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Alicia Morgans: Hi, I'm so excited to be here today with Professor Cora Sternberg, who is the Englander Institute for Precision Medicine Professor and here visiting from Cornell University. Thank you so much for being here.

Cora Sternberg: It's a pleasure to be here as always. How are you?

Alicia Morgans: I am well, thanks, and so excited to talk with you. There has been so much buzz about the EV-302 presentation made at ESMO 2023, and I love the opportunity to speak with you, someone who is so familiar with the evolution of care in urothelial cancer, about this study, its results, and how we think about it in the context of care for metastatic bladder cancer. Let's start. Tell me a little bit about the EV-302 study design.

Cora Sternberg: First of all, until this study came about, patients with advanced metastatic urothelial cancer were treated primarily with cisplatin-based combination chemotherapy or with carboplatin-based chemotherapy or with dose dense MVAC or MVAC. So cisplatin or carboplatin was the standard of care. EV-302 is a very interesting study. EV is enfortumab vedotin. It's an antibody-drug conjugate and attacks cells at Nectin-4 and its payload is MMAE, which is a topoisomerase inhibitor. It's very potent because the antibody-drug conjugate goes directly to the cell and the toxicity is not, supposedly, in the environment. EV-302 is given together in this study with pembrolizumab, which is an anti-PD-1 inhibitor immunotherapy. The combination has been given, I've been giving it for quite a long time, and it has been approved for patients who are even cisplatin ineligible, a term that we always use based upon the creatinine clearance of being less than 60. In many studies it has been approved for patients who had creatinine clearance as low as 30.

In fact, in this study, patients were randomized between the combination of enfortumab vedotin and pembrolizumab versus chemotherapy with either gemcitabine and carboplatin or gemcitabine and cisplatin. The entry criteria were that they could have had a creatinine clearance as low as 30, which is usually never seen in cisplatin-based studies. They also stratified patients based upon whether or not they had liver metastases and their performance status. In that study, 886 patients were randomized to either receive EV and pembrolizumab versus the combination of chemotherapy.

Now, EV was given at a dose day 1 and day 8. When EV has been approved in second line after patients have failed chemotherapy or immunotherapy, we give it 3 weeks in a row, which is more toxic, I think, than the way it was given this way. It was given just 2 weeks in a row with pembrolizumab given IV every 3 weeks. This is given indefinitely and the pembrolizumab is usually given for up to 35 cycles, more or less for 2 years. The gemcitabine and cisplatin or just gemcitabine and carboplatin is given for six cycles of therapy. And that's the way the trial was designed. Looking at radiologic progression-free survival and overall survival.

What they saw was absolutely incredible, that people were standing up and cheering in the room to see the difference and the wide separation of the curves. While this study was going on, they stopped this study, but 33% of the patients were still on the EV and pembrolizumab arm. They looked at the radiologic progression-free survival, and there was a 55% improvement in radiologic progression-free survival. So the PFS was something like 12.6 months in the EV arm, and when you think about the old MVAC studies and GC studies, the overall survival was between 12.6 and 15 months. So that was the PFS.

When they look at the overall survival, the overall survival had a hazard ratio of 0.47, which was a 53% improvement in overall survival with EV and pembro as compared to chemotherapy. So again, the curves were really widely separated, with overall survival of 32 months for the patients on the EV and pembro arm as compared to the patients on the chemotherapy arm, which, approximately, I think it was 16 months there. So the patients at 16 months is not terrible compared to older trials, but it's always difficult to do cross trial comparisons.

If you looked at the response rates as well, the response rates with the combination arm was 68% with 29% complete responses. And if you looked at the response rates with the gemcitabine and carboplatin or cisplatin, it was in the 44% range with about 12% complete responses.

Now, the toxicity of the EV and pembrolizumab was actually less than I would personally have expected having used this combination, and I think it has to do with the fact that the EV was only given twice instead of three times in that period. The main toxicities that we see with this drug have to do with peripheral neuropathy. We see skin rashes and we see hyperglycemia. Those are the worst toxicities. The toxicities, as you know with immunotherapy, again, skin rashes, thyroid disease, pneumonitis. They were the ones that we're used to seeing. And so it was actually pretty well tolerated with curves that really were very well separated. People think now that this is a new standard of care as compared to cisplatin or carboplatin-based chemotherapy for first-line patients with locally advanced or metastatic urothelial cancer.

Alicia Morgans: I think that you certainly captured the excitement in the room, but really just to emphasize the overall survival was about 2.5 years on average. That is crazy for metastatic urothelial carcinoma, which we know is highly aggressive, and even with the best chemotherapies, as you said, the survival was expected to be somewhere around 12 to 15 months. So I think that it is no surprise, from my perspective, that we were so enthusiastic in that room and cheering.

One of the things, as you mentioned, to think about whenever you have a transformative therapeutic combination, and this is one that everyone should be aware of, is really the toxicity profile as you described. One thing that's interesting with EV is that it was given indefinitely in this study, but patients didn't necessarily take it indefinitely. I think the average number of cycles was somewhere around 12, which, I agree, seemed higher than I thought potentially that they would reach. But can you comment on this and on the, perhaps, durability of effect you've at least seen in clinical practice, we can't really comment necessarily on the trial?

Cora Sternberg: I have participated in trials with EV and pembro in patients with very poor creatinine clearance, and I almost invariably have to lower the dose of EV. And then if they're on it for very long amounts of time, I start separating out the dose. There's absolutely no data on patients who have a creatinine clearance of less than 30. I've treated patients with this on dialysis. We have no data on that whatsoever. I've looked it up many times, I've just sort of made up doses. So I think that EV given very long periods of time is a problem. I think the toxicity is important.

I'm not sure if the company maybe got the dose wrong originally when they were giving it three times. With the combination with pembro, it's only twice. But I think that very often many of my colleagues start out with a lower dose and they don't even start, I'm saying, off trial. So I think that giving it a lower dose or being quick to lower the dose when patients have neuropathy or terrible skin rashes is very important or hyperglycemia. Those are the worst toxicities that we do see with EV. It's not that easy. It is a drug that has to be managed and you have to know how to use it.

Alicia Morgans: Well, what I think is interesting, at least in my experience with EV, is that there is a learning curve, but once you get it, you can proactively decrease the dose or skip a dose or however you want to do it to sort of limit exposure. But by doing that, you allow exposure over time, which I think is so important for disease control.

Cora Sternberg: Exactly.

Alicia Morgans: I've also seen when I have had to stop, as I imagine may have happened in some of those patients who got 12 cycles, that there can be a durability of response even when patients are not being treated. And I have also re-treated some patients and had some renewed response after a disease control period with treatment cessation and then renewed response after I've restarted. I don't know if you've had anything like that.

Cora Sternberg: Remember, this is given with pembrolizumab, and you can continue the pembrolizumab even if you stop the EV and pembrolizumab should prolong the response. We've seen that in other studies giving immunotherapy, even in the JAVELIN 100 study. You can't compare cross study comparisons, but giving maintenance immunotherapies is effective. So I think that that is something that will happen. We need to understand how to best manage this, see if we can reduce the dose, see if we can reduce the cost eventually. There are many questions that we have to ask that I think that the academic community will want to ask those questions, and I think they're important questions to ask if this becomes a new standard.

Alicia Morgans: Absolutely. When you think about it, and of course you mentioned there's a similar response to the treatment EV pembrolizumab, the similar benefit, whether the patients had cisplatin based-combination therapy or carboplatin based-chemotherapy. They were both...

Cora Sternberg: Do you know the ones who had carboplatin based chemotherapy, if you look at the curves, they did better than the ones who had cisplatin? It's unusual. And the ones who had PD-L1 expression less than 10, as opposed to the higher expression, did better. I can't explain that either. Maybe that's just the way it turned out. Maybe it's just a question of numbers. But everybody responded. There were quite a number of patients with liver metastases and lung metastases, no matter what the metastases were, that all subgroups responded better to the EV-pembro than they did to the combination chemotherapy.

Alicia Morgans: So what would your message be about this therapeutic combination, this presentation, and the publication that started to follow?

Cora Sternberg: I think we clearly have, it's been a long time since we developed the MVAC chemotherapy regimen and the high-dose MVAC and gemcitabine and platinum, and I think we've had a lot of excitement with immunotherapy. And now I think we have a new standard of care after some 30 years, finally, which I think people will start using it and they'll learn how to use it better. I think it's very exciting to have a new standard of care for our patients, one that makes them live longer, too.

Alicia Morgans: Wonderful. Well, I really appreciate you taking the time to talk this through. I think the challenges that remain are how we really get this therapeutic combination out, not just in our academic centers, but how we educate our community, colleagues, and make sure that everybody feels comfortable using this, because I do think it's the new standard of care and so important as we engage in practice, even tomorrow. So thank you so much for your expertise.

Cora Sternberg: My pleasure, my pleasure.