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Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist at Vanderbilt University in Nashville, Tennessee. If you haven't been to Nashville lately, I think you should spend some time there. It's a wonderful city. We were fortunate to actually have Dr. Woodson Smelser. Woody is one of our former urologic oncology fellows. He's currently now an attending at Washington University in St. Louis, Missouri. And when he was a fellow here, he spent a significant amount of time putting together what's called an investigator-initiated trial. And it's actually focusing on immunotherapy in the upper tract, but I don't want to steal any of his thunder because really all the work and the credit goes to Woody. And so I'll turn it over to Woody. Woody, it's great to see you, great to catch up with you, and really excited about kind of what you started with this trial and hopefully what'll help answer. So I'll turn it over to you, Woody.

Woodson Smelser: Thank you, Dr. Chang. I appreciate the words of encouragement, and I certainly owe a lot to you in terms of not only developing this protocol, but just sort of overall mentorship in thinking about future ways to address these problems that are common in our clinical practice and sometimes frustrating. And we sort of get tired of not having great alternatives to the way we've always done things. And you've always pushed not only me, but other people that you've trained and mentored to sort of think outside the box. And almost you're sort of like a wizard that can predict the future about which way trends, particularly in urothelial carcinoma, are going. And so I owe a lot of credit to you for development of this protocol. So I appreciate you inviting me to talk about this trial that's going to be opening soon.

And it is going to be a multi-site trial. And we'll talk a little bit about the ideal patient that we're looking for and how we came to the strategy that we developed for treatment in this case. And with your permission, I've got a couple of slides that sort of outline what we're envisioning and what we're looking for with this trial and sort of how we got here.

This is going to be a trial utilizing pembrolizumab as a treatment strategy for patients who have high-risk upper tract urothelial carcinoma that's localized, but who either are unfit either medically or surgically or unwilling to undergo sort of the standard of care with radical nephroureterectomy. And you and I know very well from sharing tumor board together for a couple years that these patients are actually more common than one would expect just because there are a lot of folks that have been treated for urothelial carcinoma in different settings, or maybe they've had a cystectomy and they've had chemotherapy and they have chronic kidney disease, or maybe they just have medical kidney disease, or maybe they just don't want surgery, in whom the proposition of radical nephroureterectomy is really a non-starter. And so we face those sort of challenging clinical situations, and we've been looking for modern solutions.

So just in terms of disclosures, I am going to receive grant funding from Merck as well as drug for this trial, but I have nothing else relevant to disclose.

So when we think about how we got here, we know, as I'd sort of outlined, that localized upper tract disease is a very challenging entity. You have an elderly population, even statistically older than our typical bladder cancer patients. They have a lot of comorbid medical conditions. They have high prevalence of previously stated chronic kidney disease. And then because of their age and frailty, they have sort of an enhanced surgical risk profile.

We also know that they can get disease on both sides, either concurrently or metachronously. And that is a particular challenge. We know that 10% to 20% of these upper tract tumors are multifocal, and up to 5% of patients may even present with bilateral disease, which is particularly challenging if you're thinking about radical surgery. And then you can also be at risk again for metachronous development in the contralateral upper unit. And that may now be in the setting of a solitary kidney, which would basically relegate a patient to dialysis if you manage the contralateral side the way you had the original side. And so these patients are out there, and it seems like every month or two at tumor board, we have two or three cases like this, not only when I was at Vanderbilt, but now here at Wash U, where we're sort of scratching our heads about what to do.

So there's also kind of an evolution going on in our management paradigm. And you have been running a series really featuring and highlighting changes in upper track lately with UroToday. And we know sort of with the POUT trial that we do have data for efficacy of adjuvant chemotherapy, but the problem is that a lot of these patients are not eligible. And there've been some population level studies that show that as many as two-thirds of patients can't get cisplatin after a nephroureterectomy because of the deficiency in their kidney function.

And then, of course, that has led to sort of the debate that continues to rage on at every major meeting about the use of neoadjuvant chemotherapy in this setting and whether or not that might be a better strategy to use it up front, but to date, we still don't have level-I data.

And then I think another sort of subtlety in this is that the US at present doesn't have risk-adapted guidelines like those found in the EAU. Now, the EAU guidelines, strictly-speaking, would classify most of these patients we're going to be talking about today as high-risk and they would still recommend nephroureterectomy, but that sort of lack of nuanced guidelines leads to sort of some lack of personalization or management. And I know that the AUA particularly has an upper track guideline committee in place and is working on that. But at present, we're sort of left with one-size-fits-all management.

There has been a recent development, which is this use of mitomycin gel or Jelmyto based upon the OLYMPUS trial. But the problem is it's not FDA-approved for high-grade disease. And if you use endoscopic ablation alone as a strategy for control of high-grade disease, it has a very high failure rate. And when we look sort of at pooled results, recurrence-free survival is estimated at less than 30% at one year, and in some studies it's as low as 10%. So a lot of recurrence, which, of course, puts the patient at risk for progression as well.

But I think kind of another evolving management paradigm that's occurred in parallel is that in bladder cancer, we have seen some studies that have demonstrated mixed but promising results using IO agents in our treatment strategies sort of across all stages, not only in non-muscle invasive disease with the KEYNOTE trial, but also as adjuvant therapy after cystectomy and even in metastatic disease. And so that has sort of led us to think about ways in which we could integrate this into the management of upper tract.

Because of some of these trends that we've seen in bladder cancer with use of IO agents, we started to sort of think about the biology of upper tract tumors. And there's really minimal data that exist in use of these agents in localized upper tract. There was one small trial, the PURE-O2 trial, that was fewer than 15 patients that was biomarker unselected. So in other words, they didn't really look for PD-L1 positivity or anything like that, in which an immuno-oncology agent was given as essentially a neoadjuvant treatment. And their endpoint was a pathologic complete response at the time of nephroureterectomy. And this was actually a negative trial, but I think that's a very high bar to set. And it's still a little bit of a different strategy than we're what we're looking at in the trial that I'm going to talk about on the next slide, just because it really does not function in the strategy of organ preservation or kidney-sparing because they still ultimately took out all the kidneys in these patients, even after they were treated with IO therapy.

What we do know is that UTUC tumors do have high rates of microsatellite instability, which makes them susceptible to IO agents, particularly MSH2. And we know there's also the link with genetic syndromes like Lynch syndrome, which since patients are at risk for multifocal and metachronous development of tumors, this could be a particularly helpful strategy because organ-sparing may be paramount in those patients in whom UTUC actually starts decades earlier. And we have more decades of kidney function to try to protect. And then, of course, IO agents, particularly pembrolizumab, which is the drug that we're planning to use in this trial, have shown anti-tumor activity towards these mutations and other solid organ tumors like colorectal cancer and prostate cancer. And they've actually got FDA-approval in a couple of these spaces as a result.

So let's kind of get to the trial and the concept. The ideal patient, really, for this study would be a patient with high-grade, localized, upper tract urothelial carcinoma up to clinical stage II, who's either medically or surgically unfit or, as we discuss, unwilling to undergo the standard of care with nephroureterectomy. And our strategy would be that we would give them perioperative, and note that I choose that word carefully, because it's really not neoadjuvant because the goal here would be organ preservation, but we would give them perioperative pembrolizumab in IV form in combination with maximal endoscopic ablation for up to a year.

And I've enjoyed a couple of your segments you had on strategies for managing upper tract disease endoscopically. And I think all of those strategies would potentially come into play in this sort of trial, including potentially using antegrade access or using high quality digital scopes, using new types of lasers, et cetera. And I watched your recent segment with Drs.Kabuci and Luckenbaugh with interest because I think all of that's really relevant to this strategy. And, of course, since UTUC is a rare disease, this would require multi-site enrollment. And we have commitments from some of the highest volume centers around the country to help open this trial.

Our primary outcome would be a six-month complete response rate. And this outcome, we had a great debate, as you know, over the last couple of years, and we've spoken to multiple sort of thought leaders around the country about what to choose. But really, I think with high-grade disease, few of us would feel comfortable with anything less than a pretty significant response. And so we're defining this as no visible tumor at the primary disease evaluation, when we actually go back in and look endoscopically, and a negative ureteral wash cytology. And that's a fairly high bar, but I think, unlike with low-grade, where endoscopic management is pretty reasonable, it could be a high-risk proposition to continue ablation in the presence of either stable or increasing disease burden on subsequent ureteroscopy.

So this is a trial schematic, and this really tells you kind of everything that we're looking for. And you can see we've estimated, just based on historical response rates with endoscopic ablation, that we need about 68 patients for this single-arm trial. And this trial was a product of the Vail clinical trials course, which is an excellent course that's put on by the AACR and ASCO. And so that was really the main impetus for sort of developing the specifics of this trial as I took this trial protocol through the course to ultimately help develop this IIT. And so we've chosen a q6 week dosing strategy for pembrolizumab. There's not strong data that q6 week 200 milligram dosing or q4 week dosing is better. However, every time we've spoken to patients or patient advocates, they've said fewer infusions would be preferred and so we've chosen it basically for that reason. So we would give people, after enrollment, this pembrolizumab 400 milligrams IV. And they would essentially get two cycles and then they would undergo evaluation with ureteroscopy. And at that point, that's really where I think people are going to separate into two large groups.

You're going to have people who are complete responders, in which you don't see anything when you look in, cytology is negative. Particularly if they had a larger lesion, we're leaving it to the investigator's discretion about getting cross-sectional imaging with either CT or MR imaging to just make sure that no local nodes or anything have popped up.

And then you're going to have either partial responders, and those could be people in whom the disease burden is lower but the cytology is either negative, positive, or there's not any visible disease, but they have a positive cytology. And at that point, patients would basically have the option, with the consultation of their physician, to either continue pembro or move on to any other treatment choice, including nephroureterectomy.

And so, of course, the goal here is organ preservation as long as possible. And you can see that one of our endpoints, similar to the literature in bladder-sparing and trimodality, is actually nephroureterectomy-free survival. And the complement, obviously, in trimodality would be cystectomy-free survival. And so we sort of borrowed that from that strategy. And then I think there's also potential for some interesting collateral research here, looking at biomarkers, particularly in the area of circulating tumor DNA. So we have a parallel plan in place to analyze that throughout the course of the trial.

And I think really the last thing I'd like to mention is, when you see these IITs and large national trials, there's always a principal investigator listed, but really this trial would not be possible without input from dozens of people. And this is in no way an exhaustive list, but these are a few people who have helped me through my clinical trials development journey. And I just wanted to take a moment to sort of acknowledge their contributions through this entire process.

Sam Chang: Woody, I'll take the opportunity here to ask you a few questions now about the trial and where you see it going next. First, what would you consider to be the ideal patient here? Would this be someone with a single larger lesion, you think, or is it multiple lesions? Do you have any sense of kind of where you think you'd gain the most benefit or at this point you really don't know.

Woodson Smelser: I really don't think we know for sure. I think this is a little bit hypothesis-generating. I am a little worried about the very bulky patient with 2, 3 centimeter renal pelvis tumor, because I think that UTUC has proven in a lot of other studies to be a systemic disease, which just responds well to some systemic therapies. But we just don't know if this is sort of going to have the treatment potency that neoadjuvant or adjuvant chemotherapy has in sort of downstaging those sorts of patients. And as I kind of mentioned in that prior investigation with the PURE-02 trial, they were looking for that complete pathologic response and that was a negative study.

But I really think the patient who may be ideal for this is exactly like a patient I actually treated today before we put this recording together, who had two areas, one in the distal ureter and one in the renal pelvis, that were positive. He's had multiple biopsies that have shown that the renal pelvis lesion is low-grade, and he has one focal, less than 1 centimeter distal ureteral lesion that is high-grade. And he is vehemently opposed to radical surgical management. And he has a number of medical comorbidities that I think do put him at risk for decline in his kidney function with surgery. And so I think that's kind of the ideal patient here.

Someone who just barely is across the line as a high-risk is defined by EAU, in whom organ-sparing may have seemed like heresy 5 or 10 years ago, but now that we have potentially more tools in our arsenal to treat and prevent a systemic progression, this might be a good patient. I think the other patient is someone who's already been treated for upper tract on the contralateral side and now has a high-grade lesion. And I think we all have a deep groan of frustration when we encounter these patients that we've got a longstanding relationship or a new relationship with, and they develop kind of the worst case scenario, which is high-grade disease on the other side. So I think that would be another patient in whom there might be some value proposition here.

Sam Chang: So I know investigators, as you were putting this trial together, they would always be asking us, how's Woody's trial doing? Is it open? We want to get it out there. So as you've gotten funding support and as you go through the IRBs, give me a sense of your timeline of when you think patients will actually be able to be enrolled and how that process will take place.

Woodson Smelser: Yeah, so I think we've moved along quickly. Obviously, I've transitioned to Washington University, a new institution, but we've got a very robust infrastructure here. And my goal is to be enrolling the first patient by the end of the fall/early winter. And I think that's a pretty realistic timeline. I think, in terms of the lower overall prevalence of upper tract disease and the fact that this is a non-standard of care option, meaning we're not taking the standard of care, potentially adding the next best practice, it will take a little longer to accrue this trial. We've estimated it may take two and a half to three years with multiple sites. But interestingly, just as you've sort of related about other investigators that we've worked with, since I've started here, I've had multiple partners who said, hey, I've got a guy or I've got a lady who's had a cystectomy and has a solitary high-grade lesion, and they think that they would be a perfect candidate. So I think that these patients are there, and urologists are looking for innovative strategies to treat them.

Sam Chang: Woody, along those lines, I mean, you've focused on definitely a huge need in terms of nephron-sparing in this high-risk population. What other areas of interest, in terms of upper tract disease, do you find exciting in terms of research, in terms of future areas of need of research? Kind of what, at this point, is on your radar of further investigation or things coming down the line that may actually, in fact, be quite effective?

Woodson Smelser: ... are really exciting to me. And they're exciting, not only for me, but for patients. And I think one is just innovative ways to deliver drug locally. We've had a pretty abysmal experience, as you know well, with delivery of things like BCG into the upper tract so just really not that effective. But there's a lot of new technology that I'm hearing about from other UTUC researchers, where we're using biotech and potentially implantable devices, or in the case of mitomycin gel, like a reverse thermal gel, things that really just we didn't have the technology to do 10, 15 years ago. And now they're making their way out into mainstream practice, even beyond academic centers, but out into the community. And I think that's super exciting because they're new approaches to old problems.

And then I think the second area is in the area of sort of tumor genetics and tumor genomics. And we mentioned Lynch syndrome earlier. And just from when I started training in medical school till now our understanding of the association between upper tract disease and things like Lynch syndrome is so much greater. And now we're actually screening these patients. And so I've had to put together a new clinic SmartPhrase for when I actually meet a patient that sort of outlines my screening strategy. Because a lot of these patients have been diagnosed on colonoscopy, for screening for colorectal cancer, or because of cascade testing from a family member. And now we know they're at risk for UTUC. I think the fact that we have that knowledge now will allow us to leverage targeted therapies much the same way that we've done in kidney cancer. And just over the course of my training, there's probably been 8 to 10 new drugs approved in advanced and metastatic kidney cancer. And I think we're really on the cusp of seeing that same sort of boon for patients in upper tract.

Sam Chang: I agree with you, totally. I think this is really an exciting time for urothelial carcinoma, for upper tract disease in terms of options and in terms of the research going on. And it's research like yours that will actually help answer these questions and help our patients in the future. So, Woody, you have no idea how proud we are at Vanderbilt and how excited the, I think, urology field is with these types of investigations and trials and having an investigator-initiated trial by a urologic surgeon within a big drug that's been used by a lot of our medical oncology colleagues really speaks volumes to your future success. And so we look forward to the trial and its outcomes. And thank you for spending some time with us.

Woodson Smelser: Yeah, I appreciate it. And I miss the music and the barbecue already.

Sam Chang: Great. Fantastic. Well, come down soon.