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In this exclusive roundtable video from 口袋女优, three expert leaders in the field of bladder cancer discuss the latest emerging data presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU).

Moderator , of the Icahn School of Medicine at Mount Sinai in New York City, is joined by , of AdventHealth Cancer Institute in Orlando, and , also of the Icahn School of Medicine at Mount Sinai, in this second of four episodes, in which they discuss the various combinations available in the neoadjuvant setting.

Following is a transcript of their remarks:

Galsky: Hi, my name's Matt Galsky from the Icahn School of Medicine. Welcome to this roundtable on bladder cancer news from ASCO GU 2023. I'm thrilled to have with me Dr. Guru Sonpavde from Advent Health Orlando and Dr. John Sfakianos from the Icahn School of Medicine at Mount Sinai.

So we spoke about adjuvant therapy in bladder cancer. So let's talk about neoadjuvant therapy. Neoadjuvant therapy, arguably the standard of care. Cisplatin-based chemotherapy has shown a survival benefit in two randomized studies. Part of all practice guidelines. But certainly there is room for improvement there. And so there's been a number of studies trying to move immune checkpoint blockade into the neoadjuvant setting, either by itself or with cisplatin-based chemotherapy.

Guru, can you tell us a little bit about the data so far and what we know, what we don't know, with concurrent chemotherapy plus immune checkpoint blockade?

Sonpavde: Right, so in the neoadjuvant setting, immune checkpoint inhibition has looked promising. So single-agent PD-1, PD-L1 inhibitors have been examined showing path CR [pathologically complete response] rates of around 30%, 35%, sometimes 40%. And similarly cisplatin-based chemotherapy, cis/gem [cisplatin plus gemcitabine], and actually once redosed it's MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), and cisplatin] combined with the various PD-1/L1 inhibitors have looked promising. But it's not clear that it is clearly better than combination chemotherapy alone. The path CR rates with the chemo-IO [immunotherapy] approach have been in the 45% range. The less than pT2 rate has been in the 60% range, approximately.

But I think we need to wait for phase III trials, which of course are ongoing. In a cisplatin-based setting the cis/gem plus/minus various PD-1/L1 inhibitors, nivolumab [Opdivo], pembrolizumab [Keytruda], durvalumab [Imfinzi] is being looked at.

And in cisplatin-ineligible patients, there are immune checkpoint inhibitor-based treatments. And also interestingly, EV/pembro [enfortumab vedotin (Padcev) and pembrolizumab] approach, which would be, I think highly promising in this space in both cis-ineligible and cis-eligible settings.

Galsky: And Guru, you're running a trial in that space with carboplatin-based chemotherapy, is that right?

Sonpavde: That's right, Matt, so we have a randomized phase II trial going on at SWOG and Intergroup. This is in cisplatin-ineligible patients. The trial was planned some time ago, so this is comparing in both upper tract and bladder muscle-invasive disease, no neoadjuvant therapy, which is standard. So going to upfront surgery in the standard arm versus carbo/gem [carboplatin and gemcitabine] plus avelumab [Bavencio] in the experimental arm.

The difference is there is not an upfront stratification for PD-L1. So it's a user/patient-friendly approach, a quick neoadjuvant therapy or surgery, and then the adjuvant component is not mandated to be anything, so the physician can decide to do adjuvant nivolumab or just observe after carbo/gem/avelumab.

Galsky: John, you've operated on patients, you've had single-agent immune checkpoint blockade neoadjuvant therapy, combinations of antibody-drug conjugates, chemotherapy plus immune checkpoint blockade. Any concerns from an operative standpoint about getting these drugs in the neoadjuvant space?

Sfakianos: Yeah, thanks, Matt. I mean, thanks to partnering with you, we've had a lot of different clinical trials. So we have operated, like you said, on all these various combinations of patients who received these various combinations. And honestly speaking, I really don't see any difference. There hasn't been any, at least substantial, delays that I can think of for combination chemotherapy plus checkpoint. And we don't see any differences in outcomes -- morbidity or mortality -- after doing these procedures on the patients. So I think from getting patients to surgery after these neoadjuvant combinations, I really don't see any concern from the surgery standpoint.

So very promising data, really exciting time ahead. But to just echo Guru's point, I'm not sure how well these are going to do compared to standard chemotherapy in these large randomized trials. So we'll wait and see.

Galsky: Yeah, I think those trials are going to be really interesting, because I think we're banking on these path CR endpoints as being appropriate for these combinations. And I think that's one consideration. I think the other consideration is that the adjuvant component, which obviously isn't reflected in the path CR is going to drive the time-to-event outcomes. And that could certainly make a difference. Even if you don't see a benefit in the path CR endpoints, you might see these long-term benefits, and some of that might be driven by what's given in the adjuvant setting.

Sfakianos: I have to agree 100% with that. I think it's more about what's given in the adjuvant/maintenance setting that I think really is going to help the survival benefit even without the path CR in the neoadjuvant setting. There are some exciting maintenance- or adjuvant-type studies that are ongoing with combinations that I think are the ones that I'm most excited to see what the readouts are, rather than the path CRs for the neoadjuvant setting.

Galsky: And there seems to be this emerging theme. You see this with switch-maintenance treatment in the metastatic setting, in the subgroup analysis. In CheckMate-274, you see a larger effect size in patients who receive neoadjuvant chemotherapy. So maybe this sequential approach with chemotherapy followed immediately by immunotherapy is doing something special.

Watch episode one: Updated Results on Adjuvant Immunotherapy in Muscle-Invasive Bladder Cancer

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