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So let's jump right in. Today, I'm gonna talk about the role of CTDNA in yourothelial cancer. Here are my disclosures. And our learning objectives today are to critically appraise clinical trial designs involving the use of circulating tumor DNA to inform treatment decisions in patients with urothelial cancer. So let's start with what we know, what we don't know, and what we might want to learn in ongoing studies. What we know right now is that CTDNA really does tell us who needs adjuvant treatment after radical surgery for muscle invasive urothelial cancer. What we don't know for certain, although there are certainly some compelling evidence, is whether or not CTDNA tells us who doesn't need adjuvant treatment. Um, I would say that right now, what we really don't know is whether or not CTDNA can inform us who needs neoadjuvant therapy or not. There is some early data, but we need more data to define that particular treatment decision. So I'm gonna go through the data that informs each of those points, and then we'll circle back to those at the end. So CTDNA as a measure of minimal residual disease, certainly not a new field, uh, CTDNA, in fact, circulating, uh, um, uh, free DNA was first recognized in 1948, uh, and the technology has evolved over time to be able to determine that CTDNA can represent a measure in individual patients of molecular. residual disease and might serve as a key therapeutic decision point for individuals who've undergone radical surgery for a solid tumor in determining whether or not there's residual disease in informing the use of adjuvant therapy. The technology that I'm going to be discussing mostly today is tumor-informed cTDNA testing and specifically tumor-informed cTDNA testing using the Signaera assay, and the reason that I'm focusing on this assay is that this is where the bulk of evidence has been generated to date in urothelial cancer. So this assay involves whole exome sequencing of a patient's primary tumor. Identifying up to 16 alterations using that um DNA sequencing data, and then, uh, designing a bespoke PCR-based assay to identify those 16 alterations in plasma samples to try and detect minimal amounts of CTDNA. Uh, that's informed by a patient's primary tumor specimen. And you can see in the schema that this can be done at baseline, this can be done prior to surgery, it can be done immediately after surgery, it can be done serially. And those different endpoints probably inform different treatment decisions and have different prognostic implications as well. So let's move to this polling question. Your patient with muscle invasive bladder cancer has undergone radical cystectomy. They ask whether their CTDNA results should determine whether they should receive adjuvant immunotherapy. You recall the results of the adjuvant PD1 PDL1 trials that included retrospective CTDNA analysis, and based on these data, how would you advise the patient? Would you use CTDNA as a validated tool to decide if they should receive adjuvant immunotherapy? Would you explain that CTD analysis and relevant trials were retrospective and prognostic but not treatment guiding? Would you recommend adjuvant immunotherapy only if the patient has a CTDNA positive? Would you advise advise against adjuvant therapy if the patient's assay is CTDNA negative, or would you use cTDNA to determine whether neoadjuvant therapy was necessary? So, uh, please log in your answers. Which of the following do you feel is, is appropriate based on the data? So, let's talk about the data that might inform that decision, uh, and then later we'll get to some prospective data that really, uh, in addition to establishing clinical validity for cTDNA testing, uh, which is really based on the data that I'm gonna show you now, uh, establishes clinical utility for cTDNA testing. So we have 3 studies that have asked a very similar question in patients with high risk muscle invasive urureythelial cancer after radical resection, and that question is, should patients receive adjuvant therapy with immune checkpoint blockade, with PD1 or PDA1 blockade, or should they just proceed with observation? These studies were very similar in design, used very similar eligibility criteria, though there were some nuances and some slight differences in the primary endpoints of the studies, but there's a little bit of difference in how the studies read out. The study called Invigor 10, which randomized patients to a year of atizalluzumab, the PDA-1 inhibitor versus observation, did not meet its primary endpoint of disease-free survival. Ambassador, which studied a year of pembrolizumab versus observation, did meet its primary endpoint showing an improvement in disease-free survival, and checkmate 274 met its primary endpoint showing an improvement to disease-free survival, uh, with adjuvant nivolumab. Of these studies, checkmate 274 has led to regulatory approval for adjuvant nivolumab, uh, in patients with high-risk muscle invasive urothelial cancer after radical surgery. So let's take a closer look at that data and really think about the value proposition of adjuvant immune checkpoint blockade in an unselected patient population. So here you see the disease-free survival curve for adjuvant nivolumab versus placebo in patients with high-risk muscle invasive urothelial cancer after radical resection, and you can see. Some, some really important points here by just inspecting these curves. One thing that you see is that patients on the placebo arm, a fair amount of them do really quite well and are likely already cured with the surgery that they received plus or minus neoadjuvant chemotherapy that they received. So arguably, these patients do not need further treatment. These patients, uh, the, the space between these two lines, of course, indicates the patients who both, uh, need treatment and benefit from treatment. These are patients who got adjuvant immune checkpoint blockade, where it really seems to make the difference in terms of recurrence versus not. And then of course these patients received adjuvant immune checkpoint blockade, but still did not derive benefit from treatment, still developed disease recurrence. So if we think about these three scenarios, it really paints the perfect picture for implementation of a precision medicine-based approach, because clearly there are patients here that were overtreating, there are patients here that were undertreating, and there are patients here for whom this is really the appropriate treatment. So how do we determine this better? Well, if we can identify who needs treatment in the adjuvant setting, that would be a start. And sometimes it's conflated biomarkers of patients who need treatment versus biomarkers of patients who benefit from treatment. In the adjuvant setting though, there's a double biomarker dilemma. Not only don't we know who benefits from specific drugs, but we actually don't even know who needs additional treatment because we don't know who has residual micrometastatic disease. And this is where CTDNA comes in. CTDNA is really the most promising biomarker that we've seen that might indicate who quote unquote needs additional treatment. So here's The retrospective data from the InvigorPen study that I was referring to, you'll remember that this was a study of adjuvant atizaluzumab for a year versus observation. The study didn't meet its primary endpoint, but the investigators from the study did a really important analysis. And what they did is ask retrospectively, would the results of this study have been different if we could determine CTDNA status immediately. After surgery and determine whether or not that separated individuals into those who needed treatment versus those who maybe didn't need treatment. And you can see here in the first Kaplan-Myer curve, disease-free survival, the second overall survival, the curves are stratified according to CTDNA status with patients with CTDNA undetectable assays on top, CTDNA positive assays on bottom, and then each curve indicates. Patients who were on the atizaluzumab in blue versus the observation arm in red, and you can see immediately that patients with undetectable CTDNA did not seem to derive benefit from the adjuvant immunotherapy and had a much lower risk for recurrence. Patients with detectable CTDNA at that single time point after surgery had a much higher risk of recurrence and are the ones who seemed to benefit from adjuvant immune checkpoint blockade. So really important uh retrospective data establishing clinical validity for cTDNA testing in this setting. So let's go to this polling question. Your patient asked whether their postoperative CTDNA result could be used to predict whether adjuvant immunotherapy will improve their long-term outcomes. Recalling the Invigor 10 CTD analysis CTDNA analysis findings that we just reviewed, how should you interpret the role of CTDNA-based minimal residual disease test.