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David Crawford: Hi everyone. I am E. David Crawford, Professor of Urology in the Department of Urology at the University of California in San Diego. It's my honor and pleasure to welcome to this edition of Crawford's Corner, Dr. Dan Petrylak, who is a professor of medical oncology and urology at Yale University Medical Center. Dan has distinguished himself in so many areas in urological oncology, and now we're going to focus on one where he has really spent a lot of time, and that's advanced urothelial cancer. Dan has worked in the Southwest Oncology Group as the organ site chair for advanced prostate cancer for a number of years with us, and during that time we saw the evolution and development of cisplatinum combinations with MVAC, gemcitabine, cisplatin, and so forth.

There have been a lot of great things that have happened in bladder cancer, both superficial and advanced disease, in the last few years, and we're going to focus on one of these that Dan was involved with, and that's a new combination that was originally presented at ESMO, enfortumab and pembrolizumab, that resulted in FDA approval and offered a significant survival advantage, and this was in December of last year. Dan has given an update on this at ASCO this year and this important study and focused on quality of life and other things.

And Dan, thank you for being with us to share this major step forward in advanced urothelial cancers. So tell us about these studies and where we are and where we're going to be.

Daniel Petrylak: So enfortumab vedotin is what I call a smart bomb. And what that is, is an antibody-drug conjugate. So there's an antibody to a target called nectin-4, which is expressed in about 90% of urothelial cancer specimens. And this particular antibody-drug conjugate delivers something called monomethyl auristatin, which is an antitubulin agent, to the cancer cell. The conjugate is internalized, and then this antitumor activity occurs. This drug was initially FDA approved about three years ago on an accelerated basis based upon phase two data, which demonstrated a response rate of approximately 40% in patients who had failed either primary chemotherapy, which was platinum-based, and a checkpoint inhibitor. The full approval of that came from a study called EV-301, which randomized patients to receive standard chemotherapy or enfortumab vedotin, and that showed a survival benefit.

Around the same time, there was a phase one trial that was looking at the combination of enfortumab plus pembrolizumab checkpoint inhibitor, and we saw some pretty spectacular data with that. The response rate was about 70%, and it looked like the median survival was somewhere around 25 months. So EV-302 was a trial that was designed to look at EV plus pembro as first-line therapy. And this was compared to the standard of care, either GemCis or GemCarbo, in patients who had not received chemotherapy for metastatic disease. The data was presented back at ESMO last fall. It's also appeared in the New England Journal of Medicine, and demonstrated that there was a 30% complete response rate with EV-Pembro, and the median survival was basically doubled. It was somewhere around 30 months compared to the standard of care, which was about 15 months. And so this is now accepted as a front-line standard of care for metastatic urothelial carcinoma.

So there were two presentations at ASCO that looked at EV. One, of course, was a study that looked at EV-Pembro compared to chemotherapy in terms of quality of life parameters. And I think that one of the things that we've observed with this combination in patients who have bone pain is that there's pretty dramatic improvement fairly rapidly. You can tell if a patient is responding based on their pain patterns. And the study that looked at quality of life found that the quality of life was better in those patients who received EV-Pembro versus those patients who received standard chemotherapy with GemCis.

The second trial, which I presented, was a summary of data from three studies with enfortumab vedotin. One of the difficulties with the drug is that peripheral neuropathy can ensue, and that can occur, what we found, usually around anywhere between four and six months after the start of treatment.

And so, there's a dilemma, of course, in the patient who's responding: what do you do? Do you dose reduce? Do you hold doses? And what we found from this analysis of the data in patients who were just treated with enfortumab alone is that the dose intensity of the drug, if you maintain that in the first two cycles, your responses turned out to be the best. And you could dose reduce patients later on without affecting the progression-free survival or overall survival. So, this basically gives the clinician the ability, or the confidence, to dose reduce if necessary to avoid toxicity such as neuropathy. Other toxicities seen with the drug are skin rash as well as hyperglycemia. So that's the summary of what we found.

David Crawford: That's certainly a major, major step forward. If we go back and look at our studies with MVAC and GemCis, GemCis sort of evolved out of the toxicity that we saw with MVAC. And certainly that was always something. You'll remember our SWOG study with neoadjuvant MVAC and cystectomy, which showed an advantage. And then, it was actually presented at the plenary session of ASCO quite a while ago.

I guess the first thing I would say is, this is not a home run, but it's certainly a two-bagger or something like that, at least second base. And do we take this now, based on the data? There's so much interest right now in bladder cancer sparing, and use platinum and radiation and things like that. Do we take that into trials that, or are they ongoing?

Daniel Petrylak: There are trials that are evaluating EV plus Pembro in the neoadjuvant setting. So that's certainly one area where we're awaiting data compared to GemCis in that area.

The other thing which I think is very, very interesting about this combination is that it has the same degree of activity in those patients who are cisplatin-eligible, as well as the cisplatin-ineligible patients. So that's going to open up a whole new field of patients in the neoadjuvant setting who could not receive cisplatin in the past. Now they can. So I think that in the neoadjuvant setting, or also the pre-radiation therapy setting, there's going to be a lot of good data generated. The real question is going to be, now what do you do then in a patient who progresses and how do you treat that patient? So it's basically changing the sequence that we're going to be using for treating patients with metastatic urothelial carcinoma.

David Crawford: So you talk to a patient that is in your career, you've seen a lot of people get MVAC, GemCis, and now this. How would you rate the patient acceptance and side effects comparing those three side-by-side?

Daniel Petrylak: Well, I think that the side effects are different. You don't see the degree of neutropenia that you do see with MVAC or GemCis. It's better tolerated, in my opinion. And we see this from the quality of life data as well.

But you do have to be careful about monitoring the patient's blood sugars, monitoring for rash. We demonstrated in that study the summary of the three different studies, that rash occurs pretty much quickly within the first month of treatment. So you've got to watch out for it. It can, in some situations, degrade to Stevens-Johnson syndrome. So you've got to be careful about that. So steroids, holding doses is important at that particular point, but you've got to monitor for that. And of course, the neuropathy dose reduction as well as holding doses is appropriate.

But in my experience, this has been a much, much better tolerated regimen. There was data recently presented comparing GemCis to GemCis combined with nivolumab, and that showed a survival benefit, GemCis to nivolumab over GemCis. And years ago we would've been jumping up and down over a two to three-month improvement in median survival. And here we're seeing this really, really large improvement in median survival. So I think this is a big leap, but there are patients who don't respond. And the question, of course, as we said before, is how are we going to treat these folks?

David Crawford: Do you have any idea what the pedigree is of the patients that don't respond?

Daniel Petrylak: No, we don't. There have not been any molecular studies. The interesting thing about enfortumab, is when you look at the nectin expression, we see responses across all levels of nectin expression. And also, in the phase one trial, and I haven't seen the data from phase three, but the phase one trial, we found that responses were seen irrespective of the PDL-1 level. If you had low PDL-1 levels, you still responded to the combination just as frequently as if you had high levels. So we need good molecular markers in this area.

David Crawford: The Kaplan-Meier curves and the survival that you see, the difference between the combo and chemotherapy is significant. You usually don't see that in a lot of trials that are out there. Where are we going to be five years from now with this and with broader advanced disease, Dan?

Daniel Petrylak: Well, I think in five years, I don't see any reason why this combination will not be moved up front to the neoadjuvant setting. If you've got such great activity in the metastatic setting, there's no reason in my mind that this would not work in neoadjuvant.

So then in five years, how are we going to manage our patients once they progress after these particular types of treatments? Pretty much giving sequential immune therapy, in other words, giving sequential checkpoints if they've been exposed to it, other tumors doesn't really seem to work well. So we're going to need to have new immune therapy approaches. We have other drugs that are out there. We have FGFR-3 inhibitors such as erdafitinib, HER2/Neu is coming into play with urothelial carcinoma with some of the new HER2/Neu targeted ADCs we have, which is a Trop2 ADC that delivers SN38, which is like topoisomerase-I. So there are a variety of different drugs. What we have to work out is what the marker pattern is for these patients and how we can rationally use them such that patients are not unduly exposed to toxic agents and can benefit from the drugs.

David Crawford: More personalized medicine and focus.

Daniel Petrylak: Exactly.

David Crawford: You think that's going to happen in the next 5 years?

Daniel Petrylak: I think it will. I think that as time goes on, we'll learn more about the biology of the disease and how to focus our treatments.

David Crawford: As far as you mentioned in neoadjuvant roles and even earlier, is that we always start with the worst-case scenario and move up the treatments. And every time we do that, they work better. And then there's always the argument about lead time bias and things like that. But I think this is a keeper in all this stuff going on in bladder cancer. I applaud you and all the colleagues that have really jumped in and started working in this area that was sort of dormant for a long time.

So Dan, thanks for your time. And our listeners are excited to hear about this and that there are protocols we need that they're out there, they can put patients on bladder cancer and other studies do it.

Daniel Petrylak: Absolutely.

David Crawford: Thank you.