Enfortumab Vedotin for Advanced Urothelial Carcinoma - Jonathan Rosenberg

March 8, 2020

Alicia Morgans is joined by Peter O’Donnell and Jonathan Rosenberg to discuss enfortumab vedotin (EV). This offers a new mechanism of action and is the first antibody-drug conjugate (ADC).  This represents a targeted therapy and was studied in metastatic urothelial carcinoma.   In reviewing the clinical data and side effects of the drug, the three clinicians highlight the effectiveness and tolerability and safety of EV.   


Peter O'Donnell, MD, Associate Professor of Medicine, Department of Medicine, University of Chicago Medicine, Chicago, Illinois

Jonathan E. Rosenberg, MD, Chief of the Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology; and the Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, New York City, New York

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Read the Full Video Transcript

Alicia Morgans: Hi, I'm so excited to have here with me today, Dr. Peter O'Donnell, who's an Associate Professor of Medicine at the University of Chicago, and Dr. Jonathan Rosenberg, who is the Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center. Thank you both for being here today.

Jonathan Rosenberg: Thank you.

Alicia Morgans: So we wanted to talk a little bit about a drug that was recently approved, enfortumab vedotin, or EV, and I think that this is a really important drug for us to review, and to think about as clinicians, who've had some experience with this drug, have participated in the trials, and who may actually be using this in our routine clinical practice at this point, particularly because this is a new mechanism of action for many of us in GU Oncology, an antibody-drug conjugate. I'd love to hear the two of you just talk about EV. What is it? How is it constructed? What is an antibody-drug conjugate? Peter, can you tell us a little bit about that?

Peter O'Donnell: Sure. So the drug has an antibody portion like we're used to for our immunotherapies. The antibody portion binds to a molecule called Nectin-4, which is almost universally expressed on urothelial cancers. Almost every urothelial cancer will express Nectin-4. And so, then once the antibody binds, the molecule delivers a taxane-like molecule, theoretically, into the cancer cell. So it is this dual-portion molecule with an antibody part and a more cytotoxic traditional payload.

Alicia Morgans: Great. So it's sort of a targeted chemotherapy. The goal of this, of course, is to decrease side effects systemically, and really target a higher payload, or a higher amount of toxic agent to the cancer cell directly. So this was tested in a metastatic bladder cancer, urothelial cancer population. And can you tell us a little bit about that trial, the pivotal one that led to its recent approval?

Jonathan Rosenberg: Sure. So, that trial was EV-201, which enrolled 125 patients who had previously been treated with platinum-based chemotherapy and immunotherapy. So all patients were heavily pretreated, at least two lines of prior therapy. And the response rate, the objective response rate, was 44% in that clinical trial. And when we think historically about the response rate of salvage regimens, we think about taxanes with response rates in the 5% to 15% range. So when you're seeing a drug with a 44% response rate, it really puts your antenna up that something different is happening here. The median progression-free survival was a bit over six months, and the median survival was about a year on that clinical trial. And that actually mirrored the data from EV-101, one which was the Phase I study with the expansion cohort that had a very similar patient population.

One of the most notable things about this drug is that it seems to be active even in patients with some poor prognostic features, like liver metastases. We've had a very hard time treating these patients. There really aren't many drugs that have good activity in patients with metastasis to the liver. And the response rate in those patients seems to be about the same, roughly around 40%. And so again, a very potent agent that we now have FDA approved, as of several weeks ago, that we're able to use in our clinical practice.

Alicia Morgans: Absolutely. And just to really emphasize that, the patients with liver metastases, in clinical practice at least, they're not necessarily as responsive to things like checkpoint inhibitors, for example.

Jonathan Rosenberg: Right. And so, they tend not to respond as well to chemotherapy. They tend not to respond as well to immunotherapy. And the prognosis of those patients is quite poor. And perhaps, and I say this because we're not 100% sure yet.

Alicia Morgans: Of course.

Jonathan Rosenberg: But perhaps this drug might actually bend the curve more dramatically for that patient population.

Alicia Morgans: Which is really important, the ones who are most in need in some situations. But I think one of the other really interesting things about EV is that because it is a targeted agent, it has some specific off-target effects. And this can explain some of the side effect profile. I think generally, in my experience with the drug, it's actually quite well-tolerated, and I've even had elderly patients who have done quite well on the drug who may have had a borderline performance status, and we can talk about its tolerability generally. But Peter, I'd love to hear your thoughts on some of the side effects that seem to be really related very closely to on-target effects that we might expect in many of our patients, so skin effects, and maybe some others.

Jonathan Rosenberg: When I explained this drug to my patients, the patients are used to most recently having been on immunotherapy, almost always. And so they're used to usually having a pretty good course, with not a lot of side effects. And they do remember the days of when they got chemotherapy as well, and this drug falls in the middle, in my opinion. It is not as easy as getting immunotherapy, but it's probably not as challenging, at least in the short term, as traditional chemotherapy. The three toxicities that really are of note for me, you mentioned the skin rash. It is present in the majority of patients. Patients will experience it, sometimes like a sunburn all over. Some patients will actually get a darkening of their skin as if they've been out in the sun for quite a long time. Other patients can get a more traditional macular papular rash.

I haven't had patients need to stop therapy for prolonged periods of time because of the rash, and it sometimes is accompanied by itching, which can be annoying to patients. But usually, we use barrier treatments like Aquaphor®, agents like that, which helps somewhat. One thing for oncologists to note is, in my experience, using topical steroids, like we're used to giving for immune-related rashes, hasn't been that successful. I think we're still searching as providers for the best treatment for the EV-related rash, which is pretty common.

The other one that I mention to all patients is the issue of neuropathy. We have to face it with this drug, it's got the taxane-like payload, and for patients that are on this for any prolonged period of time, they really are at risk of developing neuropathy. Usually, it tends to occur right around that three or four-month point of being on the drug, where they'll start to show some symptoms. And it's a tough toxicity to deal with for this drug because the drug itself has a very short half-life, and so it needs to be given on this weekly basis for three weeks out of every four. And holding the drug for prolonged periods of time is not good from a disease control standpoint, and yet neuropathy tends to lag behind. And so my advice to clinicians is to really be very attuned to the earliest signal of neuropathy and think about early dose reduction with the EV as a way to manage it. We've also used other treatments like duloxetine, which has an ASCO indication for chemotherapy-induced neuropathy, and that's been successful in some patients.

Alicia Morgans: Wonderful. There is definitely some other side effects we need to think about though in terms of safety. Jonathan, can you tell us a little bit about hyperglycemia? It's really not just in patients with preexisting diabetes, and it's not just a routine type II diabetes that we can treat easily, particularly if we don't identify it. So it's something that we often need to identify, and then educate patients about.

Jonathan Rosenberg: So in clinical trials, it was noted that there were a few patients who had severe hyperglycemia that was refractory to standard therapies like insulin. It turns out to be a very rare event for it to be severe, but there was about a 10% incidence of hyperglycemia patients on the clinical trials. And it is something to be mindful of, people who may be on concomitant steroids for some reason, who have some insulin resistance. Those patients need to be monitored a little more closely. But there are some patients who it becomes more of a major problem. But it is a rare phenomenon for it to be severe, but it's one of those things where if you don't pay attention to it, it can become severe in short order in a small number of patients.

Alicia Morgans: And for close monitoring, do you recommend monitoring more than weekly when they come in for their doses, and what is your experience?

Peter O'Donnell: I just wanted to piggyback on something Jonathan said, is that that toxicity, unlike the other, seems to be idiosyncratic, in that it occurs very early in the course of getting the drug. Within the first couple of infusions, this is when these patients' glucose will quickly start to go up. And it tends to respond very quickly to also stopping the EV. The glucose comes down quite rapidly, and it does not seem to be, in my experience, related to people who have issues with diabetes before. In fact, those patients are really good at monitoring their glucose levels, and they're on antihyperglycemic agents. It's those patients that aren't familiar with the concept of even paying attention to glucose. So we only monitor once a week. With the infusion, we're monitoring the glucose, but it's something to pay attention to in that first month of EV.

Alicia Morgans: Absolutely. So at this point, this drug is approved after chemotherapy, and after a checkpoint. Are you using it elsewhere? And then, are there combinations? There was a really exciting EV plus pembro, which really had me shocked and excited. So can you tell us a little bit about earlier use, if that's coming, and then also these combination studies? And maybe each of you can take one of those questions.

Jonathan Rosenberg: So EV-103 was the Phase 1b study that was investigating different combinations of chemotherapies in EV or immune checkpoint inhibitors with EV. And so EV-pembro, EV-pembrolizumab, the first data was reported at ESMO 2019 showing a 71% response rate, which was higher than cisplatin-based chemotherapy.

Alicia Morgans: Yes.

Jonathan Rosenberg: It's higher than dose-dense MVAC. It's higher than gemcitabine cisplatin.

Alicia Morgans: It's higher than most treatments in oncology.

Jonathan Rosenberg: Right, right. So we were pretty shocked, and surprised, happy, obviously, to see those data. The cohort had 45 patients, so a modest-sized trial. We need to see the durability of this. So the data being presented at the GU Cancer Symposium shows that the progression-free survival is about one year in this patient population, when we'd expect six months maybe, or less, progression-free survival with our standard treatments. In addition, the response rate is actually going up over time in this cohort, now up to 73% from 71%. And it seems like there are no combination emergent events that are occurring from a safety perspective. And so, it's really very exciting to be thinking about the combination of a cytotoxic that might be affecting the tumor microenvironment leading to the up-regulation of processes that allow pembrolizumab to be more active in that patient population. And it suggests perhaps that it's more than just additive benefits in this patient population.

Alicia Morgans: Absolutely.

Jonathan Rosenberg: It's going to be very interesting to see what the survival data will show over time. They're still not mature with a median follow-up of about 10 months. And so, we're hoping that we'll be seeing a new possibility for those patients in the first-line setting. And there's a randomized Phase III trial that's actually launching right now, that we'll be testing this in comparison to standard treatment.

Alicia Morgans: And just to reiterate, was this a selected population for pembrolizumab?

Jonathan Rosenberg: Great question. So pembrolizumab is restricted in the United States in the first-line setting, based on PD-L1 status. But this trial did not select patients, and there was no significant difference between PDLM positive and PD-L1 low patients. The response rates were within a couple of percentage points of each other, and there did not seem to be a difference in the durations at this time point. So very exciting that it may overcome the limitations of a checkpoint inhibitor in terms of PD-L1 status.

Alicia Morgans: Really, really exciting. So I'm excited to see where that survival data goes. And then for you, Peter, moving this drug earlier, even the expanded access protocol, which has actually since closed, wouldn't allow patients if they hadn't received chemotherapy in prior settings. But there are many patients who can't get chemotherapy, or maybe can't get immunotherapy with checkpoint inhibitors because of autoimmune disease. Are you ever moving this drug earlier in your clinical practice when you can't use those drugs?

Jonathan Rosenberg: Well, I think we need to be careful to follow the label indications for a drug, but I am really excited about the chance that this drug could be a disruptor to the first-line setting as we know it. Because you think about it, it has a 44% response rate in a highly refractory third-line setting, when gem-cis right as about a 49% response rate in the frontline setting. So this has frontline activity, in a third-line setting. And so what could it do in the frontline setting and with combinations? It's really exciting.

Alicia Morgans: Absolutely. Well, I sincerely appreciate both of your time, and as we wrap up, I'd love to hear your high-level take-home message, one from each of you, EV and clinical practice. What are your thoughts, Peter?

Peter O'Donnell: Impressive activity as I just said, and this signal for patients that have poor prognostic factors like liver metastases, which really used to be an unfortunate death sentence for a patient with urothelial cancer. Now, these patients are able to respond to this drug, and it's great to have a new option.

Alicia Morgans: Great, thank you. And Johnathan?

Jonathan Rosenberg: And I think moving it earlier in the disease is where this drug is going to find its natural home in the future, although we're clearly not there yet, and we need a lot more data, and a lot more evidence to support its use in the first-line, and even peri-operative settings down the road.

Alicia Morgans: Absolutely, so wonderful. So thank you so much for this overview. A drug that we can use in the third-line setting in an unselected patient population that seems relatively well-tolerated, as long as we think about the side effect profile, counselor, patients, and care for them as we always do. So I appreciate you so much sharing your thoughts on EV, thank you.

Peter O'Donnell: Thank you.

Jonathan Rosenberg: Thank you very much.

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