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So now let's talk about how we might apply CTDNA results to guide individualized care. And of course we've spoken a lot about retrospective data, which establishes clinical validity, but to inform practice, we really want data prospectively establishing clinical utility. Um, so we're gonna talk about interpreting CTDNA results to inform patient-centered decisions, balancing escalation and de-escalation of approaches, uh, in the adjuvant setting and, and potentially the neoadjuvant setting moving forward as well. So let's start with a polling question. Your patient who had a CTDNA negative assay immediately after cystectomy has a new detectable CTDNA result at surveillance follow-up. There's no evidence of disease on imaging. To optimize their care based on current evidence, how should you interpret this finding? A, consider conversion clinically insignificant unless imaging shows recurrence. B. Repeat the test in a year because CTDNA is not clinically meaningful. C, consider the results indeterminate, continue surveillance without changing treatment. D, recognize this as molecular recurrence that may warrant treatment escalation, or E, recommend immediate repeat cystectomy. So go ahead and log in your answers. So let's talk about the prospective data that is now informing some of these treatment considerations. Invigor 11 is a study that really mimicked Invigor 10, which we already discussed, but it was done in a prospective fashion, seeking to validate the retrospective CTDNA findings from Invigor 10. The study enrolled a very similar patient population, patients with high-risk muscle invasive urothelial cancer after cystectomy, and a high risk was defined by the pathological criteria outlined on this slide, but after surgery on this study, patients underwent CTDNA. Testing using the Signaera assay, and if they had detectable CTDNA immediately after surgery, then they were randomized to receive atizalutzumab, the PDA-1 inhibitor, or placebo, and atizalusumab was given for a year. In patients with undetectable CTDNA, they had serial CTDNA monitoring every 6 weeks initially, and if they had conversion of their assay from undetectable to detectable, then they entered the randomization later, and that could be any time during the. First year of follow-up. So there's really two groups of patients to consider. There's the patients who had a detectable CT DNA assay immediately after surgery, and then there are the patients who had conversion from undetectable to detectable anytime during that first year of follow-up. The study was designed really to look at patients with detectable cTDNA treated with atizallizumab versus placebo, regardless of the timing of that cTDNA detectable assay, and so the, the, the data are presented in the manuscript and, and when the study was initially presented in that fashion, but of course there is some subgroup. Analysis of patients who had a detectable CTDNA immediately after surgery versus later that are relevant to our clinical decision making as well. And so some of these numbers here are reconstructed as best as possible from the paper to try and contextualize this data into how we think about informing treatment decisions and how we advise patients. So 607 patients were included in the analysis. 459 of those patients had a baseline undetectable cTDNA test, and those patients, remember, were monitored with serial cTDNA testing. Of those patients, 102 had conversion of their CTDN assay from undetectable to detectable during that year of follow-up, first year of follow-up. So a conversion rate of about 22% during that first year. 148 patients had a baseline uh detectable CT DNA test. Here are the results of the impact of atizalizumab versus placebo on disease-free survival and overall survival. In the top panels, those are patients with detectable CTDNA immediately after surgery, and in the bottom panels, those are patients who had detect undetectable CTDNA initially, which converted to. Detectable during follow-up and what you see in all of the curves is that there's a significant benefit to a tealluumab versus placebo in patients with detectable CTDNA if that CTDNA was detectable at baseline after surgery or if it was detected during follow-up in a conversion from an undetectable to detectable assay. These lower panels here, this is really a new clinical disease state. This is molecular recurrence of bladder cancer, um, and it's really the first demonstration that intervening on molecular recurrence is clinically relevant. That is, one can improve. Outcomes by treating individuals with an intervention who have a conversion from an undetectable to a detectable cTDNA test. And of course, the panels on top reinforce that patients with detectable cTDNA after surgery certainly need to be considered for adjuvant therapy. The study also evaluated the potential impact of undetectable CTDNA on treatment decisions, but here the data are a little bit more nuanced. So what I'm showing you here are the outcomes of patients. Who had undetectable CTDNA serially during that year of follow-up, both disease-free survival and overall survival. And what you see here is that if an individual has a persistently undetectable cTDNA test, then their outcomes are really quite good with a small risk of developing recurrence. However, patients who had a conversion of undetectable to detectable CTDNA during that first year of follow-up before developing metastatic disease on a on a scan are not represented on this curve. These patients entered the randomization and so they're removed from this curve. So remember this only represents patients who are serially negative. And when you're informing a treatment decision immediately after cystectomy in a patient with a baseline CTDNA undetectable assay after surgery, of course, you don't know that they will be serially negative, uh, during a, a year of follow-up. Uh, and so, what we don't know for sure is that the watch and wait approach is non-inferior to the treatment of all approach immediately after. mastectomy, but of course, if we treat everyone with an undetectable CTDNA after surgery, we will be overtreating people, and we saw that treatment upon molecular conversion, uh, improves outcomes. And so that really reinforces that this is a concept, uh, that we should, uh, collect additional information on, uh, to, um, confirm that, uh, we can watch and wait in the setting of an undetectable CTDNA test. So really the take home here are the messages that I just outlined. Patients with detectable CTDNA after surgery really should have adjuvant therapy. Molecular recurrence is a new clinical disease state that's clinically actionable, and patients with serial CTDNA negative. Assays have an excellent prognosis. Uh, uh, of course, uh, if we knew patients would have undetectable CTDNA serially at the time that adjuvant treatment decisions need to be made, then of course, that would allow us to de-escalate treatment in a much more rational way. So these concepts are are really being explored further in the ongoing modern study, uh, which is randomizing patients, similar patient population, patients with high risk muscle invasive urothelial cancer after radical surgery. Patients after surgery have CT DNA testing using the Cigna care assay. Patients. detectable CTDNA assays are randomized to adjuvant nivolumab, PE1 blockade standard of care, versus a doublet of nivolumab plus reatimab, seeking whether or not we can escalate treatment to try and improve outcomes even further in patients with detectable CTDNA after surgery. And patients with undetectable CTDNA, we're really trying to address that question that I, I just reviewed, which is, is it as good to just monitor patients and treat only the subset of patients who develop molecular recurrence, which is quite a compelling approach in terms of trying to not overtreat patients. Is that approach non-inferior to treating all patients with adjuvant nivolumab? And so the study is enrolling. And hopefully we'll address some of these uh key uh remaining questions. So let's return to a polling question. Your patient.