Sam Chang: Hi. My name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee, and I have the opportunity to be joined with a real star in our field of urologic oncology. Hristos Kaimakliotis is an associate professor at Indiana University, and he shared at the SUO 2025 winter meeting some very important findings in a late-breaking abstract session, looking at perioperative treatment options for muscle-invasive disease. And the presentation he's going to share with us really, I think, may change actually the way we treat patients with muscle-invasive bladder cancer. So Hristos, thank you so much for spending some time with us, and we look forward to your presentation.

Hristos Kaimakliotis: Thank you. Thank you, Sam, for the kind words, and I'll take a few minutes just to summarize a little bit about KEYNOTE-905 on the primary efficacy and surgical details of the study. As I shared at SUO, for the purposes of the publication and presentation, we're focusing on the two arms, comparing upfront cystectomy in patients with muscle-invasive bladder cancer who are cisplatin-ineligible or declining, compare them to neoadjuvant enfortumab and pembrolizumab, receiving three cycles, followed by radical cystectomy and six cycles in the adjuvant setting. The primary endpoint for this study was event-free survival, which was defined as any progression of disease, any recurrence, or any death from any cause. Key secondary endpoints here that we studied were overall survival, pathologic complete response, and adverse and safety profiles.

About 170 patients were enrolled to each arm, of which 150 eventually made it to surgery. Important to note here that there were no delays from last dose of neoadjuvant enfortumab and pembrolizumab to the cystectomy, with a median time from last dose to surgery for about five weeks. There is really no difference in the baseline characteristics between the two groups with about 60% of patients having a creatinine clearance anywhere from 30 to 60. The adverse event profile for preoperative enfortumab plus pembrolizumab was very manageable, centering around skin toxicity and very similar to what has been reported in the literature from previous studies in patients in the advanced setting in bladder cancer. There were no differences in the types of surgery that was offered, whether laparoscopic, robotic, or open, type of lymph node dissection, or urinary diversions, with about 20% of patients receiving continent diversions.

This plot shows the complications at time of surgery, and it's encouraging to see that enfortumab plus pembrolizumab did not confer any increased risk of surgical complications. It was very exciting to note that the Kaplan-Meier curves for event-free survival separated early and remained separated in the long-term with immediate event-free survival not reached in the treatment arm and 15 months in the control arm, with a hazard ratio of 0.4 and a significant p-value of less than 0.001. Median overall survival was also not reached in the treatment arm and 41 months in the control arm with a hazard ratio of 0.5. Pathologic complete response rate was also tremendously increased from 8.6% in the upfront cystectomy group to 57% with neoadjuvant EV plus pembrolizumab, and this was a conservative estimate as patients who were noted to have a complete clinical response after treatment and chose not to undergo surgery were considered as non-responders.

So to conclude, preoperative or neoadjuvant EV plus pembrolizumab followed by cystectomy and adjuvant EV pembrolizumab meaningfully and significantly improved event-free survival, overall survival, and pathologic complete response without impacting the ability of these patients to undergo surgery or time to the OR, with a very manageable safety profile and no increased risk of complications. So very encouraging to say that KEYNOTE-905 is a first phase 3 study to show an improved efficacy with preoperative therapy compared to upfront surgery in patients who are cisplatin-ineligible, and offering a new treatment option for this patient with a high unmet clinical need, and also recently approved by the FDA as treatment for this patient population. So with that, Sam, I'll take any questions as this is a very exciting time for patients in this cohort.

Sam Chang: I think everybody would say these results are very impressive. The differences in the event-free survival, the differences in overall survival, and the differences in pathologic complete response rate. Never seen numbers like this before, so let's start with that pathologic complete response rate. Almost 60% of patients at the time of cystectomy had no evidence of disease, and you mentioned that that doesn't actually even account those that had a clinical CR that did not go on to cystectomy. Do we have any idea the percentages or rough numbers regarding that population of patients?

Hristos Kaimakliotis: Yes. So about 15 more patients out of the 150 that eventually received neoadjuvant therapy declined surgery based on the clinical response on CAT scan. So a conservative number of 57% that was reported, perhaps add another five to 10% at least. There's some follow-up of those patients with cystoscopy and TURBTs to ensure that they were disease-free, and it's very encouraging to see them maintain their bladders without recurrences.

Sam Chang: Yeah. So just as you were conservatively, let's say half, 5% of those in fact are true pathologic CRs, you're talking a greater than 60%, a significant change in the paradigm for sure. Let's talk about how patients did. We saw that the adverse event profile really wasn't that significantly different. As a treating physician now, I've got a patient that we've diagnosed with muscle-invasive bladder cancer. Let's say they truly are cisplatin-ineligible. We'll keep them within the FDA criteria, so that's, I think, an important point that you mentioned at the end. This regimen is now FDA approved as a treatment option for those patients that are cisplatin-ineligible. Let's take the scenario where we have that patient. Tell me a little bit about the time course. How difficult is it? We see the adverse events. Tell me overall how patients do with the perioperative initial neoadjuvant treatment.

Hristos Kaimakliotis: So when I describe this to patients, I definitely put in perspective the toxicity profile compared to chemotherapy. So chemotherapy, for some patients, it's not as hard to tolerate, but it's definitely not a walk through the park for a lot of our patients. But comparing it to standard chemotherapy dose that's MVAC or GemCis, this is a lot easier to tolerate. Immunotherapy, we've seen over the last few years, much, much easier to tolerate. Enfortumab vedotin adds some neurotoxicity, and patients who obviously have neurotoxicity are excluded fortunately from this trial, but it is very manageable for this patient population. This is a frail patient population, but they do very well with pembrolizumab and EV.

Sam Chang: Yeah. I think as we educate not only urologists, but medical oncologists who may have a general practice, who in fact may not be familiar with enfortumab vedotin, a little bit different kind of risk factors, dose adjustment may be necessary in terms of that neurotoxicity, neuropathy, et cetera, but clearly a medication that has incredible efficacy and relatively quickly being able to see the efficacy. So time for some provocative questions, Hristos. This is what we're facing already at this point. We give neoadjuvant EV pembrolizumab, the combination therapy. Patients say, "Okay, how do my scans look? What do things look like? Okay, everything looks great. I want you to take a look inside my bladder, evaluate it, biopsy." Okay, you do that. Everything is negative. We may even get circulating tumor DNA. That's really not even discussed in this, but say everything's negative. The patient goes, "I don't want you to take out my bladder. I don't want you to do anything." What do you do at this point? Because we're starting to get that question.

Hristos Kaimakliotis: Well, even before we go to the bladder... Well, I'll start with that. So it's unbelievable to see such tremendous responses. We've never seen responses like this with chemotherapy, and I think pathologic complete response of 60% is really a big testament. So patients will ask this. "Why did you take out my bladder?" And we do have to take a step back and look at that and maybe assess, is this an opportunity to truly engage in a bladder preservation protocol under a clinical trial, doing it the correct way, safely? Reassess with the TURBT imaging, whether it be CT scans or MRIs, circulating tumor DNA, which is not perfect but is an additional tool in our armamentarium to safely say, "Can we truly preserve this patient's bladder?"

And there are clinical trials underway currently, so we're participating in one such trial, and anecdotally, we are seeing 60% long-term being two years where we're able to preserve bladders without recurrence. Another 20% of patients are undergoing cystectomy within that first year, and another 20% may or may not lose their bladder at two years with early recurrences. As part of the protocol, any recurrence, whether Ta, CIS, or T1, we proceed with cystectomy, but maybe there's a role for intravesical therapy after early superficial recurrences. So it is really a brave new world in patients who have a complete clinical response with pembrolizumab EV, and whether or not bladder preservation is really in short reach.

Sam Chang: Yeah. I think some really important points you raised, Hristos. Very much so, one, the idea of not proceeding with cystectomy is a very attractive idea, but we need to understand that the results of this trial were dependent upon actually cystectomy, following through with this cystectomy, following through with treatment afterwards. Secondly, being able to evaluate this on a trial, just as you and your institution is doing, I think is very, very important, because it'll help us answer that question with evidence as opposed to, yeah, that sounds good, that makes sense, et cetera. So I think being able to identify then with more data who really is a pathologic complete responder that truly does not need bladder removal I think will be really, really important.

But it's a very new and exciting time, and I think it's really important that urologists as well as medical oncologists who are seeing patients with muscle-invasive bladder cancer need to understand that, wow, our paradigm for cisplatin-ineligible, and obviously studies are undergoing for cisplatin-eligible, but for cisplatin-eligible patients, the role of this combination therapy really has changed the paradigm, just as you mentioned. So Hristos, thank you so much. We look forward, I would love to get you back and give us some of the early data regarding the idea and the rationale and the eventual results of, "Hey, we have a clinical CR, what do we do now with these patients?" That would be really important and I think really, really interesting to those patients who currently are in this situation, so thanks again and really appreciate the excellent presentation you gave at the SUO this past winter.

Hristos Kaimakliotis: Thank you. I appreciate you taking the time to talk about this, and very exciting time for our patients going forward.