opportunity to spend some time with you.

Alicia Morgans: Wonderful.

Brenda Martone: Today, I'm going to be presenting a case that reflects the EV-302 study. So, Mr. H is a 79-year-old male. He was diagnosed in March 2022. Had a radical cystoprostatectomy with pelvic lymph node dissection, and he had locally advanced urothelial carcinoma.

Based on the stage and at the time of diagnosis, he underwent adjuvant cisplatin with Gemzar followed by nivolumab maintenance. And he completed a year of treatment in July of 2023. We followed him with subsequent imaging. And unfortunately, in July of 2024, he was diagnosed with metastatic urothelial carcinoma. And this was confirmed via a lymph node biopsy. His baseline review of symptoms was basically unremarkable. He did have chronic hearing loss due to serving in the Army.

The rationale for our treatment choice to use EV-pembro was based on the EV-301 trial, and it showed a significant and meaningful benefit of combining EV with pembro over chemotherapy. And this was not only a benefit in radiographic progression-free survival, but overall survival.

Mr. H. again—ECOG was 0. He had a history of hypertension and hyperlipidemia, and his creatinine clearance was 48. He was started with EV at 1.25 milligrams per kilogram and pembro 200 milligrams. He was treated and tolerated the first two cycles fairly well.

He presented for cycle 3, and at that time he presented with a painful rash on his back, underarms, and in the groin. And this rash was hyperpigmented, very erythematous, and resembled a sunburn. We held his treatment, and he was evaluated by derm-onc. Thank goodness they could see him so soon. He was diagnosed with EV-induced desquamation, and he also had intertriginous eruption.

So treatment was based on this diagnosis and included urea moisturizing cream, Clobetasol 0.05% ointment BID to the axilla, and triamcinolone 0.1% cream BID to the groin. He came back that week after. He had significant improvement in his rash—basically, down from a possibly grade 3 to a grade 2, almost 1.

We restarted the EV, but of course at a dose reduction at 1 milligram per kilogram. His rash remained improved throughout treatment. CT scan imaging revealed decreasing adenopathy. Signatera, which was at baseline elevated, fell nicely to below 1. He continues on EV pembro, and he has an ongoing response. And Signatera still remains below 1.

During treatment, we continued to monitor Mr. H for any particular side effects. And of those side effects, we continued to monitor his skin rash, which remained a grade 1. He continued with his topical treatments as prescribed by dermatology-oncology, and he continued to follow with them throughout treatment.

He started to develop some peripheral neuropathy. Initially, it was grade 1. He felt that there was some intermittent, maybe numbness of his toes. His wife started to express some concern about his balance. Mr. H., at initial presentation of these complaints, really didn't feel his balance was that much affected. But eventually, during treatment, it did progress to a grade 2 after cycle 7. And we'll be talking about what was done at that time in just a little bit.

We monitored his phosphorus and glucose—again, very important labs to follow that are a little different than other treatments that we use in the setting, to watch for elevations both in phosphorus and glucose. And we watched his renal function throughout. Thankfully, phosphorus, glucose, and his renal function remained stable, and everything was within normal limits.

After cycle 8, he did develop more significant peripheral neuropathies, and he felt his legs were heavy. And there were some other issues that we were concerned about in terms of weakness and strength. And so after evaluation, there were no acute findings, but peripheral neuropathies of his feet remained a grade 2.

So the choice was to hold EV at the present time and continue with pembrolizumab, which he is continuing today. We are continuing to evaluate his peripheral neuropathies and to monitor if we feel we should restart the EV, or if we should just continue with the pembrolizumab.

Alicia Morgans: Wonderful, Brenda. Thank you so much for sharing such an exciting case. I think that it was really bold to share a case, especially with such a significant skin rash. Because this is something that both makes people feel a little anxious sometimes about using this combination, but also is such an important part of the treatment.

Because in truth, pembro and EV can both cause skin rash. And it's really, really important to figure out which one is actually the underlying cause here, especially because there have been rare but real associations between EV and TEN even.

And so, we do have to take skin rashes seriously. We do have to make sure that we are hyper-vigilant there, and that we take steps to avoid having that rash progress. So you said that you were able to get that patient over to onco-dermatology, which is a wonderful resource. How do you think through, or what could you imagine, if you were in a practice that didn't have a really rapid referral pattern—what would your approach have been in order to make sure that you were keeping the patient safe, but also, of course, keeping an eye on disease control?

Brenda Martone: So I think one of the more important things to do, especially given how this rash can present—and it does look pretty distinct compared to a pembrolizumab rash—but if a rash does develop, and you have to look in all the cracks where things rub, because again, this can appear on the trunk, on the legs, but it is more prone to the axilla and groin, where trousers rub.

You have to have the patient make sure he takes off clothes, puts on a gown. If they say they have an itchy rash, you really need to examine it with your own eyes. And then in terms of safety, if you don't have the resources of derm, definitely don't be shy about holding the medication, the EV, and then getting some assessment.

And also, there is a great—I believe, a resource paper out there that—maybe we can find that to share—that actually goes through EV rashes and how to manage. And it gives the recommendations about topical things to use.

And, of course, I think feeling more comfortable with this, or at least being aware of it and realizing just in terms of everything with EV, it's a marathon, not a race. So being respectful of what you're seeing. And then reaching out to colleagues, I think, is important if you're unsure about how to manage.

Alicia Morgans: Completely. And I do think it's a good idea to, as practices are starting to roll out EV use more and more, to have those connections in the dermatology community so that we hopefully can get our patients in quickly.

And to your point, it is different. If it's really showing up in these areas where things rub, this is different than a traditional maculopapular type of a pembrolizumab rash. And if you're not sure, just hold and get that patient over to dermatology, I think, is a very good message in order to keep patients safe.

Now, one of the other toxicities that you mentioned that I want to make sure we think through is this neuropathy that can tend to happen. And it often happens with increasing exposure over time. It sounds like your team was able to do a dose reduction, actually, probably for skin, but also may have helped the neuropathy. And then at some point, discontinued and continued on with pembro as a maintenance strategy.

How do you make those decisions, and how do you move forward in terms of understanding whether you should skip a dose or dose reduce? How do you think that through?

Brenda Martone: I would have to say it's based on a lot of experience with EV. And early on, we didn't truly—I mean, this is true—we didn't truly understand the peripheral neuropathies and the extent. And of course, there's always the goal of wanting to give a patient the maximal benefit.

And so early on, we saw that these peripheral neuropathies are kind of persistent if you continue to push through. So we learned to really respect patients in assessing them for these neuropathies. And I actually ask patients all the time, do you have any numbness, tingling in your fingers, toes? Which is typical, right? An easy question.

I also ask them, does it feel like you're walking around on thick socks? Can you feel the floor under your shoes? I actually watch their gait. You know this. Sometimes I'll sneak around the corner when a patient is being roomed, and watch how they're walking in. Are they picking up their feet? Are they shuffling? Are they holding on to the wall? Because if they tell me everything's fine and I see this happening, I generally disagree. And I'll point it out.

I also find out if they're zippering zippers, tying their shoes. Are their clothing choices changing? Are they no longer wearing buttoned shirts? Are they in sweats? Are they in slip-on shoes? Things like that—subtle signs to keep an eye out for things.

If we do feel peripheral neuropathies are a grade 2, and that's generally interfering with some sort of function, I will not be shy about holding a dose and evaluating and seeing how things go. If the neuropathies don't really improve, we do know that dose reductions of EV are built in. We do know dose reductions work.

And again, as I mentioned before, this is a marathon and, not a sprint. So I think we need to be mindful that if we really want our patients to get the best benefit, the exposure to treatment, being respectful of those side effects and adjusting the dose.
I always say for one person sitting in front of me, we know the data, we know what dose to start at, but we don't know if that's the right dose for you. And so dose reductions help us do a better job of having a more personalized approach to treatment.

Alicia Morgans: I think that makes sense. And then the final question I want to ask is really around how did you choose the regimen? I think it's a big question in the field, especially if a patient has nivolumab maintenance. Should we use a strategy that's EV and pembro after a patient's had exposure to that immune checkpoint inhibitor?

And in this case, the patient tolerated it and now is still on maintenance, and everything seems to be going in the right direction. Even the Signatera assay really decreased. So this is all positive. But how did you make that decision? Because I think that's still a question in the field.

Brenda Martone: It was definitely a mutual decision with the patient and discussion of the fact that he had prior checkpoint inhibitor, but also adding in the EV. And again, just reflecting back, he had no immune-related adverse events with the nivo and tolerated it well. Not that that predicts for the same thing with pembro, but again, tolerated well.

And then the combination, just adding in the EV, was a novel mechanism for him. And so we had that discussion. We reviewed the data, the outcomes, just the overall survival and progression-free survival. And so mutual decision making that that was the right therapy for him with the understanding of close monitoring.

Obviously, any new information that were to come out that would affect treatment, or if he had any sort of side effects or progression, we would rethink that strategy and treat with something different.

Alicia Morgans: I think that makes a lot of sense, and the possibility of synergy is absolutely there. And you're not relying on single-agent pembro here. We're really using that combination of EV-pembro, and I think a shared decision is absolutely warranted.

And until we have data that tells us one way is right or another, then I often probably would err on the side of the possibility of synergy in that combination if the patient didn't have, as you said, checkpoint inhibitor toxicities or problems in the earlier setting. Because you never know.

And as long as there's not a complication and you can get it approved and covered for that patient, it seems like a reasonable approach to have. So if you had to just give us some final thoughts on your use of EV and pembro in this setting and how that experience has been for you and your team, what would that be?

Brenda Martone: It's certainly an exciting combination and therapy, and I've had the privilege again to see patients respond. It's exciting for patients who have metastatic disease to get—again, with the data showing some complete responses, partial responses, extended overall survival—it’s very important that we use good assessment techniques and follow-up questions.

And remember, we really do have to examine that patient. Be mindful in what you're looking for. Remember that phosphorus and glucose—don't underestimate. Always keep that in mind. And then, don't be afraid, I should say, to hold doses if needed, and also to do dose reductions.

Because outcomes can still be obtained—efficacy and outcomes can still be obtained. But you need to balance everything for that patient and look at the risk-benefit ratio.

Alicia Morgans: Absolutely. I love the way that you really relate this approach and the experience here to a marathon rather than a sprint. And it is that exposure to this drug over time, in my experience too, that seems to help patients the most, rather than getting the largest amount in the shortest period of time.

So thank you so much for bringing such a really thoughtful case to our attention, and sharing your insights and expertise with us today. We appreciate your time.

Brenda Martone: Thank you very much. It's been a pleasure.