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Sam Chang: Hello everyone. My name is Sam Chang. We are here at GU ASCO 2024, and we're quite fortunate to have Dr. Andrea Apolo from the NCI, who will be focusing her discussion today on a late breaking abstract looking at adjuvant pembrolizumab. So Andrea, thank you so much for being here, and obviously, everyone's always excited to hear about the late breaking abstracts, cutting edge, data that's just come out. So tell us a little bit about what this trial involved, who were the patients' eligibility criteria, and then obviously we want to get to the results.

Andrea Apolo: Thank you for having me here. I'm really happy to be discussing the AMBASSADOR study. This is a cooperative group study run by the alliance, but it's also intergroup, so it has the other cooperative groups also in there. It's the study of adjuvant pembrolizumab versus observation in patients with muscle invasive urothelial carcinoma. So I'll say that patients with muscle invasive urothelial carcinoma, it's a very aggressive disease and the relapse rate is very high, and the standard of care is neoadjuvant chemotherapy. And then patients undergo radical surgery. But a lot of patients cannot undergo neoadjuvant chemotherapy or they're not fit to undergo their cisplatinum ineligible. So then you have patients that go on to radical surgery.

And at that point, when the trial was established and when it started, there was really no options for adjuvant therapy. If they never received neoadjuvant chemotherapy, they could have received it in the adjuvant setting, but it's hard to give platinum-based chemotherapy in the adjuvant setting. So the question was can we give these patients one year of adjuvant immunotherapy in order to improve outcomes? And that was one of the rationales for initiating the study. So the study was designed as an open label multicenter study. It's randomized phase three where patients with muscle invasive urothelial carcinoma and the muscle invasive could be bladder urethra, renal pelvis, ureter-

Sam Chang: So upper tract as well?

Andrea Apolo: ... upper tract as well. Those patients, they could have received neoadjuvant chemotherapy and be greater than PT2 lymph node positive or positive surgical margins, which is kind of a unique eligibility criteria that we had or not have received neoadjuvant chemotherapy and be at least PT3 or greater lymph node positive or positive margins and have undergone radical surgery within about four to six 16 weeks. So that was the key eligibility. And then we also stratified the patients based on a PD-L1 status based on neoadjuvant chemotherapy.

Sam Chang: Received or not?

Andrea Apolo: Right, right.

Sam Chang: Okay.

Andrea Apolo: And the pathologic stage. All right. And patients received one year of pembrolizumab versus observation and the endpoints, the primary endpoints were dual primary endpoints of disease-free survival and overall survival.

Sam Chang: Both. I see. Okay.

Andrea Apolo: And we did have the secondary endpoint of PD-L1 status, so the DFS and the OS based on the PD-L1 status. Of course, we have a lot of correlative science also including ctDNA, which we did not present at this meeting.

Sam Chang: Okay. So tell us about the results.

Andrea Apolo: The study was positive. It met the primary endpoint of disease-free survival. The patients that received pembrolizumab had a median disease-free survival of 29 months versus 14 months for the observation arm.

Sam Chang: So almost double, basically double.

Andrea Apolo: Yes, yes.

Sam Chang: In terms of disease-free survival.

Andrea Apolo: Yes.

Sam Chang: I see. And how about overall survival?

Andrea Apolo: So overall survival, it was the interim analysis. We did not yet complete all of the events needed for the final analysis, and it did not meet the endpoint for overall survival.

Sam Chang: At this point?

Andrea Apolo: At this point but the data continues to mature for the final analysis. The hazard ratio was 0.98.

Sam Chang: Got it. And so with that disease free interval that basically the doubling with the adjuvant therapy, that was with one year of Pembro, when you looked at the data as it accumulated side effect profile, obviously there's going to be a bit of a difference, but did many have to discontinue, et cetera? How did people do on the one-year following radical cystectomy?

Andrea Apolo: Yeah, so that's a great question. I think Pembro in general was really well tolerated. The most common side effect was fatigue, pruritus, things that we see, hyperthyroidism. It was generally well tolerated. I mean, these treatments are not without side effects, so that's something to consider. But generally there was no new safety signals or any concerns with the one year of pembrolizumab.

Sam Chang: And then was it once every three week dosing or once every six week dosing?

Andrea Apolo: Every three week dosing.

Sam Chang: Three week dosing. And so when looking at this of a significant difference, when you look at disease-free survival findings, interim analysis, and now we're in this environment of, okay, what do we give these patients? How do we treat these patients? Where does it now stack up? What do you think is going to happen?

Andrea Apolo: Oh, it's a great question. We do have nivolumab now that is approved U.S. FDA approved for the treatment of adjuvant therapy. And the data looks exactly the same as the pembrolizumab data. So I think pembrolizumab can now become an option too, to be given in the adjuvant setting.

Sam Chang: Maybe too early and maybe the numbers aren't big enough. But tell me, did you see differences in the upper tract versus the primary urothelial? That's the first question. The second question I'm going to ask you is about those positive surgical margin. If you saw any glimpse of data that suggests that this may be helpful in those patients.

Andrea Apolo: So for the upper tract tumor, the cohort was small. There was no limit to the number of patients with upper tract enrolled. The study enrolled about 20% of upper tract urothelial carcinoma. And there was no difference in DFS between the patients that received pembrolizumab.

Sam Chang: Interesting. Okay.

Andrea Apolo: So I think that cohort really needs to be better explored because I would expect there to be a benefit in these patients with upper tract disease. Although we have seen similar data before, these patients tend to have deficiency in mismatch repair. They tend to be MSI high. So you would think that they would have a great response. I think a lot has to do also with that these patients, there's no standard for lymph node dissection for these patients. Some of them get lymph node dissection, some of them don't. And that can be not only diagnostic, but therapeutic too. And I think that has something to do with it in terms of how we stage it and where they fall into the pathologic stages. But I think we really need to further investigate why these patients did not-

Sam Chang: At least at this point.

Andrea Apolo: At least in this small cohort, we didn't see the great benefit we saw with the bladder primary.

Sam Chang: And then hopefully small too, the positive surgical margin. Did you see any signal? Or hopefully you'll tell me and you'll say, well, there were just only one or 2% of positive surgical margins.

Andrea Apolo: 2.5%.

Sam Chang: So that's encouraging news. And then so it's too small probably perhaps to say that there's a difference between the combination.

Andrea Apolo: But actually the hazard issue was very impressive and it did look like there was a benefit, although wide, definitely it looked like patients benefited from adjuvant pembrolizumab.

Sam Chang: For those with positive surgical margins?

Andrea Apolo: Yes.

Sam Chang: So at least dictum from a surgical standpoint is of all the risk factors we know node positive, et cetera, but positive surgical margins from our standpoint, clearly puts those patients at risk for almost guaranteed recurrence in some way.

Andrea Apolo: And we don't know what to do with them. Right?

Sam Chang: Exactly.

Andrea Apolo: That's also...

Sam Chang: Exactly, so that's why I find this really helpful in that you're right, this was usually an exclusion from other trials. We don't know what to do. Is it adjuvant? Is it salvage in a sense because we've left disease behind? Is it measurable, is it not? And so the fact that there was at least a signal and that these were actually studied, I think a very important initial first step. So that's great. So as we looked at the landscape, looking at iOS in the adjuvant setting, do you think as you look at the data, the neoadjuvant chemo versus the no neoadjuvant treatment were last question regarding differences. Did you see a difference? Was there advantage if they hadn't seen neoadjuvant or were they, again, too small to compare? Tell us about that comparison.

Andrea Apolo: They actually both benefited. So whether they received neoadjuvant or not, both groups benefited from the adjuvant pembrolizumab.

Sam Chang: So today in patients that undergo radical cystectomy at this point, standard of care, if there are high risk patients, just as you outlined the lymph node positive, the positive surgical margin, T-3 plus disease, et cetera, those patients should at least be offered some type of adjuvant therapy. Don't you agree?

Andrea Apolo: I agree with that. And I think it's important to discuss with them the data we have, the disease-free survival benefit, that's pretty large. And the overall survival benefit is not mature yet. And I also think that there was a lot of crossover. So a lot of patients in the observation arm did go on to receive nivolumab or other checkpoint inhibitors.

Sam Chang: Right, right. Because the trial was going on as... Absolutely.

Andrea Apolo: Right. And that actually the trial was closed a little early after it accrued only 96% of the patients as opposed to a hundred because nivolumab became approved as adjuvant therapy for the same indication, muscle invasive urothelial carcinoma.

Sam Chang: Right. So for clinical equipoise for overall medical ethics, you've got to do. So if anything, you hate to conjecture, but if anything, perhaps actually the curves may be even wider in the fact that these patients that were the control patients may have actually or did receive additional therapy.

Andrea Apolo: That's right.

Sam Chang: Andrea, one of the reasons that, and you've led the program committee for urothelial carcinoma in the past through the late breaking abstracts, are the ones that we consider important, really important in terms of the next steps for standard of care. So thank you so much for spending some time with us, and thank you for helping to lead this effort doing any cooperative group trial takes just as you said, a lot of effort from a lot of different-

Andrea Apolo: And perseverance.

Sam Chang: ... individuals and patience. Exactly, exactly. And strength of character, all those things. So we want to say thanks and congratulations, and we look forward to the overall survival date as well.

Andrea Apolo: Thank you.

Sam Chang: So thanks again.

Andrea Apolo: Thank you so much for having me. I appreciate it.