Navigating the Shift to Enfortumab Vedotin and Pembrolizumab in Advanced Urothelial Cancer: Key Considerations for Clinicians - Cora Sternberg

April 24, 2024

Cora Sternberg discusses the significant advancement in the treatment of urothelial carcinoma, focusing on enfortumab vedotin (EV) in combination with pembrolizumab. This combination, recently approved in the US as a first-line therapy, has shifted the treatment paradigm, offering a potent alternative to traditional platinum-based therapies. Dr. Sternberg highlights the importance of this development, noting its effectiveness even in patients with reduced creatinine clearance, a group traditionally considered ineligible for cisplatin. She explains how this allows more inclusive treatment criteria, which could potentially phase out the distinction between cisplatin-eligible and ineligible patients. The conversation also addresses the importance of managing side effects, particularly neuropathy, to ensure patient comfort and drug efficacy.


Cora N. Sternberg, Professor of Medicine, Clinical Director of the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi, I'm so excited to be here today with Professor Cora Sternberg, who is joining me to talk about enfortumab vedotin. Its changing role in the landscape of treatment of urothelial carcinoma and how we can all work together to really feel comfortable using EV as a treatment for our patients. So thank you so much for being here with me today, Professor Sternberg.

Cora Sternberg: Alicia, it's always a pleasure to be here with you.

Alicia Morgans: It is always a pleasure to talk to you, and I just love your global perspective on the way therapies come into our treatment algorithms, and I really appreciate it if you could review for us, in which settings do we use enfortumab vedotin, either as a single agent or in combination. And please start with the US, and then we should acknowledge where things stand currently in Europe as well.

Cora Sternberg: Well, in the US, things have changed dramatically since the presentation at ESMO in September and the approval of the combination of enfortumab vedotin with pembrolizumab in December by the FDA as first-line therapy for patients with locally advanced or metastatic urothelial cancer. When you consider when we developed the MVAC regimen some 30 years ago, and then we had cisplatin and gemcitabine, we've really had nothing that has been better than a platinum-containing regimen in over 30 years. So this is really something very, very remarkable. At ESMO, there was a standing ovation at the plenary session when they heard the progression-free survival, and they heard the amazing improvement in overall survival with this combination of drugs.

The other thing about this combination of drugs is that it can be given to patients with poor creatinine clearance as well. It was given to patients with creatinine clearance as low as 30. Although I personally have been using this for years, I've given it to patients on dialysis, I've given it to patients with worse conditions. But that was how the study was organized. And until now, we've always used these criteria called platinum eligible or ineligible, and many people have used cisplatin eligibility as having a creatinine clearance of at least 60.

So if they didn't have that, they would get carboplatin, which we all felt was a little bit inferior to cisplatin. So the fact that you can give it to patients with lower creatinine clearance means that we can do away with this cisplatin eligibility for one thing. I think that in the United States, they're already changing the NCCN guidelines to include enfortumab vedotin and pembrolizumab as first-line therapy for patients with metastatic or locally advanced disease. Now, it's definitely not a treatment for everyone; it's not for patients who have peripheral neuropathy, for example, which we can talk about later. But that's one of the most serious side effects that I've found with enfortumab.

And again, people who perhaps have very serious immunologic diseases might have problems with pembrolizumab, but I have even published a study on 1,000 patients taking atezolizumab given to patients with autoimmune disease. And if that's well controlled, even immunotherapy can be given to those patients. So in the United States, this has now become the number one treatment, okay. And then they say other treatments are also dose-dense MVAC or MVAC or gemcitabine and platinum in the first line, but that is the first line. At ESMO there was also an interesting presentation of gemcitabine and platinum with nivolumab, which was a very positive trial. They chose patients who were cisplatin eligible. It wasn't a combination of carboplatin and cisplatin, and it was a very positive trial. So I think in countries where they don't have enfortumab vedotin, that may become something that people will use that combination of cisplatin, gemcitabine, and nivolumab.

The other thing is that until now we've been using maintenance therapy with avelumab after chemotherapy. And so even in this trial, they amended the trial in the middle. They didn't even know it wasn't really a part of the trial to give maintenance therapy in the arm of the trial that got the chemotherapy. In this trial, patients received enfortumab vedotin and pembrolizumab. They received the pembrolizumab for two years, but the enfortumab vedotin was given indefinitely as compared to the chemotherapy, which was gemcitabine with either cisplatin or carboplatin, not necessarily just cisplatin as was in the other nivolumab trial. And that was only given for six cycles. So when you talk about toxicity, you have to remember that one was given for six cycles, one was given for 12 cycles, and one was given for a longer amount of time. But nonetheless, the progression-free survival and the overall survival are really quite remarkable if you look at the results, and I think this quickly will become a first-line therapy, but you need to know how to manage the side effects of enfortumab vedotin.

We've been using it for a very long time. It was first approved as a second or third-line therapy in patients who had already had platinum and already had immunotherapy. We were giving it as a single agent. We were giving it three times a month instead of two times a month as it's given with pembrolizumab, and patients have experienced toxicity with it. For me, the major toxicity has been neuropathy. In Europe, I know for a fact that the European agency has approved it as an idea, as a concept, but it's not approved in most of the countries. Many countries, such as Italy, for example, where I used to work, I know they have now, just now, enfortumab vedotin alone. They don't have the combination and they have it for patients in later lines of therapy. So they usually are many drugs behind the United States, which is much quicker to approve drugs after we've had positive trials and publications.

Alicia Morgans: Great. Well, thank you for walking us through that. And I'm hopeful that we will have a relatively speedy process to get this access available in Europe, although it does take some time, and you're very familiar with that. As people are getting ready to use EV, whether they're in Europe or whether they're already using it here in the US, I think it's really important, as you mentioned, to acknowledge the learning curve that goes into our comfort with using EV as a single agent or in combination for our patients with urothelial carcinoma. And I think we wanted to focus on three main toxicities. We can take them one at a time. Let's talk a little bit about neuropathy, just so that we are all aware of this potential side effect and think through ways that you consider trying to limit that toxicity and ensure that patients have adequate exposure to the drug because it does seem to be so effective for this disease. What do you do about neuropathy?

Cora Sternberg: It's such an effective drug that when people develop neuropathy, they often hesitate to tell us, but if a patient tells you that they... Or even mention neuropathy, you have to take this very, very seriously. And what I do is I usually hold the dose and most often I lower the dose of the drug. And it may even be that the dose of the drug that was first designed by the company is too high of a dose because so many people do develop neuropathy and patients don't like to talk about it, but I ask them questions like, "Can you button your shirt? Can you tie your shoelaces?" I've had patients who had car accidents because they couldn't feel the pedal in their foot on the car, or they've tripped on the sidewalk. It's a sensory neuropathy, but it is a serious neuropathy.

And I think that the patients who have done well with this drug don't want to stop it, so they don't often tell you about it. So you have to ask them all kinds of questions like, "Can you button your shirt easily? Can you do this? Can you do that?" Or watch how they do that. Watch how they walk. It's a serious problem. We can give them drugs like gabapentin, which can help a little bit. But for me, the most important thing is to... When I understand they have neuropathy, is to immediately lower the dose or to hold the dose and then lower the dose. I think that's essential.

Alicia Morgans: I completely agree. I think being as proactive as possible in asking about neuropathy, numbness, and tingling is important because by the time it becomes more of a challenge for the patient, or could be a motor neuropathy, which I have also seen relatively rarely, it is more difficult to reverse. So, it is reversible, at least in my experience, if you hold the drug and give patients a holiday. Asking proactively, reducing the dose, skipping a dose when needed, because ultimately, we want to get the drug to the patient over time. So reducing the dose and allowing that drug over time to not be so challenging for the nerves, I think is—

Cora Sternberg: No, you're so right. If they even mention neuropathy or numbness or tingling, you just don't wait until it sets in and becomes more serious, because then it's much harder to reverse. So you have to be on top of it, really, you have to think about it and be on top of it even more than the patients who often will not admit that they have it.

Alicia Morgans: Yeah, agreed. So let's talk about the next of the three that we wanted to really touch on today. And this is skin toxicity, potentially a very dangerous skin toxicity, though that is rare. How do you talk to patients about skin toxicity and rash, especially in the setting of the combination of EV and pembrolizumab where things can be a little bit more challenging to figure out?

Cora Sternberg: The combination is more challenging because sometimes you don't know if it's the pembrolizumab or the EV. Most often it's the EV. If it's a maculopapular rash, I usually stop the drugs. I use topical corticosteroids, I use antihistamines. In some cases, we even have to give oral steroids if that's what's needed, depending on how bad it is. When I was overseeing one of the older trials that was EV alone, I saw rashes from all over the country.

And during COVID, I had a patient that was on EV alone. His skin didn't turn red. A white man turned black; his whole skin turned black, and I begged him to stay out of the sun. He said, "I'm never in the sun. There is no sun. It was cold, I'm in my house." He turned black. And that was maybe the weirdest rash that I've ever seen. But most of the rashes are red raised maculopapular rashes that cause itching, and people complain of the itching. It's not usually that serious, but you have to be on top of that too. With both, I give them big tubs of triamcinolone, and we often treat them with corticosteroids as well.

Alicia Morgans: Absolutely. And I would just add from my end that whenever that rash becomes painful, if it's becoming a mucosal rash, I have a very low threshold to involve a dermatologist, have them assess and evaluate, and give some guidance there, because there have been rare cases of TEN associated with EV, and certainly, we want to be, again, proactive about this toxicity to just try to keep our patients safe.

Cora Sternberg: Even with Johnson's, there have been TEN cases, and people have died with this, and it's in their black box warning to be careful.Be careful. Stop it completely if you suspect any of those diseases.

Alicia Morgans: Absolutely. Before we get to the third toxicity that we wanted to mention, it sounds like this is incredibly challenging to manage, but I would say it's relatively easy to manage. We just, I think, really need to advocate for awareness, proactiveness around these toxicities because it's an incredibly effective drug, and patients in general do really well. So as we move on to the third one that we wanted to touch on, hyperglycemia, I would love to hear your thoughts. How do you keep patients safe in this setting? And is it usually people who have preexisting diabetes who have elevated blood sugars, or is it maybe a population that hasn't been diagnosed that's experiencing this when they do?

Cora Sternberg: In my experience, many of the patients already have a preexisting low-level diabetes and might perhaps be on metformin, not necessarily insulin-dependent, but I've seen people who became insulin-dependent and have had even serious problems with EV. This is just when you've been using EV alone, so the hyperglycemia can be serious. It's not one of the most common effects, but when it happens, it's a serious effect and we need to know about it. But it happens to me more often in patients who are on metformin or have low-level diabetes, and I explain to them that, "Your diabetes could get worse. We need to stay on top of this. You need to talk to your diabetes doctor all the time," et cetera, et cetera, et cetera. And they may need a second drug or something else.

Alicia Morgans: Yeah. Well, thank you for sharing that. I think one thing we should acknowledge and remind everyone is that the guidelines in the package insert do suggest that we hold the dose for patients with a blood sugar over 250. So it is always something that we check and identify, and we really get those sugars under control if we see that the blood sugar is elevated.

Cora Sternberg: Absolutely. We also have to look at the liver function tests with EV. They don't talk about it that much, but maybe it doesn't even bother the patient, but it bothers us. We have to look at the liver function tests and be careful about that too.

Alicia Morgans: Absolutely. Well, thank you so much, Professor Sternberg. I always appreciate getting your expertise, and I think this conversation today hopefully will help practitioners as they're trying to use the drug for the first time or expand its utilization given the new approval in combination with pembrolizumab—a highly effective drug, really transformative for our patients, but one with which we do need to be proactive in terms of those side effects. Thank you so much for your time and your expertise.

Cora Sternberg: It's absolutely a pleasure as always. Thank you.