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Zach Klaassen: Hi, my name is Zach Klaassen, a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined today by Dr. Andrea Apolo, who's a medical oncologist at the NCI. Andrea, thanks so much for joining us today.

Andrea Apolo: Oh, thank you for having me.

Zach Klaassen: So we're going to discuss your ESMO presentation looking at AMBASSADOR, and this is extended follow-up of previously presented data, even as recently as GU-ASCO 2024. So why don't you walk us through the background of this trial, the trial design, and some of the data that you presented at ESMO?

Andrea Apolo: Well, thank you so much for allowing me to present on the follow-up data for the AMBASSADOR study that I presented at ESMO. This is very exciting for us to have additional data, even though we presented the initial data at GU-ASCO, which is not that long ago.

We presented data that had a cutoff date that was over a year old by the time we presented it at GU-ASCO. So we do have extended follow-up available for the ESMO presentation.

Okay, so we'll start off with some background. As you know, muscle-invasive bladder cancer is an aggressive disease with high rates of relapse. And the AMBASSADOR study, when we initially presented it, had a significant improvement in disease-free survival in the primary analysis with 22-month follow-up.

So here, we report the extended 45-month follow-up of the intent-to-treat population. We also show data in terms of PD-L1 status and lymph node-positive disease. So this is the schema for the AMBASSADOR study.

This is a phase 3 randomized trial, open-label, multi-center, of adjuvant Pembrolizumab versus observation in patients with high-risk muscle-invasive urothelial carcinoma. So when we say high-risk, what does this mean?

Well, these are patients that either did not receive cisplatin-based neoadjuvant chemotherapy because they were not eligible or they refused and had PT-3 disease or higher, including lymph node-positive disease.

We also included patients with positive surgical margins. Or they received neoadjuvant cisplatin-based chemotherapy but had persistent muscle-invasive disease, positive lymph nodes, or positive surgical margins. The patients were randomized to receive Pembrolizumab versus observation with the dual primary endpoint of disease-free survival and overall survival.

So 702 patients enrolled. We did close the study a little bit early. We had 96% of the patients accrued because Nivolumab received FDA approval in this exact setting. So we didn't fully accrue, but we did accrue 702 patients, which, like I said, is 96% of the planned enrolled patients.

One of the issues was that because Nivolumab became FDA approved in this setting, a lot of patients withdrew consent from our trial who were already on the observation arm and went on to receive Nivolumab. We even had patients in the Pembrolizumab arm move on to receive Nivolumab.

So we do have a lot of unplanned crossover. The trial was not designed to have crossover, but we had a lot of patients go on to receive a checkpoint inhibitor off protocol or withdrew consent, and we don't have their follow-up. So that is an issue with the trial.

So again, in this presentation, I have the follow-up disease-free survival data at 45 months. And we see that Pembrolizumab continues to improve disease-free survival for patients in this setting, with a median disease-free survival of 29.6 months versus 14.2 months for the patients on the observation arm. So Pembrolizumab almost doubled the improvement in disease-free survival in this setting.

We also looked at the PD-L1 status. And again, this was very consistent with what we showed in the first presentation in that the patients who were PD-L1 positive by the combined positive score of 10% or greater, actually it was prognostic. They did better overall, and Pembro improved outcomes in these patients. But they also improved outcomes, actually, with a larger delta in patients who were PD-L1 negative when we look at the combined positive score.

So these findings again are very consistent with what we showed in the previous presentation in this extended follow-up now. We also looked at lymph node-positive disease. And just like we would expect, patients who had a lymph node dissection and had no positive lymph nodes actually had the best overall outcome, and receiving Pembrolizumab improved that outcome.

And we saw that patients who had N-1 disease did worse than N-0, and then if they were N-2 or N-3, they did the worst. But in all these settings, Pembrolizumab still improved the outcome in this exploratory analysis. And for fun, we looked at specifically patients with lower tracts.

So this is patients with bladder tumors, specifically bladder muscle-invasive disease, and we also included the urethra patients. And we saw that patients who had no lymph nodes did the best, had a great outcome.

And Pembrolizumab improved the outcome in these patients in terms of disease-free survival. And patients who were positive in terms of the lymph nodes had a worse outcome compared to N-0. But again, Pembrolizumab improved the outcome.

And again, for fun, we looked at the upper tract patients to see how these patients did. The numbers were very small, and this is all exploratory and it's hypothesis-generating. But we do see that again, Pembrolizumab did improve outcomes for these patients, whether they had no lymph nodes... They had a dissection and they had no positive lymph nodes, or they had a dissection and they had positive lymph nodes or negative lymph nodes.

So there was a group of patients that did not have the lymph nodes assessed. And for those patients, the findings were mixed in terms of whether there was a benefit with Pembrolizumab. Another thing that we did is we looked at common sites of metastatic disease where when the patients do have the recurrence, where are they recurring more commonly?

And we divided it by Pembro versus observation. And the more common sites of metastasis were the lymph nodes, and this includes the abdominal lymph nodes, most commonly the retroperitoneum, the chest, neck, most commonly the mediastinal lymph nodes.

And then of course, the pelvic lymph nodes followed by bone, liver, and lung. There were some interesting patterns. Again, there were more recurrences of course in the observation group. And a lot of this is hypothesis-generating and interesting to look at.

So in summary, adjuvant Pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in disease-free survival versus observation for patients with high-risk muscle-invasive urothelial carcinoma, with this extended follow-up of 45 months.

The subgroup analysis showed that the comparable DFS estimates with Pembrolizumab versus observation were true regardless of PD-L1 status or lymph node-positive or negative disease.

And metastatic recurrences were common in patients on the observation versus the Pembrolizumab group. Of course, they were a little bit more common in the observation group, and the common sites of metastatic disease included lymph nodes, pelvic lymph nodes, and lung, bone, and liver.

So based on the doubling of the disease-free survival and the manageable toxicity, this supports adjuvant Pembrolizumab as a therapeutic option in patients with muscle-invasive urothelial carcinoma.

And I wanted to end just by saying that this was a humongous effort through the cooperative groups, through the Alliance Cooperative groups, and all the other cooperative groups, including SWOG, NRG, ECOG, and ACRIN, who all helped enroll patients to this trial.

And helped us really own this data and be able to show all the data to investigators and to clinicians who treat patients with bladder cancer. So with that, I'll end. Thank you very much.

Zach Klaassen: Thanks so much for sharing that. Great follow-up data from the AMBASSADOR trial. A couple of quick follow-up questions. You mentioned that we have extended disease-free survival benefit. Now, are there plans for additional analyses to look at the overall survival benefit?

Andrea Apolo: Great question. So we, of course, plan to look at the overall survival. We haven't met the number needed of events for the final analysis yet. And one concern that we have is that even when we do meet the number of events—right now we're at about 80% of events—we may still not be able to answer that question because of all the confounding issues like the patients who went on to receive a checkpoint inhibitor on the observation arm.

And also a lot of patients withdrew their consent, so we don't have access to their overall survival. So that is a concern with this data set. But once that's available, we do plan to present the overall survival data.

Zach Klaassen: Excellent. Then one more final follow-up question. You mentioned in your trial that Nivolumab became approved. Obviously, it's great for our patients and options for us. How do we, at this point, post-ESMO 2024, put Pembro into context with Nivolumab in this disease space?

Andrea Apolo: So that's a great question because Nivolumab is a treatment option for our patients right now in this setting. So what this study would add is that Pembrolizumab is also an option. Right now, I give Nivolumab or I give Pembrolizumab in the adjuvant setting to our patients.

And the nice thing about Pembrolizumab, although in the trial we gave it every three weeks, there is an FDA-approved option of giving it every six weeks. So that is really nice in the adjuvant setting to be able to provide that alternative schedule for patients.

And we see that in terms of disease-free survival, it's very effective and the data looks very similar to what we see with Nivolumab in terms of disease-free survival.

Zach Klaassen: Excellent. Maybe just a couple of wrap-up questions or comments for our listeners, some take-home messages?

Andrea Apolo: So I think that it's really nice that we have this data showing such robust disease-free survival benefit in patients receiving adjuvant Pembrolizumab. To me, I view this as a stepping stone for what is next in the perioperative setting.

This trial is so important because there are many trials ongoing right now that are building on the work that we have here and that we have done in a metastatic setting too, and moving a lot of these treatments to earlier stages of disease and using biomarkers to select patients.

But having this data as a backbone to compare it to is going to be really important. So combination therapies are being developed and I think that although this treatment is active, some patients need more therapy, the ones that do need it. But there's a large number of patients that don't need any therapy and we're over-treating.

So selecting those patients with biomarkers will be really important. And those trials are ongoing, and I'm excited to see what the next phase of treatment outcomes will be from clinical trials that are being done right now using Pembrolizumab as a backbone.

Zach Klaassen: That's great. I think it's been a great couple of years for metastatic urothelial carcinoma. We're starting to see it in the adjuvant setting. And as a surgeon, having these options for patients when we see them post-op is excellent. So thank you again for sharing your AMBASSADOR data from ESMO, and we appreciate your time and expertise.

Andrea Apolo: Oh, my pleasure. Thank you for having me.

Zach Klaassen: Thanks.