Sam Chang: Hi, I'm Sam Chang. I'm one of the urologic surgeons at Vanderbilt University in Nashville, Tennessee. And we're very fortunate to have today Dr. Min Teo. Dr. Teo is an assistant attending at Memorial Sloan Kettering Cancer Center, and he focuses on medical oncology. And so Min, thank you so much for spending some time with us. You're going to be discussing the abstract presented at ASCO GU 2023, looking at actually, neoadjuvant ipilimumab and nivolumab, for patients who are about to go nephroureterectomy for upper tract cancer. So obviously, we've looked at perioperative chemotherapy for bladder cancer. Now, we've got some actually data from Memorial looking at neoadjuvant chemotherapy, and obviously we had the POUT trial for upper tract disease. Tell us about your abstract, and what you all have actually presented.

Min Yuen Teo: Hi. So Dr. Chang, thank you very much for the opportunity to have me here to talk about our ongoing clinical trial. So the trial they're representing at this ASCO meeting is looking at neoadjuvant immune checkpoint inhibition, with both a combination of nivolumab and ipilimumab in patients with high grade invasive upper tract urothelial cancer who are cisplatin ineligible.

Sam Chang: Okay, so cisplatin, not platinum ineligible, cisplatin ineligible.

Min Yuen Teo: Correct. Yes.

Sam Chang: Okay. So what'd you guys find?

Min Yuen Teo: So it was designed as a Phase II study. So it's assignment two stage design. So because as we do not know what's clinical activity from these agents in this disease setting, especially upper biologically, they're different from what we see in bladder cancer. So it's designed as two stage design. So here, we presented the results, the immediate pathologic outcomes for the first nine patients out of the 24 patients trial as a first step. So the original design was, if we see more than one pathologic complete response, which is the study primary endpoint, it shows then we'll determine that is this enough signal to move on to the second stage of design of this trial to complete the entire study.

Sam Chang: And so, these were then, at least clinically, what you all were thought, at least T2 disease, is that correct?

Min Yuen Teo: So correct, yes.

Sam Chang: Okay.

Min Yuen Teo: So as you know, and as many of us know who do the lower upper tract, the actual staging can be quite challenging. So we pretty much based the inclusion criteria based on all the existing cisplatin based clinical trial, including that which my colleague Jonathan Coleman and Dean Bajorin have been working on in the last 10 years, recently reported in JCO cisplatin eligible trial, as well as the ECOG trial. So of course, it's hard to 100% demonstrate the T2 status, but most of the entry requirement will be based on high risk histology or cytology with videographic or endoscopic evidence of tumor.

Sam Chang: Of basically tumors.

Min Yuen Teo: Correct.

Sam Chang: So that combination of, you definitely want to get, obviously, the high grade disease, just as you all have reported earlier in the JCO article-

Min Yuen Teo: Correct.

Sam Chang: ... looking at neoadjuvant chemotherapy, but then clinical evidence of real disease, T2 plus disease.

Min Yuen Teo: Correct.

Sam Chang: And so, for those first nine patients, what did you all find?

Min Yuen Teo: So of course with the very first concern would be safety, and especially if ipilimumab and nivolumab, we use the higher dose of ipi, the three milligrams per kilogram dose. And we find that most patients do tolerate very well, there's no new safety signal, there's no treatment related adverse events that led to significant delay in surgeries. And of the nine patients, all nine of them were able to get the surgery. We actually saw three pathologic complete response, which was a pleasant surprise. And we saw three additional patients with pathologic down staging, those three or had YPTA disease.

Sam Chang: Oh. So basically, so although perhaps a little bit of grain of salt, because you weren't positive that they were in fact invasive.

Min Yuen Teo: Correct.

Sam Chang: But at least we go from possibly or probably invasive to clearly not invasive following that therapy.

Min Yuen Teo: Correct. Yes.

Sam Chang: Did you see any radiographic changes in those patients as well?

Min Yuen Teo: So that is still undergoing analysis. Definitely in some cases anecdotally, because some of those were my own patients as well. I've seen some radiographic responses as well. Yeah.

Sam Chang: So what now? And so, you're reporting and reported on those nine patients, what next?

Min Yuen Teo: So because we saw more than one pathologic complete response, so we are moving on to the second phase of the trial, and with a hope of getting all 24 patients, in total, to a confirm the findings.

Sam Chang: And this combination of ipi and nivo, you all have used it obviously in the advanced setting for kidney cancer, et cetera-

Min Yuen Teo: Correct.

Sam Chang:... for high volume disease. So the fact that there were no surprises, you wouldn't expect surprises in the safety profile in these patients, correct?

Min Yuen Teo: No.

Sam Chang: Right.

Min Yuen Teo: I think the biggest challenge, we would not anticipate new safety signal.

Sam Chang: Right.

Min Yuen Teo: But the biggest concern is, if any one of them do get grade three or four side effects, how-

Sam Chang: Do we delay?

Min Yuen Teo: Correct. So that's always the biggest concern. And we didn't see any significant delay, in terms of time to surgery. And our median time from end of system, end of immunotherapy to surgery's less than two months is all within acceptable range.

Sam Chang: Hopefully, a safe time period.

Min Yuen Teo: Correct.

Sam Chang: Right. What is your strategy then as you start to enroll the rest of these patients? Just because odds are at some point, they're going to have grade three or more. Somebody's going to have a grade three or higher kind of adverse event, due to the combination, or whichever one that may be causing it. What is your strategy going to be in terms of delay, then we do straight to surgery? Do we delay and try to decrease dosage? How hard are you going to try to get the immunotherapy and weigh against the safety of, gosh, are we delaying a definitive treatment? What's your strategy with it right now?

Min Yuen Teo: Yeah. I think our top priority will be safety. And I've always been telling patients, the key thing is, we want to get them to surgery safely. If we do encounter bad enough side effects that it's interfering with the ability of that, we would rather abort subsequent doses, and get them fixed up and get them to surgery as soon as possible.

Sam Chang: Yeah, I agree with that totally. And I think that's the case, fortunately, with the majority of the neoadjuvant trials for bladder cancer, because there's, as you know, great number of those that the emphasis is, we're learning about possible beneficial neoadjuvant treatments.

Min Yuen Teo: Correct.

Sam Chang: But we can't sacrifice the possibility of lifesaving-

Min Yuen Teo: Correct, yeah.

Sam Chang: ... procedure. So by doing that, yeah, let's learn as much as we can, but we're never going to put the patient at risk. So I think that's really important.

Min Yuen Teo: Yeah.

Sam Chang: Go ahead.

Min Yuen Teo: Sorry. On the same point, okay, I know it's a fairly small number of patients, but just as a example, we do have one patient, patient number nine, who received two doses, and we have to drop the third dose because of a class that's a grade two event.

Sam Chang: Okay.

Min Yuen Teo: And we're like, okay, you have way too many grade two events, we are not comfortable, let's stop it and move on the surgery and get pathologic complete response. So we still do not know how much treatment do we actually need?

Sam Chang: Sure. Sure.

Min Yuen Teo: And the decision for three doses is, or is really based... In fact, a lot of this neoadjuvant immunotherapy trial, the duration of treatment, is really just a reflection of what we do with cisplatin-based chemotherapy.

Sam Chang: Right. I see. I see. And not necessarily maybe the biology of immunotherapy.

Min Yuen Teo: Correct.

Sam Chang: It's just a historical use of cytotoxics, this is what we've done.

Min Yuen Teo: Right.

Sam Chang: We've been at this limit for a response, et cetera.

Min Yuen Teo: Yeah. It's a time window where the urologic surgeon will be comfortable, and patient will be comfortable.

Sam Chang: Right.

Min Yuen Teo: And we are hopefully not missing a window for the surgery.

Sam Chang: Right. I think that's probably almost as important a question of when we can deescalate treatment, limit treatment, as much as it is in terms of efficacy. I think the surgeons are always concerned about the long term, say maintenance therapy, of do they really need say two years of immunotherapy, or a full year or with avelumab maintenance, you continue it, continue it, continue it.

Min Yuen Teo: Yeah.

Sam Chang: So it's hard to know exactly where that proper stopping point is.

Min Yuen Teo: Correct. Yeah.

Sam Chang: Are you following this? If we see a positive signal, and it looks like that this neoadjuvant regimen is safe, can be tolerated in the pre-operative setting, and that we may have similar results, what's the next step? Are we going to go multi-institution, are you going to go cooperative group? Are you going to tweak the protocol? What are you all thinking about next?

Min Yuen Teo: Yeah. I think that's definitely interesting to see. I don't think we have definitely fixed plan, the top plan, the next top next step is to get all, to get the trial completed. And if the signal persists, it's definitely worth expanding it to a larger multicenter setup. Or even as you said, call it cooperative group. And definitely for a rare and orphan disease like this, we definitely would need a multicenter-

Sam Chang: Sure.

Min Yuen Teo: ... approach to confirm the benefit, and hopefully potentially, practice changing.

Sam Chang: Right. Right. So a Phase II trial of that I think would be enough. Do you think though, that as you accumulate these patients, is there going to be a standard of care of gem/carbo as a neoadjuvant, or do you think the standard of care currently is in cisplatin ineligible, it's still standard of care is proceeding with nephroureterectomy?

Min Yuen Teo: Yeah. I think the question of carboplatin has caused a lot of contention among medical oncologists.

Sam Chang: Right.

Min Yuen Teo: Especially if extrapolating from the bladder data, the carbo based regimen has not really been that effective.

Sam Chang: As robust. Sure.

Min Yuen Teo: But POUT-

Sam Chang: That's a nice way of saying I don't think it really works. But, then we have the POUT data that-

Min Yuen Teo: Right. Yeah. So the POUT data is interesting. Depends on how one wants to look at the data.

Sam Chang: Sure.

Min Yuen Teo: It could be a sample size issue that the sub analysis or some statisticians say we shouldn't look at subanalysis at all.

Sam Chang: At all.

Min Yuen Teo: Right.

Sam Chang: Sure.

Min Yuen Teo: But I think right now, of course, if they're cis ineligible, definitely if they can get certain neoadjuvant cisplatin-based regimen, that would definitely be our prefer the project. I think a lot of groups would share the same thought. And if they still have high risk disease post surgery, and they can't consider adjuvant nivolumab per the Chapman data.

Sam Chang: Right.

Min Yuen Teo: But if they go for upfront surgery and they are cis ineligible, then I think it's a much bigger discussion. Should they go for nivolumab, or should they go for carboplatin? I think right now, there's no real answer. I don't think that's a real answer. There's a lot of-

Sam Chang: Sure.

Min Yuen Teo: I think this is where biomarkers like circulating tumor DNA and do get minimum residual disease may be useful.

Sam Chang: And maybe PD-L1 expression-

Min Yuen Teo: That too.

Sam Chang: ... in terms of who actually. I think helping to tease out those populations. And we'll take obviously, many more patients. But to have an idea of, perhaps this indicator would advocate say, the IO therapy as opposed to the chemotherapy.

Min Yuen Teo: Yeah.

Sam Chang: So I think, which I think this is a credit to your research. Every research project, everything that's put out there, if it raises more questions, and helps answer some of the questions that we have, it's a very successful project. So I applaud you, and the folks at Memorial, for all the work that I know has gone into this, and we look forward to the future results as well.

Min Yuen Teo: Thanks. There's one tiny, one comment I'd like to make as an interesting observation, because when we did this, when we are doing this trial, we tend to do a lot of isometric genomic analysis and genomic analysis, and especially upper track. One of the side question that always come up is, it's a big one of the, it's known as Lynch related syndrome disease.

Sam Chang: Sure.

Min Yuen Teo: And especially more recent data from other cancer types emerging, like rectal cancer and colon cancer, and with using immune checkpoint blockade in the neoadjuvant setting. So of nine patients, coincidentally, three of them has had a germline-

Sam Chang: H2 or some type of-

Min Yuen Teo: H1, yeah. In fact, two of them were picked up because of the enrollment of the study and the other testing.

Sam Chang: And that was in germline testing.

Min Yuen Teo: Correct. Yeah. So one of the three, one was known Lynch. She came knowing that she has Lynch syndrome.

Sam Chang: Sure.

Min Yuen Teo: And the other two was diagnosed because of this diagnosis.

Sam Chang: A germline event. I see.

Min Yuen Teo: Correct. Yeah.

Sam Chang: I see. And two of those then were some of the complete responses then, is that what you're saying?

Min Yuen Teo: Yeah, they were all responders. So one had complete response, and two had YTPA. At least none of those with invasive vessel invasive disease had germline, what they call MSI high.

Sam Chang: Right.

Min Yuen Teo: So it definitely kind of ties in with what we have seen. Definitely supports MSI high status as a potential, a very strong biomarker for immune checkpoint inhibitor. Yeah.

Sam Chang: Which makes sense from the early data regarding any solid organ.

Min Yuen Teo: Right.

Sam Chang: Having that marker that, hey this, we have IOs that I can actually then be therapeutic, beneficial. It again, I think is just another step forward, as we attempt to improve our precision oncology.

Min Yuen Teo: Absolutely.

Sam Chang: Understanding what's going on, not only within germline testing, but perhaps somatic, in terms of actual-

Min Yuen Teo: Right.

Sam Chang: ... mutations within how we're going to attack these tumors.

Min Yuen Teo: Yeah.

Sam Chang: So I think we're definitely making those steps forward, and the research that you all doing will definitely contribute to that. So Dr. Teo, thank you so much for spending some time with us, and good luck as we wait for future results.

Min Yuen Teo: Okay. Thank you very much. Once again, thanks for the opportunity to discuss our research here.

Sam Chang: Thanks.

Min Yuen Teo: All right.