Sam Chang: Hello everyone. My name is Sam Chang. I'm a Urologist in Nashville, Tennessee. And I am very fortunate to have Dr. Jason Brown, who's an Assistant Professor at University Hospitals at Case Western in Cleveland, Ohio. Cleveland Rocks, from what I've been told. And Jason will be speaking on a presentation that he had presented actually on behalf of a multi-institutional group looking at results of neoadjuvant combination therapy prior to cystectomy and nephroureterectomy. So Jason, thanks so much for being here and look forward to having you give us a review of the abstract that you presented.

Jason Brown: Thanks, Sam. So, as you know, standard of care for neoadjuvant chemotherapy and muscle invasive bladder cancer and upper tract urothelial cancer is cisplatin based chemotherapy for patients who are eligible prior to receiving definitive surgery. Many patients aren't eligible for this treatment based on kidney function, possible neuropathy, hearing loss. And so those patients will go directly to surgery.

In this study, we had two cohorts, one for cisplatin eligible patients in which they received gemcitabine, cisplatin, and pembrolizumab, as well as for cisplatin ineligible patients, where they received just gemcitabine and pembrolizumab. We looked at as the primary endpoint, the PaIR or rate of down staging to why PT1, N0, or less.

Sam Chang: So basically better than muscle invasive disease, either no disease or non-muscle invasive disease?

Jason Brown: Exactly.

Sam Chang: Okay.

Jason Brown: Exactly. And to be eligible for consideration in the primary endpoint analysis, patients had to have received at least two cycles of pembrolizumab, and they could have received up to five in the study.

Sam Chang: Okay. Okay.

Jason Brown: And what we found was actually an excellent PaIR rate in both cohorts, 61% in the cisplatin eligible cohort, and 54% in the ineligible cohort. The no hypothesis, what we were expecting for it to be a positive study was 23% and 18% respectively. So that was quite exceeded by the results.

Sam Chang: Right. If you think historically about the SWOG data looking at neoadjuvant chemotherapy, you had response rates in terms of pathologic down staging around 40% with CR rates around 29-30%, if my memory serves me correct. So you're talking about 60% plus response rates with down staging to less than... So pretty impressive data. As you go through the data, I interrupted you totally, but I was struck by that's a pretty significant response. How did they tolerate the treatments?

Jason Brown: So, actually treatments were tolerated fairly well. So the most common grade three or higher toxicities were cytopenias, but that was typically due to chemotherapy. So for patients who receive cisplatin, we see that anyway. In terms of immune related adverse events, they're actually very minimal. The most common that we saw that was grade three or higher was elevated liver enzymes, and that was only in three patients. So overall is very well tolerated.

Sam Chang: And how did the pathologic invasive disease, the PaIR

Jason Brown: PaIR.

Sam Chang: Yes. How did that endpoint do for upper tract disease? For your nephroureterectomy? Did you have any nephroureterectomy patients?

Jason Brown: So, we had a few nephroureterectomy patients, but not enough where we went granular into that data-

Sam Chang: Got it.

Jason Brown: ... on terms of the numbers there.

Sam Chang: Got it.

Jason Brown: But on the whole, both the bladder cancer and the upper tract patients did well. The other notable thing with the study was actually the high number of T3 or greater patients enrolled. So looking at similar studies like BLASST-1 or 0617, what we saw was not that high a number of T3 or greater patients, whereas this had 42% of the cisplatin eligible arm and actually almost 60% in the cisplatin ineligible arm that were T3 or greater.

Sam Chang: And that was based on radiographic and slash clinical staging by the investigators?

Jason Brown: Exactly. Exactly. Exactly.

Sam Chang: Right. Did you have T3+ patients then respond in this way?

Jason Brown: So a number of the T3+ patients respond. We also saw similar responses in the survival analysis as well, which is actually what we're newly presenting at this meeting.

Sam Chang: Okay. And so the median number of the immunotherapy, the pembrolizumab dosage was five, if I'm... What are the next steps now? Are we going to see an overall survival difference or are we going to see a disease specific survival difference? What are we waiting on now in terms of results?

Jason Brown: Yeah, so we actually, today, presented the disease-free survival as well as the overall survival data. We saw about 80% relapse-free survival at 18 months in the cisplatin eligible cohort. And that was about 65% in the cisplatin ineligible cohort. Medium follow up for the cisplatin eligible cohort was 54 months, with planned up to 60 months. So we're actually pretty close on that one.

Sam Chang: Pretty close there.

Jason Brown: In the cisplatin ineligible cohort, we're still waiting on more data because the medium follow up at this point was about 29 months, as those were the latter patients to enroll in this study.

Sam Chang: So do you think, I know this is early, this was exploratory data, but do you think there's a possibility now that urologic surgeons have done a better job of integrating neoadjuvant chemotherapy. It took us, we're slow. We're not that smart. It took us some while. But we've done better with perioperative chemotherapy, undoubtedly. Will the next step be perioperative chemotherapy plus immunotherapy?

Jason Brown: So I think it could be. We're still waiting on results of some phase three trials, notably a KEYNOTE study that looks at pembrolizumab in cisplatin eligible patients, as well as the NIAGARA study, which is perioperative. The other thing that we're looking into is EV and pembro. That's made great waves in the metastatic setting that were presented at the recent ESMO meeting. But also there's a trial out there looking at that in the perioperative space as well.

Sam Chang: So Enfortumab Vedotin plus pembrolizumab, that combination seems to have gotten definitely a lot of steam in the metastatic setting, and we have to wait and see what happens in the neoadjuvant setting. That's great. Well, thank you so much for presenting on behalf of all your investigators. It looked like a multiple number of institutions that enrolled patients on this, and they need to be applauded and thanked as well. So thanks for all your efforts.

Jason Brown: Absolutely. I'm grateful to all the other investigators, the institutions, and most notably the patients and their families for their support on this study.

Sam Chang: Great. Thank you, Jason.

Jason Brown: Thank you very much.