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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, a friend and colleague, Dr. Tom Powles, who is the Director of the Bart's Cancer Center in London, in the UK. Thank you so much for being here with me today, Dr. Powles.

Thomas Powles: Alicia, it's really nice to be here. Thank you for inviting me.

Alicia Morgans: Wonderful. So, Tom, I wanted to talk with you a little bit about IMvigor010, which was a study that you worked on, presented.  This was a large phase 3, and you recently presented some really interesting biomarker data around CTCs. I'm wondering if you can remind us a little bit of the study, and then talk to us a little bit about the CTC data.

Thomas Powles: IMvigor010 is a prospective, randomized, adjuvant trial, testing atezolizumab versus best supportive care in a high-risk population. Dr. Maha Hussain presented it and Dr. Joaquim Bellmunt is the chief investigator and will be the first author of the publication. I was on the steering committee and I was involved in the biomarker program.

The biomarker program focused, to some extent, around circulating tumor DNA, and I will talk about that in a second. Overall, the trial did not hit its progression-free survival or overall survival endpoint. But in the biomarker work, we measured ctDNA at baseline after cystectomy, and then 6 weeks later. We did this in both arms and we did this in about 600 patients. The ctDNA technology we measured, there are two ways of measuring it, well, there are many ways of measuring ctDNA, but two main ways. One is a panel-based approach, where you look at specific genes, they are pre-existing, you can drag them off the shelf, and it's always the same genes. There is a second method, and that second method is, you do whole-exome sequencing and you do germline sequencing, you identify somatic mutations, and then, from the tumor, you then identify those in the plasma and you track those, and you track up to 16. And if you have more than two in the plasma, you are defined as positive, and if it is less than one or zero, you are defined as negative.

We did this on the 600 samples and we showed the first thing, that it was very prognostic. So, your chances of relapsing, if you were positive, was about 80%, versus 20% if you were negative. That is not spectacularly novel because it's been shown in urothelial cancer in a phase 2 study, not in a randomized trial, but in a phase 2 trial out of Denmark, which was a terrific study. But, we then went on to look at the effect of atezolizumab in the ctDNA-positive population.

What we showed is in that positive population, the intervention with atezolizumab was associated with a survival advantage and a progression-free survival advantage of a hazard ratio of 0.58 and 0.59, respectively. So, it appears prognostic and it also appears predictive. We then went on to look at the cycle three day 1 sample, and we could show that of those positive patients, about 20%, just two cycles of the drug, cleared ctDNA. And that shows a normalization, suggesting the drugs having an effect, which I think is important. And again, those patients that cleared their ctDNA did extremely well.

We then, in the final part of this analysis, correlated ctDNA expression with other immune biomarkers, and we showed a strong correlation between ctDNA positivity and further enrichment for the outcome if you are a PD-L1-positive or TMB-high, linking the immune biology and the ctDNA together, which is really cool, because it's suggesting a link between the primary tumor and the ctDNA positivity, and also suggesting that those immune biomarkers are boosting the immune response. The final bit we did was, we also did a neoadjuvant trial. This is of only 40 patients, also with two cycles of atezolizumab, and we showed that the ctDNA-positive patients, atezolizumab was associated, again, with a 20% clearance, which is cool, and clearance was associated with really good outcomes.

So, what I would say in summary is that this has different implications. Firstly, it is important to say that it's a preplanned, exploratory analysis of a randomized trial. It doesn't have alpha associated with it. So it's not a positive randomized trial in a traditional sense and we won't be going to the FDA and getting approval, but it is a very powerful exploratory analysis. What it is doing is, it's telling us that we can identify the minimal residual disease with quite straightforward technology, and we can intervene and improve outcomes in that setting.

This has the opportunity to completely change the way we think about post-operative cancer care in bladder cancer, and potentially much wider as well, because if we can reproduce these results in bladder cancer and in other tumor types, instead of doing radiological scans, which, to be honest, probably, I think, in 20 years time, we won't be looking at radiology in the same way we do now. I think it is going to be much more sophisticated. If we can identify those patients at risk and then intervene, that is going to be a huge step in the right direction in post-operative cancer care, which I think is why this data is the first chapter of a new whole book of how we rethink the perioperative period.

Alicia Morgans: I completely agree, and it reminds me almost of, in hematologic malignancies, when we are using minimal residual disease. Sort of this molecular marker of remaining disease that requires further eradication. That, in that sense, is so much more sensitive, as you said than the radiologic assessments that we are doing. And if it then is associated with a way for us to define which patients may benefit from therapy, we are not only getting the right treatment to patients, but we are avoiding ineffective treatment in patients that do not need to have additional therapy. So, I think that this is truly groundbreaking though, of course, early days, but something that we now have a way to evaluate moving forward. Is this something that you are putting into additional studies that you're doing in urothelial cancer?

Thomas Powles: Yeah. Well, I'm trying to put it into all the studies we're doing, and that is the neoadjuvant trials. We've also done a little bit of work in metastatic trials. So we did a study called BISCAY. BISCAY was a study that looked at different combinations of immune therapy and targeted therapy. And we've done the same technology, both paddle-based and tumor-specific approaches showing dynamic changes to ctDNA, but also dynamic changes to specific FGF markers in those patients in whom we gave FGF inhibitors.

And so, we can track disease, but we can also track specific mutations moving forward. So, it is a really exciting technology in its infancy. It, in my opinion, is going to have a really important role in perioperative disease.  It's going to be having an important role in selecting therapy, at the moment, it's immune therapy, but it could easily be targeted therapy in the future. We could be selecting PARP inhibitors, FGF inhibitors, other types of treatment beyond immune therapy as well.

And I think, again, in 10 years' time, will we really be pulling a tumor sample out of a bucket taken 4 years ago and looking whether or not it's tumor mutation? I don't think we're going to be doing that. I think we are going to be focusing on the here and now. I think it's more accurate, it's easier to do, and I think it is very, very applicable and it's with us today and tomorrow. Yes, we have to improve the sensitivity and some of the technologies of some of the panels, not all of them, some of them, and yes, there is a lot of work to do in terms of the turnaround time, it's currently 2 or 3 weeks, we need to narrow that down, the tests are obviously expensive. There is a lot of work to do, but it's a new chapter.

Alicia Morgans: Well, I sincerely appreciate you taking us on this road through those new chapters, through those next steps, because your enthusiasm is infectious. And, of course, this technology, these advances are so exciting and can really make a difference for patients as we try to do, as you said, treatment in the here and now, not relying only on things that we have from years ago. So, thank you so much for sharing your insights and for continuing to do this work. It truly does make a difference. We appreciate your time.

Thomas Powles: Thank you so much. I really appreciate it.