So, you presented today data on utDNA from the NIAGARA trial. So, what can we learn from this important correlate from this randomized phase-3 trial?
Michiel Simon Van Der Heijden: Yeah. So first of all, thanks for having me here. It's great to talk about this study. I think it's important work, as we're in this meeting talking a lot about these new powerful systemic therapies, and how we can bring this to what patients really want, is bladder preservation.
NIAGARA, of course, a large randomized phase-3 study testing perioperative durvalumab when added to neoadjuvant cis-gem. It was positive for EFS and OS. And in a previous analysis, we looked at circulating tumor DNA, and we found that ctDNA is prognostic at every time point where you measure it for outcome. If you look at path CR, then ctDNA presence was quite good at predicting non-path CR. However, when ctDNA is absent, that didn't mean that you have a path CR. So we were hoping to improve on that.
So, in this study, we looked at urinary tumor DNA, and also integrated it with circulating tumor DNA. We looked at urine at baseline and after neoadjuvant treatment, but before cystectomy. So what we found is that urinary tumor DNA is more present in a majority of patients. 85% of patients has baseline urinary tumor DNA, which is more than circulating tumor DNA. And just as we've seen with circulating tumor DNA, there's clearance of urinary tumor DNAs associated with better outcome. Also, the durvalumab arm had a higher percentage of clearance than the control arm.
I think where it gets more interesting is when you compare urinary tumor DNA to the pathological response. So, patients who were negative for urinary tumor DNA had a 72% chance of having a path CR. So, when it was also associated with not having a path CR if you still had urinary tumor DNA, so basically the reverse comparison, but a little bit less so than ctDNA. So, if you integrate all that with each other, so these two assessments, then you find that ctDNA, generally speaking, is giving an impression about systemic disease, so nodal, and also invasive bladder disease. Whereas urinary tumor DNA is an assessment of local residual disease, so either invasive or non-invasive disease in the bladder. So, this could be particularly informative in ctDNA-negative patients. So this is the group of patients where you would perhaps consider de-escalating consolidative therapy. And in those patients, we saw that the double negatives, so ctDNA-negative and urinary tumor DNA negatives had the highest chance of having a path CR.
Whereas patients who are ctDNA-negative, but still positive for urinary tumor DNA, those were the patients who had local residual disease. And actually, that's also the group where we found the non-invasive disease, residual non-invasive disease patients.
Elizabeth Plimack: That's great. So by combining these biomarkers, we're getting a clearer picture of the intravesical and extravesical components.
Michiel Simon Van Der Heijden: Yes, exactly. And it's not perfect yet, but I think this is really a nice step forward to look for this patient population that everybody is wanting to do, which is this patient population where we can hopefully later predict that they have a both CR and perhaps not do any consolidative treatment.
Elizabeth Plimack: Yeah, absolutely. Tell me a little bit about the assay that was used in this study. There are lots of different utDNA assays. There's tumor-informed, tumor-agnostic. Which one was used here and what are your thoughts on the landscape of this test?
Michiel Simon Van Der Heijden: Yeah, so this was the personalized Signatera assay. So it was basically pretty similar to the plasma ctDNA tests that most of us are used to. Different from the plasma ctDNA, there's not so much data in urinary tumor DNA. Actually, very, very little data. So, the thresholds are basically copied from plasma ctDNA, but perhaps there are still more looking into the threshold. We see that some early signs, it's small groups of this, not an enormous group of patients. We see some early signs that perhaps the quantity of urinary tumor DNA could also make a difference in prognosis, and also perhaps a response prediction. But that's all kinds of things that we still need to figure out in future studies. We also know that some assays can be even more sensitive, deeper sequencing, more broader panel, broader panels.
Elizabeth Plimack: Right.
Michiel Simon Van Der Heijden: So all of these things will, I think, very rapidly develop in the years to come, but at this point we stuck to an assay that we sort of all can understand and know, which is the Signatera assay.
Elizabeth Plimack: Yeah, that makes sense. So I have one question none of us can answer, but I'm eager to hear your thoughts. If you have a bladder that comes out and it's a pathologic CR, but the utDNA was positive, how do you explain that finding? Hiding cancer, that the pathology didn't pick up, some sort of mutational pattern in the urothelium?
Michiel Simon Van Der Heijden: Yeah, that's a very good question. And we've seen this also in our previous trial, NABUCCO, which used another assay, the RADAR assay, which worked also pretty well in there. We also did urinary tumor DNA. We've been thinking a lot about that. We see in some patients that there's still a lot of necrosis, maybe there's still tumor DNA present there that might leak out. Some interesting work came out recently about bladder field effects so that you sort of already can show mutants DNA in patients, although they get to more, even an oncogene. So, this could also be a source for mutations. So we have some hypotheses, but in the end, we really don't know yet.
Elizabeth Plimack: Yeah.
Michiel Simon Van Der Heijden: Yeah.
Elizabeth Plimack: Well, more to come. Thank you so much.
Michiel Simon Van Der Heijden: Thank you.