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Sam Chang: Hello, my name is Sam Chang. I am a urologist in Nashville, Tennessee and I work at Vanderbilt. And today we have Wesley Yip. Wesley is a former resident, graduated from the residency program at USC, and is a fellow at Memorial Sloan Kettering Cancer Center. And he is the lead author of one of the late-breaking or breaking abstracts, short rapid abstracts is I think what they call them, in a session here at GU ASCO in 2022. And so, I want to thank Wes for being here today. And Wes, your abstract focuses on the use of neoadjuvant chemotherapy prior to nephroureterectomy, and it's a topic that I think has gotten a lot of interest because we know that there has been a shift in terms of the possibility of the benefit of adjuvant chemotherapy following nephroureterectomy. Tell us a little bit about the accrual, who you enrolled in the trial, what situation, the chemotherapy regimens, and we will start with that.

Wesley Yip: Thanks, Dr. Chang, very excited to be here. So this trial has been going on for a very long time. I think it took actually over 10 years to finally finish because upper tract urothelial carcinoma is a relatively rare disease. Prior to this trial, there weren't any prospective trials looking at neoadjuvant chemotherapy. Over the course of the trial, the landmark POUT trial came out showing the benefits of adjuvant chemotherapy.  But we also know that after a nephroureterectomy, really not that many patients are eligible for chemotherapy, it comes down to about 15% of patients who are left can get cisplatin-based chemotherapy. So we wanted to look at neoadjuvant chemotherapy to try to treat these patients prior to surgery. And most of the endpoints of this trial were developed based on what we've seen in bladder cancer.

So the trial regimen used gemcitabine cisplatin as a split dose, so 1,000mg per meter square of gemcitabine on days one and eight, and 35 of cisplatin on days one and eight also, because we've seen in bladder cancer that this split dosing has similar efficacy, but is better tolerable for more of these patients. So patients on this trial had to have high-grade disease on biopsy, which defines a high-risk population, or they could have imaged with T2 to T4 disease and positive selective cytology if they couldn't have a high-grade biopsy. They could not have any metastases and had to be able to receive cisplatin-based chemotherapy, so we had criteria of eGFR greater than 55, Karnofsky performance status over 70%, and then, of course, no prior hearing problems or cardiac dysfunction.

Sam Chang: So, anything that would exclude them from getting cisplatin.

Wesley Yip: Yes, cisplatin. That's correct. Exactly.

Sam Chang: And then were patients with previous bladder cancer also excluded from this trial or not?

Wesley Yip: If they had non-muscle invasive disease or if they just had it surgically resectable, not by cystectomy, but by TUR, bladder cancer that was allowed in the trial.

Sam Chang: I see. And only unilateral obviously as opposed to bilateral?

Wesley Yip: Yeah.

Sam Chang: Okay, great. And so how do the patients do with this kind of regimen?

Wesley Yip: So they actually did really well overall.  In the trial, there were 57 patients who were evaluable for the primary endpoint. All of them proceeded to surgery.

Sam Chang: And the primary endpoint was...

Wesley Yip: So the primary endpoint was pathologic response and that was defined as less than PT2, N0 disease. That was defined based on prior bladder cancer studies, showing that those with pathologic response still have similar outcomes to those with complete. And we also know for the upper tract, which is dissimilar to the bladder, we can not just resect all of the superficial disease first, it's just not possible in the upper tract. So the primary endpoint was a pathologic response of less than PT2 disease.

Sam Chang: Got it. Okay.

Wesley Yip: So over the course of chemotherapy, the patients actually did very well. 89% received at least three cycles of chemotherapy, so I think only six patients received less than the three cycles.

Sam Chang: So, and the goal was three cycles?

Wesley Yip: The goal was four cycles.

Sam Chang: Goal was four cycles.

Wesley Yip: So 47% received all four cycles and then 42% received at least three, but most of those actually received three and a half. So they just missed one dose for some reason.

Sam Chang: I see. And the rationale behind that was again, similar to neoadjuvant data from bladder cancer?

Wesley Yip: Bladder cancer.

Sam Chang: I see. And so tell us about the results.

Wesley Yip: So the results were very exciting in that we met our primary endpoint. So the pathologic response rate was 63% and then the complete response rate, so PT0 N0 was 19%. So we are very happy about that. And some of the secondary endpoints were survival outcomes. So that was another exciting part of this study, is that we do have longer-term survival data. Among survivors, the median follow-up was about 3.1 years. And the two and five-year progression-free survivals were 78% and 65%. But then when we broke it down, we looked at patients who have less than PT2 disease or even complete responses, it was even better. So the two-year progression-free survival for complete response with 91% and 95% if they had a partial response and 52% for the non-responders. So those who had pathologic responses did a lot better. 

Sam Chang: They showed a big difference.

Wesley Yip: Yeah, exactly.

Sam Chang: So, and you may not know this, but of those that had the pathologic CR, the 19%, with the majority of those patients, were the biopsy papillary tumors found, or were they evenly split with a T 2, 3, 4 with the positive cytology

Wesley Yip: That I'm actually not sure. I mean, the vast majority of patients did have biopsy high-grade disease. I think it was 53 patients, 53 or 57 who had biopsy...

Sam Chang: The biopsy-proven high-grade disease.

Wesley Yip: Exactly.

Sam Chang: And at the time of nephroureterectomy, there has always been discussion, what about the no dissection that accompanied it?

Wesley Yip: So this was actually mandated in the protocol that they needed a templated lymph node dissection. So for the upper tract, I mean in the renal pelvis tumors, those ones would go with the ipsilateral renal hilar nodes, and then for the right side, para-caval left side para-aortic, intra-aortic cables were up to the surgeon if they wanted to or not. And then there were a couple of patients who had distal ureteral tumors, so they also had a pelvic lymph dissection on that side.

Sam Chang: Understood. And any of those patients, so obviously there is always a concern when we do a neoadjuvant treatment that we are delaying definitive treatment. Did any patient develop nodal disease that was positive in this trial or not?

Wesley Yip: No. Well, not over the course of chemotherapy that we knew about. So we did have, I think it was six or seven patients who were N+ disease, but not on CT scans prior. So we had no known progression of the disease.

Sam Chang: I see. So nothing that basically prior to nephro-U, no one developed enlarged nodes that had-

Wesley Yip: Yeah.

Sam Chang: Understood.

Wesley Yip: All patients enrolled went to surgery.

Sam Chang: And then in terms of the next steps, do you all have any idea, there are 57 that went through this regimen, how many ended up not going through the regimen?  It's easy or it's actually really difficult, either way, you can look at it in terms of a retrospective study of actually what happened. What is the true denominator?  So do you have any idea at all looking at Memorial's databases?

Wesley Yip: In terms of how many-

Sam Chang: How many actually underwent nephroureterectomy without neoadjuvant treatment?

Wesley Yip: That I actually do not know. We are compiling that experience. We're actually looking over the last 24 years to see, but in terms of who had neoadjuvant and who didn't, I don't know, because you would expect yes. A lot of patients cannot. I mean, I think it's 40% of upper tract patients will have CKD3 at baseline. So that's already almost half of them who can't really go through this. So I'm sure there are a lot, I don't know.

Sam Chang: So where do we go next, Wes? What is the plan here? What are we going to do at Memorial?

Wesley Yip: Well, I think that this is a standard of care option for patients who can tolerate it, and it also sets a baseline benchmark for future trials of other types of therapies that we can compare to. And it takes a long time to accrue these kinds of studies in the upper tract especially, but at least we have something that we can use as a baseline for others going on.

Sam Chang: And then do you think that as you contemplate kind of the next step in terms of neoadjuvant therapy?  Is there anything that interests you in terms of, obviously all these combinations are being looked at for bladder, in terms of radical cystectomy, is there anything that you know of on the horizon, looking at combined therapy for nephroureterectomy prior to or in combination with GEM/CIS?

Wesley Yip: I know there are a bunch of these IO trials combining neoadjuvant chemotherapy and pembro, for example. And some of them have small subgroups that include upper-tract patients in them. But I think the numbers are so small and the patients are heterogeneous. It's pretty hard to really pinpoint which ones would do well.

Sam Chang: So, a patient comes into Memorial, has good kidney function, healthy otherwise, no contraindications, has a high-grade renal pelvis tumor that we don't see any suspicion for metastatic disease. They come in to see a surgeon and a medical oncologist at Memorial.  What does that patient get in terms of their treatment regimen? Is it neoadjuvant as suggested by this trial or is it nephroureterectomy and then proceed with adjuvant as suggested by the POUT trial, in terms of evidence and treatment gains using adjuvant therapy? What do they get at Memorial?

Wesley Yip: I think they get a very informed discussion amongst both parties that are very closely involved, everyone talks together very well, and then they talk to the patient of course, about the pros and cons of those things. If the patient really were leaving it up to the treating physicians, then we would probably recommend neoadjuvant chemotherapy, and then also extirpative surgery afterward, just based on the trial results from this, and also a chance that maybe they can't tolerate neoadjuvant chemotherapy later on. If their other kidney that's remaining is not as good, we don't really know, but of course, we just get an informed discussion of all of this data prior and then-

Sam Chang: Fantastic. Where are you guys going to go next in terms of your next study?

Wesley Yip: Ooh, next study, I think is starting to look at some of these upper tract patients in these combination therapy trials, and then trying to see what we can take out from those of where we can go. And we've also looked at some of the genomic biomarkers in this subset of patients, but that data, we don't have too much of it yet. We only have so many samples [crosstalk]

Sam Chang: Because it's really difficult with the biopsies, the amount of material you have. So it will be interesting to look at if you had anything from the PT0s, it would be really helpful obviously to see what would be, what actually would happen versus that...

Wesley Yip: A couple of them had ERCC2 mutations that had profound responses. So in the presentation, I shared pictures of a pretty bulky tumor that is completely resolved after chemotherapy and was a T0. There were only two patients that had that. I think we had maybe 23 tumors that we had sequencing on. So it's small, but there are some promising.

Sam Chang: And that would fit along with the data that you all, as well as Fox Chase have in terms of who is more likely to respond to platinum-based therapy. So, well, Wesley, I'm very excited about your future, you've done great work and obviously, your training's been excellent. So looking forward to seeing great things from you in the future as well.

Wesley Yip: Thank you so much.

Sam Chang: So thanks for spending some time with us.

Wesley Yip:  Thanks.