The Treatment Landscape for Advanced Urothelial Carcinoma in 2021 - Jonathan Rosenberg

May 11, 2021

Immune checkpoint blockade is a first line therapeutic option in either platinum ineligible patients or carboplatin eligible patients whose tumors also express PD-L1. Patients who are ineligible for cisplatin and progress on immune checkpoint blockade have limited treatment options, and many efforts are underway to expand the therapeutic armamentarium for this disease context.  In this conversation with Alicia Morgans, MD, MPH, Jonathan Rosenberg MD provides a summary of urothelial carcinoma treatment data presented at the GU ASCO 2021 conference. Evidence that enfortumab vedotin (EV), an antibody-drug conjugate with promising efficacy in locally advanced or metastatic urothelial carcinoma is a focus of this conversation. EV consists of an antibody against Nectin-4, a protein highly expressed on the surface of most urothelial carcinoma. This antibody is conjugated to the anti-microtubule agent monomethyl auristate E. Once the antibody binds the Nectin-4 expressing cell, the agent is internalized, and the chemotherapy agent is released to cause eventual cell death.  EV can be considered both in advanced disease after immunotherapy and chemotherapy.  Jonathan goes further to discuss the possibility of treatment with enfortumab vedotin for patients earlier in the course of the disease. He highlights the EV-301 study, demonstrating for the first time, that a novel targeted agent improved survival in the refractory setting beyond immunotherapy. He also highlights the EV-201 cohort 2. This was a non-comparative phase 2 trial of EV in platinum-na├»ve/cisplatin ineligible/anti-PD-1 axis progressive patients with overall response rate as the primary endpoint. In addition, he highlights the landmark JAVELIN Bladder 100 study.  Avelumab first-line maintenance therapy is approved in the United States for patients with advanced urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy based on significantly prolonged overall survival versus best supportive care alone (median 21.4 months versus 14.3 months; HR 0.69, 95% CI 0.56-0.86) as reported in the phase III JAVELIN Bladder 100 trial.


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.

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Alicia Morgans: Hi, my name is Alicia Morgans. I'm a GU medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, a good friend and colleague, Dr. Jonathan Rosenberg, who is a professor of medicine and the chief of the GU Medical Oncology Service at Memorial Sloan Kettering in New York. Thank you so much for being here with me today, Jonathan.

Jonathan Rosenberg: An absolute pleasure. Thank you very much.

Alicia Morgans: Wonderful. So Jonathan, I always love to learn from you and wanted to hear your thoughts on some of the key presentations in urothelial carcinoma from ASCO GU 2021. And these were EV-301, EV-201 cohort two, and an update on the JAVELIN 100 study. Thank you so much for taking the time.

Jonathan Rosenberg: No problem. My pleasure. So EV-301 was actually quite, I think, a landmark study. It was the first time that we've seen a novel targeted agent-approved survival in the refractory setting beyond immunotherapy. And so patients who were enrolled in EV-301 were patients who had progressed on prior chemotherapy and prior checkpoint inhibitor, and they were randomized to either enfortumab vedotin or standard of care chemotherapy. And in the United States, that is a taxane and in Europe, it could be [inaudible 00:01:10] as well. It was an international study that showed that patients who received enfortumab vedotin live longer and had superior progression-free survival compared to those patients who receive taxane chemotherapy, with a hazard ratio of 0.7 for overall survival. That is, I think, quite a nice achievement in a very disease-resistant setting in a phase three trial.

In addition, the response rate was 40% for enfortumab vedotin, which is similar, although a hair lower than the phase two trial data where patients had responses in the mid-forties, but 40% of patients had objective responses. And I think what we are going to see as time goes on is that translates to at least some palliative benefit for patients, that you're getting substantial tumor reductions that are benefiting patients beyond just living longer, and living longer is obviously the gold standard, but hopefully living better, as well.

Of course, there is no free lunch. Toxicity from enfortumab can sometimes be difficult and some patients experience neuropathy, some patients experience skin rashes. Occasionally those can be difficult to deal with. And then there are some rare and severe toxicities that we occasionally see like severe hyperglycemia and we also sometimes see an acidosis-type picture that can occur in exceedingly rare cases. But for the most part, patients tolerate this reasonably well. There have been some recent reports that the FDA led to a notification around toxic epidermal necrolysis as a risk. Again, very, very rare. With enfortumab vedotin, it tends to happen very early in the course of the disease.

But overall, I think this was a substantial step forward for patients and hopefully it will lead to full approval of enfortumab in the United States as well as approval in Europe very soon.

Alicia Morgans: Absolutely. You know, these are, as you mentioned, heavily pretreated patients or patients who have actually seen the normal lines of therapy, so to be able to take that patient population and give them an opportunity to have a better option, potentially than chemotherapy, at least in terms of its survival benefit, I think is absolutely huge. I'm always so tempted though to think about some of the data that we've seen earlier, that when we combine EV with things like pembrolizumab, for example, we may even augment that power and I look to an opportunity to potentially move it forward, potentially even in combinations. I don't know. What are your thoughts on that?

Jonathan Rosenberg: Yeah, so I am very interested in seeing what the results are going to be of the randomized cohort that's going on right now as part of EV-103. EV-103 was a multi-cohort study. One cohort was reported, cohort A, which was the patients who received the combination of enfortumab and pembrolizumab and these are cisplatin-ineligible patients for whom we think outcomes are not typically so good with gemcitabine and carboplatin chemotherapy with response rates in the low to mid-forties, at the highest. And that combination showed a 73% response rate and we are going to, I believe, see some very substantial durability. The duration of responses was approaching a year in the phase 1B slash 2 cohorts, and we would expect progression-free survival could be around six to nine months with chemotherapy in that situation.

So the combination might have synergistic potential, but we don't really know yet. EV-302 is a randomized phase three, testing enfortumab and pembrolizumab in combination compared to conventional chemotherapy, either gemcitabine, and carboplatin, or gemcitabine, and cisplatin. So that study is enrolling both cis-eligible and cisplatin-ineligible patients, and that really will confirm the results. The combination was granted an FDA breakthrough therapy designation, and perhaps we may see this combination in an accelerated approval sometime in the next several years, based on another cohort of EV-103 randomizing patients to EV pembro or enfortumab alone in untreated metastatic disease. It is, I guess possible, and we will talk about this in a minute that, earlier treatment may actually show even more of a benefit from enfortumab and so maybe it really is just the enfortumab and pembrolizumab isn't adding that much. My suspicion is that it is, but we need to prove that. And so that study, called cohort K, is randomization that is ongoing and patients are being recruited.

Alicia Morgans: Well, it's amazing how one study reports out and more questions lead to more studies and ultimately it's great for patients.  But I appreciate you keeping it all sorted out for us. It is certainly very helpful. Cohort two also reported at GU ASCO 2021. Tell us a little bit about that.

Jonathan Rosenberg: So EV-201 was a two cohort study as you mentioned. The first cohort was what led to the accelerated approval. It was the same patient population as EV-301. Cohort two was actually essentially second-line patients, people who were not able to get cisplatin-based chemotherapy, carboplatin eligible patients, and they received a checkpoint inhibitor in the first-line therapy, and they either didn't respond or progressed after response and then were eligible to enroll on the EV-201 cohort two trial, and that data was reported at GU ASCO this year as well. This was actually quite an active drug in the post checkpoint setting as well, with an objective response rate of 52%, which is higher than what we might expect in that setting for anything else we've gotten, to be very honest with you. There was some significant toxicity observed in a minority of patients. It is not clear that those patients have these problems more frequently, or it just happened to be bad luck, but that is why we need further studies to evaluate it in larger populations.

But I'm very excited about the possibility that perhaps this drug is really going to move up to either first-line therapy or post checkpoint inhibitor in patients who might not be candidates for cisplatin-based therapy.

Alicia Morgans: Well, I think, the reality is that is not a rare thing, to have a patient who's not going to be eligible for cisplatin, and to have the opportunity to give those patients something that we think is going to be effective, I think is also hugely transformative. I'd love to hear your thoughts just briefly on the neuropathy, because in my clinic at least, that has been the most common symptom. It's been a bit of a more challenging symptom. I have found at least that the neuropathy seems to lag behind.  So even if I dose reduce or stop the drug, it does sometimes seem to continue on before it starts to resolve a little bit after those dose adjustments or cessations, but we've still, interestingly, actually had disease control even after we've stopped for some of these patients after we've developed some neuropathy and had to stop the drug. I just don't know, what are your experiences? Do you have any suggestions on how to deal with neuropathy with this drug?

Jonathan Rosenberg: I tell patients that unfortunately, it's often the price of success. That means, that the drug has been working and they have been on it long enough to get this. There are some patients probably who get it early and quickly, but for the most part, it happens after three, four, five, six months, that they've been on it, you have scans that show response.

I have had some success with dose interruption and then dose reduction. The pain tends to dissipate, but what is left often is a numbness that's hard to manage and there is no real antidote for that. And there are patients who also get motor neuropathy, which is different than with cisplatin, for example. And so those patients, it is very difficult and you often are dose reducing or stopping. But again, I've seen patients who have stopped for toxicity from this drug who have maintained responses for three to nine or even 12 months later without needing additional therapy. And we have had patients who've been able to then resume treatments if their toxicity does in fact reduce. And so it's an interesting and difficult problem.

I do wonder whether we need to start exploring alternative schedules. And now they are starting to use... Now the company is testing days 1 and 8, every 21 days. Should we be doing every two weeks for patients who have significant neuropathy, as opposed to day 1, 8, 15, every 28 days? These are all questions that at some point we are going to need to try to answer in a more systematic fashion and maybe people need an induction with a more intensive approach and then need perhaps a maintenance approach with enfortumab at longer intervals perhaps. But we really don't know the answers to those questions. And I would say that what I do is, I try to keep the patient on treatment as long as I can with an acceptable quality of life without the neuropathy becoming something that really impairs them from living their life. And if that means off-study, to have a patient get treated less frequently or at dose reductions, then that is what we do.

Alicia Morgans: It's interesting that you say that because I was hoping I wasn't alone. So all of the patients that I've had to take a pause for neuropathy have actually had really sustained responses like six months, nine months out, we're still following and [crosstalk]

Jonathan Rosenberg: It's totally different. Right. It's almost an immunotherapy effect in a sense which is intriguing, especially given the combination data that we saw with pembrolizumab. And there is some emerging data that perhaps targeting [inaudible 00:10:48] may have some immunologic effects, that I don't think is proven by any stretch at this point, but there are some intriguing laboratory data that are starting to emerge.

Alicia Morgans: Wonderful, well, clearly more work to do so very exciting. So there was also an update on JAVELIN 100 data. I'd love for you to just review what JAVELIN 100 is and then mention your thoughts on this update.

Jonathan Rosenberg: So the JAVELIN 100 trial was a randomized phase three trial that was testing the idea of maintenance immunotherapy in patients who responded to chemotherapy or had stable disease after chemotherapy. And to get on the trial, patients had to have had at least four cycles of chemotherapy, and then they were randomized if they had CR, PR, or stable disease to best supportive care or avelumab. And so in that trial, there was about an eight-month improvement in overall survival in patients who received avelumab, and that has scripted the standard of care overnight. So for patients who have a response or stable disease after platinum-based chemotherapy, my practice is now to initiate immunotherapy with avelumab.

There was some data presented at GU ASCO, which was interesting around, do you really need six cycles of treatment? And there have been a couple of retrospective studies that suggest that people who get six cycles do just about as well as people who get four cycles, but it's really not been any robust data. It's not trial data. And so the investigators for the JAVELIN Bladder 100 study looked at this and saw that there really wasn't a difference between four cycles and six cycles in terms of the benefits of avelumab. So the way I interpret that is, to reassure physicians that if patients are having trouble tolerating treatment, but they're responding, and you've gotten at least four cycles into them, you can feel comfortable stopping chemotherapy and switching to avelumab maintenance. But I would caution, that we know that chemotherapy helps these patients, and I wouldn't try to purposefully give them less chemotherapy if they are responding and tolerating it well. And so I wouldn't interpret this data as a license to say, oh, we don't need much chemotherapy. We really need to kind of cool the disease off probably in these patients and get them to some degree of response before we move to immunotherapy.

And I think that's notable considering all the randomized trials comparing immunotherapy to chemotherapy or adding immunotherapy to chemotherapy as concurrent therapy, hasn't really shown a benefit in urothelial cancer at this point. And then the concern in many people's minds is that immunotherapy as monotherapy is not powerful enough as a single-agent checkpoint inhibitor of PD-1 or PDL-1 to deal with a highly aggressive cancer for many patients. There clearly are a subset of people who do extraordinarily well with immunotherapy and the results of IMvigor 130 do suggest that there may be a population of patients who are going to do very well and you might be able to pick them out with PD-L1 testing for atezolizumab, but KEYNOTE-361 didn't show a benefit for patients either with PDL-1 high, or all comers with single-agent therapy in combination also. So the field is becoming clear, even though there is still a lot of unanswered questions, that really maintenance approach is optimal for patients. And as long as you get sufficient chemotherapy, and in my mind, sufficient is at least four cycles, ideally six in responders, then you are doing the best job you can for patients right now.

Alicia Morgans: Well, thank you so much for reviewing that and for putting that into context for us. I completely agree that as much chemo as we possibly can get in safely and at a tolerable level, that is what we need to try to do.

I just have one more comment, and then I want to hear your summary of GU ASCO 2021 from a urothelial standpoint. I was a fellow when you were a young faculty member a long time ago. And I have to say, this is an amazing difference from what we talked about a long time ago, and I'm not going to say how long. At that time it was all chemotherapy, and this was not even a twinkle in your eye, or certainly not in mine at that time. So kudos to the whole community and so much more work to be done, but such an exciting field. So can you give us a little bit of a summary of your experience, GU ASCO 2021?

Jonathan Rosenberg: So at this meeting, there was evidence that enfortumab vedotin has a place both in advanced disease, past immunotherapy, and chemotherapy, but also possibly for patients earlier in the course of the disease with additional evidence to come in earlier lines, but certainly EV-201,cohort two, EV-201 suggests that this is an active drug, even regardless of prior platinum therapy, which makes sense. And the meeting itself, I think, was unique in that it was in its virtual nature, but really presented a lot of very exciting and potentially practice-changing data that we will hopefully see more of over the coming year or two.

And it has been a wonderful ride in bladder cancer. I really have been lucky to be a part of that. And I feel like I'm the right person, in the right place, at the right time, in order to help our patients take advantage of that. And it's been a true pleasure to be involved in a lot of these events.

Alicia Morgans: Well, you are certainly very involved Jonathan, and thank you for all that you do to help make a difference in the lives of these patients and for the work that you're doing to continue to push that envelope. And thank you for your time today. We really appreciate it.

Jonathan Rosenberg: My pleasure. Have a great night.