Read the Full Video Transcript

Ashish Kamat: Hello, everyone, and welcome once again to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and it's a distinct pleasure to welcome to this forum, once again, Professor Andrea Apolo from the NCI, who's joining us today to talk about something that she talks so well about, which is the care of patients in bladder cancer. Today, Andrea, thank you for taking the time and spending it with us today. You're not only going to talk about what you normally do, which is groundbreaking research and practice-changing paradigms, but actually going to tell us a little bit about the panel at the recently concluded Think Tank and how you and your panel address and view these issues when it comes to bridging evidence to practice implementation and that whole science. So with that, Andrea, take it away.

Andrea Apolo: Thank you so much for having me. This is wonderful to be able to talk about the Bladder Cancer Think Tank, which is a meeting that we have yearly to really talk about everything bladder cancer, from what the evidence is, what the latest science research is, to clinical trials, to patient care issues. So it's a really great meeting. And at this meeting this year, 2024, we had a panel called Bridging Evidence Generation to Practice in Bladder Cancer with Implementation Science. And this was a really fun discussion where we talk about there's all this evidence out there, is it being used and followed by the practitioners who take care of bladder cancer patients?

And here is basically the panel that we had. We talked about what is implementation science. We talked about what is the data for bladder cancer surveillance cystoscopies. We talked about implementation of tobacco cessation programs. I talked about disrupting the paradigm of first-line therapy in metastatic urothelial carcinoma and talked about all the new data that are out in metastatic urothelial carcinoma with new treatments, specifically EV + Pembro based on the EV-302 data presented at ESMO and how this has affected the guidelines, and are people using it.

And then there was another talk on bladder cancer implementation using the NCCN guidelines. So it was really nice to hear how the NCCN guidelines themselves get modified with the new data that is out there. So that was a really fun panel. So I'll just jump into my talk, which again, is on metastatic urothelial carcinoma, and it's part of the discussion that I did at ESMO. And I was discussing two abstracts that were presented, the EV-302 and the CheckMate-901 studies, and I'll talk about what those are.

So just to start off with pre-ESMO, this is pre-2023 ESMO, the standard of care for metastatic bladder cancer had always been platinum-based chemotherapy at baseline. Are the patients cisplatin-eligible? Are they not? If they are cisplatin-eligible, then they got gem-cis or a dose of MVAC. If they weren't, then they got gem-carbo. There was a small group of patients that couldn't get platinum-based therapy and they would get checkpoint inhibitor, then they would go on to second-line checkpoint inhibitor, either as maintenance, or if they didn't respond then directly to treatment as second-line with checkpoint inhibitor. There were the options of enfortumab vedotin as a second- or third-line agent, erdafitinib in patients that had FGFR4 alterations, sacituzumab govitecan as another agent and of course, second-line chemotherapy also with Paclitaxel, Docetaxel, and of course, always a clinical trial.

So let's talk about one of the abstracts, which was the EV-302 study. This is a randomized Phase 3 trial of patients with metastatic urothelial carcinoma that randomized patients to receive enfortumab vedotin + Pembro versus standard chemotherapy, platinum-based chemotherapy. And I have here the progression-free survival slide where it shows that it doubled the progression-free survival. It also doubled the overall survival and really significantly improved the overall response rate. So this data was presented at ESMO, and it has since been published in the New England Journal of Medicine. It really has changed the way we treat patients with bladder cancer.

Now this was presented at ESMO, which was in October of 2023. The FDA approval came a little bit later in January. And another abstract that was presented at ESMO was the CheckMate-901 study, so I'm going to show you a slide from that study. That one was a combination of gemcitabine, cisplatin plus nivolumab versus just gemcitabine and cisplatin. And this is the overall survival curve here. And there was an improvement in patients who received the triple combination, the chemotherapy plus the checkpoint inhibitor, that was statistically significant.

Now of course, as a discussant, I wanted to compare what is out there and what are the overall responses of patients that we have who received platinum-based chemotherapy. So I took the control arm from the IMvigor130 study, and then I looked at the overall response rate when atezolizumab was added. I looked at the KEYNOTE-361 study, which is the addition of pembrolizumab to platinum-based chemotherapy. Then I looked at the EV-302 study. The overall response rate was 68% for patients receiving the combination of EV + Pembro, and in CheckMate 901, the overall response rate with gemcitabine, cisplatin and nivolumab was 58%. So both of these new combinations in these new data that were presented showed an improvement in overall survival compared to other studies that have been presented and standard platinum-based chemotherapy.

Now, when we look at the overall survival curves together, so we look at the gem-cis-nivo compared to cis-gem by itself or EV + Pembro, we see that the combination of EV + Pembro is superior. Now we're comparing across trials, but the population was similar except that the EV + Pembro also included carboplatin-treated patients in the control arm. And the overall survival of EV + Pembro was almost 32 months, 31.5 months. So as the discussant, I gave the prize to EV + Pembro as the first-line treatment for patients with metastatic urothelial carcinoma. So this is the new standard of care, EV + Pembro. The overall survival, the progression-free survival, the overall response rate all were superior to what we have seen in prior studies and with platinum-based chemotherapy by itself.

So you would think, so this is great. This is working. This is working so well, everybody is using it. Well, the FDA saw this data, and they approved EV + Pembro as full approval in the first-line treatment of metastatic urothelial carcinoma. And the standard of care has now changed. The standard of care—we no longer give platinum-based chemotherapy in the front-line setting. EV + Pembro is the new standard of care. And also just so the audience is aware, the gemcitabine, cisplatin and nivolumab, although it had a lower overall survival, it did meet its primary endpoints, so it also received FDA approval in March 2024, but with the caveat that it's a little bit tricky; if EV + Pembro is not available, then this is a good option. Is nivolumab maintenance another option? Possibly yes, which has been the standard of care as platinum-based chemotherapy followed by a checkpoint inhibitor maintenance. Nivolumab has Phase 3 data. So is this better than nivolumab maintenance? We don't know the answer to that, but it is a treatment option if EV + Pembro is not available.

And that's what the new guidelines show. So we have EV + Pembro now has made it, and all the guidelines, or many of the guidelines, have been updated now to include EV + Pembro as the primary treatment for patients with metastatic urothelial carcinoma. And we also have the EAU guidelines that include this, and gem-cis-nivo is also included there if EV + Pembro is not available. And then we have the ESMO guidelines have also been updated to include EV + Pembro. So the guidelines have been updated. There is, however, still a slow uptake in the community, especially in the general oncology community where these are not subspecialized oncologists. They're still learning to incorporate enfortumab + Pembro in the treatment of metastatic urothelial carcinoma. So it's an evolving attempt to change the practice for our patients with metastatic disease. So that's all I have. Thank you.

Ashish Kamat: Thanks so much, Andrea. And of course, as you might know, it was also approved just last week by EMA, right? So it was approved.

Andrea Apolo: EMA, yeah. Now it's available in Europe, which is really terrific.

Ashish Kamat: Absolutely. So one of the things that you talked about at the Think Tank and one of the things that is actually the mission statement of the International Bladder Cancer Group, and we partner with UroToday, is how do we take these developments that you have and these groundbreaking, practice-changing developments, and how do we now get it to be applied, A, in countries where it's available? So in North America, why is it not changing the standard practice? So that's question number one. And question number two is in countries where it's not available or it's just too expensive, how do you recommend that population, that government or that funding agency that's looking after poorer people who are not as fortunate, how do they look at such approvals and guidelines, and how should they then tailor their local advice to their patients? So two separate questions, if you don't mind answering those.

Andrea Apolo: Yeah, no. So the first question really applies to us here in the United States. It's available. We have robust data showing that this improves overall survival. Why isn't it being given 100% to patients with all the patients diagnosed that are eligible? There may be some patients that may not be great candidates for EV + Pembro, but I think it's education of the practicing oncologist or practitioner. And I think it has to do also with the fact that there's just so many new drugs being approved, and it's hard to keep up with all the new changes in the guidelines. So number one is have the guidelines been updated so people can look up, my patient has metastatic bladder cancer, what should I give them?

EV is only approved in urothelial carcinoma. So medical oncologists that treat other cancers and don't treat that much bladder cancer are not familiar with EV yet. So it takes a little bit of a while for uptake for the practitioner to become familiar with the toxicity, how to modify the regimen. It takes time, and I think education and continuing repetition of this as a standard of care, making things available for the practicing oncologist is going to be key to implementing and making sure that this regimen, in particular, is being used for our patients.

That's the first question, right?

Ashish Kamat: Sure. Just to follow up on that first question, do you have any high-level advice for people that are listening to this? Because obviously it's a selected audience that's listening to this. Would you recommend that there be more grassroots, like educational echoing, where folks like yourself have webinars and seminars and get people to understand what the impact of this regimen is on patients? How would you approach that educational aspect?

Andrea Apolo: I think exactly like you said. There's continuing education seminars where practitioners can get updates as to what the new standards of care are, what the data looks like. When you look at the data, it's super impressive at how well patients do with this therapy. What are the toxicities? How do I manage these toxicities? That's really important in order for people to feel comfortable using this, especially in frail patients. How do I dose modify? What are the most common side effects, and how do I work around these? These are all things that take time for people to become familiar with and for the guidelines to update this and make it available, make it available as much as possible for the practicing physician.

Ashish Kamat: And now if you could put on your international hat because I know you do travel internationally and lecture internationally too, what about countries where this is not yet available? How would you recommend their guidelines, committees or their advisory groups look at data such as these and are looking at potential approvals, number one? Or number two, even if it's approved, then how do you factor in the cost and cost in a poorer country, for example?

Andrea Apolo: No, this is a big issue. These drugs are very expensive, and now you're talking about two different drugs, and the cost is an issue. And are payers going to pay for this? Are patients going to pay for this? Are countries going to be able to support this kind of care for our patients with advanced disease? There's so many layers to being able to provide these new drugs outside of the United States or where it's approved, or now in Europe, it is approved. It's still difficult to get reimbursement, and sometimes private insurance will pay for it, but the public system won't pay for it. So there'll be a lot of disparities in terms of the treatments that patients receive. So it's an issue, and there's not one clear way of going about it. There are all different barriers to getting treatments available, but I think cost is a big issue.

So if companies that have effective drugs can make it available at a reduced cost in locations where the healthcare system can't afford to pay for these drugs at the cost that they are now. And honestly, I think that the cost should be negotiated here in the United States too, but that's a whole other issue, but especially in areas where patients just can't get it because of the cost. This is really improving the overall survival of patients significantly from the therapies that we used to have. Of course, if you don't have it, then you give what we used to have, and we had platinum-based chemotherapy followed by immunotherapy either as maintenance or second-line treatment.

And that's been approved for years, and it's taken a long time for it to get implemented and making it available for patients. If there are clinical trials available, that's always a great opportunity. If practicing physicians have access to clinical trials with novel drugs that include these medications, that's one way of getting them. But I know that's very limited and not always available for everyone.

Ashish Kamat: That's a hard problem. And one thing that we've done when we work with governments, for example, in South America or in other parts of the world where they don't have that many resources, is to try and make recommendations on how to best allocate their healthcare dollars.

So let me put you on the spot for a moment here real quick with a closing question. You did that comparison and you gave the award to EV-Pembro. But say you are advising a relatively not quite as wealthy country, and you say, "Here we have EV-Pembro with this success rate, but you could treat 100 patients, or you have gem-cis-nivo with this success rate, and for the cost you could treat 1,000 patients." Do you factor that in when you're making recommendations to a country, not individual patients, but healthcare policy-wise, would you factor that in?

Andrea Apolo: I think you have to, because you have to look at how much is this going to cost the entire public system to be able to support 10 patients or 100 patients versus 1,000 patients? I think these are really difficult decisions that have to be made. So I would say you have to. If it's not available and it's just the cost is prohibitive, then you have to go with the next best therapy available.

Ashish Kamat: I think that's where panels such as what you participated and led at the Think Tank is really useful. Because again, we have to factor so many things, and sometimes it's something that we wish we could change, but you can't. The realities of life and the realities of governments and countries not being able to afford X number of dollars at the cost of treating one patient compared to 10 patients. So really tough choices. And we're fortunate in the United States, we don't have to think about that that much. But I think, as you rightly pointed out, we have to be good healthcare dollar stewards across the board before we bankrupt everybody, right?

Andrea Apolo: Yeah. And the cost of a lot of these therapies, especially with combinations, is so high. So we have to, even within the United States, find ways to modify those costs.

Ashish Kamat: And that's a whole other topic. I won't take more of your time this time. Thank you so much, Andrea, for taking the time and spending it with us. Always a pleasure chatting with you.

Andrea Apolo: Oh, my pleasure. Thank you for having me.