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Zachary Klaassen: Hello, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by Dr. Joaquim Bellmunt, who is a medical oncologist at the Dana-Farber Cancer Institute. Today, we're going to be discussing Dr. Bellmunt's SUO 2024 presentation, looking at IMvigor011 study surveillance analysis, specifically looking at DFS and OS in patients with high-risk muscle-invasive bladder cancer who have persistent circulating tumor DNA-negative biomarker status after cystectomy. Dr. Bellmunt, thanks so much for your time and for joining us on your show today.

Joaquim Bellmunt: Thanks, Zach, for the introduction. It was a pleasure to present this poster. This was December 4, 2024, during the 25th Annual Meeting at the SUO. And here, you can see the poster. So this analysis, I would like just to start from the very beginning about the story of the ctDNA.

So I was the PI of the IMvigorO10 trial. And this trial was an adjuvant trial where immunotherapy was compared with observation in patients after cystectomy or for being high-risk muscle-invasive bladder cancer. This trial, unfortunately, was the only one of the three trials that immunotherapy didn't show a benefit. So we know that we have the AMBASSADOR and we have the nivolumab trial—those are positive for PFS. And this trial using atezolizumab didn't show any benefit on disease-free survival.

However, a retrospective analysis of this IMvigorO10 did show us that, analyzing the ctDNA based on the Signatera Natera platform, we saw that the ctDNA was prognostic. Meaning that patients having high ctDNA before starting or after the cystectomy had a poor outcome. And the interesting observation was that in those patients whose ctDNA was positive, if they were assigned to receive atezolizumab, there was a positive benefit in terms of survival and progression-free survival.

And this retrospective analysis of prospectively collected ctDNA in this trial—this was published in Nature—meaning that it was really relevant data. And then, obviously, in this trial, atezolizumab was negative, given in this adjuvant high-risk population. And we said, well if there is a benefit in patients with a ctDNA positivity, why not design a trial specifically using ctDNA as a biomarker, where patients can be selected based on that to receive adjuvant atezolizumab versus observation?

Obviously, this was designed at the time that nivolumab was not approved, and we didn't have the results of pembrolizumab.

Obviously, this trial, fortunately, has completed accrual now, meaning patients having ctDNA positivity were randomized to atezolizumab or observation. Now, likely, it would not be ethical to do this type of randomization, but as mentioned, it was designed at the time that I mentioned.

This is what is called the IMvigorO11 trial. So this is not the first one. That was the IMvigorO10. The IMvigorO11 is selecting patients who are ctDNA positive to receive, in a randomized way (two to one), atezolizumab or placebo. So what we present in this poster is patients that were not assigned to be randomized, meaning patients whose ctDNA was negative.

And the important thing of this presentation is that we only included in this analysis patients that met the criteria to be included based on the criteria shown in the poster. So 144 completed ctDNA surveillance and continuing radiographic evaluation. And then, we only included those patients that had a median follow-up of a sequential ctDNA determination for a year.

Patients needed to have one year of follow-up, no signs of recurrence, and have had at least two samples where the ctDNA was negative. And I think that the important thing here is that in this figure, Figure Four, we see the disease-free survival in these ctDNA-negative populations, where these patients have had several sequential follow-ups. The median follow-up of this cohort is 16.3 months, and these patients have had more than one ctDNA negativity.

And after this median follow-up, we see that the disease-free survival in these patients is 88%, meaning that having sequential negativity of ctDNA is telling us that these patients are likely not to recur. So obviously, this is an exploratory analysis from the IMvigorO11, but this surveillance cohort is suggesting that serial—and this is one of the conclusions here—that serial ctDNA testing using these Natera assays may have greater clinical utility than the landmark ctDNA testing. We knew that in patients receiving neoadjuvant, a single determination is prognostic, and obviously, based on these O10, predictive. But this has been testing sequentially, patients with the ctDNA platform of Natera Signatera. Within this ctDNA-negative population, the status selected patients for favorable clinical progression and prognosis. And this was regardless of the PD-L1 status and the pathologic staging at cystectomy.

So this analysis, as mentioned, is an exploratory analysis of a trial that has completed accrual. This is not reporting the final results of the IMvigorO11. It's that disease in this arm of surveillance where patients were not included in that trial. So these data increase the confidence that patients with persistent negative ctDNA status after cystectomy may be spared from receiving adjuvant treatment.

And also, in this poster, we see this was already presented at the European Urological Association in 2024. So the new results here is the overall survival: we can see here 98% of patients being alive at 18 months. So obviously, the benefit in the disease-free survival is translating in overall survival. And we didn't see an impact, as I mentioned, of the PD-L1 status, meaning that, as mentioned, these are the patients not receiving immunotherapy. This is a surveillance cohort.

Just to explain a bit more, what is the Natera assay? Because sometimes it's important just to know what we are talking about. So the Natera Signatera is a platform where, in the very beginning with that, the tumor of the patient and the normal cells, the germline DNA, we design a platform of 16 specific mutations—tumor-specific. This is a bespoke assay, so these need to be customized, and it's made for each one of the patients.

In the beginning, we sequenced the tumor and the germline. And then, we create these 16, let's say, mutation-specific findings, and we create a PCR for the follow-up, meaning that you need to do sequencing in the beginning, and then, with a qPCR test, we are sequentially monitoring these patients. And this is what this trial is presenting. So it seems that ctDNA is a tool that will help us to identify patients that likely don't need adjuvant treatment and identify patients with good prognosis.

Zachary Klaassen: Wonderful. Great presentation. I really enjoyed your background of how this trial came to be about. I think that's really important for setting the stage. So just a couple of questions just to dig a little deeper into some of the points you made. From a patient standpoint, if a patient is sitting in clinic and they have their landmark ctDNA, that ctDNA is negative, how are you counseling these patients about how the next 12 to 24 months are going to go?

Joaquim Bellmunt: Well, initially, as mentioned, nowadays, I believe that we cannot yet use this tool to select patients to say, OK, you need to receive adjuvant. And it's still a disease clinical trial, so we need to learn more about that.

But obviously, I have now patients, for example, that I'm using the ctDNA to monitor after receiving even adjuvant therapy. So it's a way to say, well, this is reassuring, or that based on the pathologic findings, we haven't identified high-risk features. And you do this follow-up meaning, the ctDNA is more and more—there is emerging information that is able to predict patients that are going to recur.

And we know that because we have seen patients where we see an increase in the ctDNA. And this is predicting in three months or six months in advance, until we capture the disease progression on imaging.

We cannot make decisions based on the ctDNA nowadays, but I believe that the field is advancing and emerging. Now, there are even trials that are using the ctDNA just to select the specific type of therapy. Meaning, if you don't have ctDNA positivity, maybe you don't need to receive neoadjuvant. So that is a question that is arising nowadays.

Obviously, the platform is sensitive and specific, but is not 100% sensitive and 100% specific—highly sensitive. In fact, this platform is using these 16 mutation-specific genes, those are truncal mutations. So those are highly prevalent during the evolution of the cancer. But still, obviously, we see here that despite that, there were these patients with a negative ctDNA, 88% were disease-free, meaning that there were still some patients—12%—that did recur despite having negative ctDNA.

Zachary Klaassen: And that's a great lead into my next question. We could look at this two ways. 88% no recurrence, which is fantastic. Among those 12%, as we sit here in 2025, are there other biomarkers or other ways of perhaps predicting who these 12% of the patients are?

Joaquim Bellmunt: Yeah, so I think that that's a great question. As mentioned, the field of ctDNA is emerging, and the platforms are improving. So even this same Natera platform, I know that the company is trying to improve the sensitivity of the test. And obviously, there are different people talking about the ctDNA. Well, ctDNA is what you need to define which type of ctDNA.

ctDNA stands for circulating tumor DNA, and this could be captured with this platform. But there are others that are capturing using a targeted panel of sequencing mutations, and it could be even more than 16. It could be specific that Natera Signatera platform is not telling you which type of gene is being seen in this patient. It's not like other platforms, like Guardant, that you can say, well, this patient has an FGFR3 mutation. And we know that there is methylation. We know that the methylation patterns are highly specific over different tumor types. So there are platforms of cDNA that are using methylated DNA methylation as a way to capture that the tumor is floating around in the blood.

Zachary Klaassen: Absolutely. I think you already alluded to this a little bit, but just to go a little further in—let's just take the next five years, maybe 10 years—where do you see ctDNA really coming into our clinical workflow among patients with MIBC, whether it's neoadjuvant or adjuvant selection, or even metastatic disease? How do you see this field evolving over the next several years?

Joaquim Bellmunt: Yeah, that's really an interesting and difficult-to-answer question because, fortunately, the field of bladder cancer is improving. We now know that we have also immunotherapy in the neoadjuvant setting. And that we have the NIAGARA trial that is positive, meaning giving chemo and immunotherapy.

We have several other perioperative trials whose readout is going to come up quite soon, maybe in a year, where we are giving antibody-drug conjugates plus immunotherapy, and then followed by adjuvant. And this is going to change exactly the landscape, the way that we are treating perioperative patients with bladder cancer. But still, the cDNA will need to be integrated.

And the fact is that now, all the trials that are being designed in this setting are collecting ctDNA to understand a bit more what the specific role of the ctDNA is going to be. As mentioned, in the therapeutic perioperative setting, it still is a good marker for follow-up of patients. But now, people are even thinking about why not use that in patients who are responding to the new chemotherapy or chemoimmunotherapy as a potential bladder preservation strategy?

So there are trials evolving in this perioperative but also in the metastatic setting. Patients that you have a complete response radiographically speaking, sometimes we can follow these patients with this platform and maybe detect early recurrence or in switching from regular imaging to a PET-CT to capture earlier the return. So I think that this world is going to expand, and more and more platforms, with better sensitivity, will come up. And for sure, it's going to be pretty attached to our treatment decision-making.

Zachary Klaassen: Yeah, absolutely. It's been a great couple of years for urothelial carcinoma, and I know you highlighted several important disease spaces. More data coming in the next year to two to three years. So we're excited about that. And I think your point about the ctDNA being collected—we're going to learn more about how this reacts to neoadjuvant treatment and adjuvant treatment. So great discussion, Dr. Bellmunt. Any final remarks for our listeners today?

Joaquim Bellmunt: No, I think that we need to pay attention. The field is changing every six months. We have meetings that are changing—new trials, new results. So that's great for patients because I was involved for 15 years, designing different trials of chemotherapy, different combinations, that nothing was advancing. And then, after 2016, where we had immunotherapy, and now the antibody-drug conjugates and all these new tools, the ctDNA, I think that those are great news for managing our patients. Absolutely.

Zachary Klaassen: Yeah, I think you hit on it—every six months, the field is changing. It's almost like prostate cancer, but now we're seeing those changes in urothelial, which is great. So Dr. Bellmunt, thank you so much for your time and expertise. Wonderful discussion. I appreciate your time on here today.

Joaquim Bellmunt: Has been a pleasure. Thank you.