 So I'm just going to kind of give you the 30,000 foot view of what's going on in kidney cancer and feel free to stop me and ask questions. And some of these slides are pulled from decks, you know, that we give at sort of professional presentations. And I'll try to break it down for you since it's in a lingo that we're used to, that you may not be used to. So I'll try not to insult your intelligence, but really just let you know. Thank you. Sort of how we look at therapies on a big picture level for groups of patients and for individual patients, et cetera. So a lot of new therapy in kidney cancer, as many of you are aware of and many of you have been treated with, is these checkpoint inhibitors. And the way I explain it to patients, as some of you have heard, is basically removing the brakes on the immune system. So it goes like this. All of our bodies obviously have an immune system to fight infections. In part, that immune system also presumably would try to eradicate cancer cells, right, as being foreign. So immune system is meant to eradicate foreign substances, foreign cells, viral cells, fungal cells, et cetera, but also cancer cells. And that sort of basic interaction, this is even better, that basic interaction is listed here. So here's a tumor cell, in this case a kidney cancer cell. And antigen is just another word for protein. So cells express proteins on their surface. It's like their characteristics. And it's sort of what makes a cell a cell. It's sort of the defining features of that cell. And normally a T cell, which is one of the immune system cells, not the only one, but the most important one, basically the way that a T cell fights a tumor cell is through this interaction right here. The protein expressed on a tumor cell engages this T cell receptor. This is called a ligand. This is called a receptor. And that engagement stimulates the T cell, right. And it stimulates the T cell to fight this tumor cell, to kill this tumor cell. So this is sort of, we'd call it T cell recognition of tumor cell. And the way it recognizes it is through this specific interaction. Now, normal physiology would dictate that you need sort of a positive and negative balance to anything, right. To blood pressure control, to anything in your body needs a positive and negative balance, including this interaction. So one of the ways that this is regulated is through this PD1, PDL1. So PD1 stands for Program Death 1, and it's called that because it's sort of a negative regulator. It would turn down this immune response. And so we talk about PD1 being expressed on T cells and PDL1, or the ligand, the Program Death Ligand 1 being expressed on tumor cells. So it's sort of a positive interaction and a negative interaction. And it's the balance of those interactions that determine whether or not this T cell is going to actually kill this tumor cell or become what we call anergic, sort of dead and lifeless and not able to do its job. And obviously, again, for normal physiology, you want a healthy balance of that. We'd all like these T cells to be stimulated, right. We want the balance of more positive than negative, but just as sort of a general look at this interaction. But it's important because it really underlies a lot of our therapy. And so I think I have this on the next, oh, I forgot my animation. Again, positive signals and negative signals. And again, we're trying to, in essence, accentuate the positive, right. So if we remove the negative, if you remember your math days, right, subtracting a negative is like adding a positive. So if we remove the negative, we're going to accentuate this positive T cell response, and that's everything. That's what we're trying to do. And now we have drugs that can basically block either PD1 or PDL1. And here are some names we'll be talking about specifically, and there are actually more on here. These are the ones in advanced clinical development and kidney cancer. It's not clear whether blocking this or this is better. Does it, should you block A or block B? We don't really know that yet. It doesn't appear to be a difference. Or should you block both of them? There are some trials that will come up in the next couple of years that will block both of them. And just to mention it, I won't talk about it, but this is not the only negative signal, the negative interaction on these T cells. There are a number of other molecules, a number of other checkpoints we would say, and there are drugs being developed against them. But this is just what has been clinically developed to date. So let's talk about specific data. So the only checkpoint drug approved in kidney cancer is this nevolumab drug. And I just told you nevolumab blocks PD1. So if it ends in AB, it's an antibody, no matter what the drug is. If it ends in AB, it's an antibody. So nevolumab is a drug that's an anti-PD1 antibody. So instead of allowing this negative interaction here, it covers this receptor. I don't have a picture, but basically this antibody binds the receptor, prevents the negative, again accentuating the positive. So there were a lot of preliminary studies with this drug. I won't go over it. This is what we resulted in this, what we would call a registration trial. That's a term that just means it's a trial meant to lead to FDA approval, which happened in this case. So these were patients who had advanced kidney cancer. Stratification just means making sure there's an equal number of patients with certain characteristics in each group. And they were randomized to either get nevolumab. It's a drug given intravenously every two weeks. In the trial, it was given as weight-based. It's now just given as a flat dose. Everybody gets 240 milligrams, but the dosing isn't important. Or a drug called Everolimus or Affinitor, which is an older drug that was commonly used in this setting, in this what we call refractory setting, meaning patients have been on one or more drugs and the drugs have failed them, and so now they're moving on to another therapy. And this was the main result of the trial. So there are a lot of ways to measure benefit of the drug. How many patients have tumors shrink? How much do they shrink? How long do they shrink? But obviously the ultimate way is, are we helping patients live longer? And so this was the primary endpoint of this trial. And as you can see, what we want to see, ideally what we'd see is a curve that does this, right? It goes straight across, right? That's what we're going for. So up and to the right is good. So when you see a comparison of curves like this, you know, the lighter-colored curve here is for patients who receive this Everolimus drug, and the darker one is for patients who got nevolumab. We commonly call it NIVO. The brand name is Optivo. You've probably seen the commercials. And basically, there was an improvement in survival of six months. So what that means is that, you know, on average, how long are we making patients live longer with this drug? It doesn't guarantee that benefit for all patients, and it doesn't limit the benefit, right? So you could get that drug, and it could make you live longer by years. Or you could get the drug, and it could not help you, right? That's true for any drug out there. So again, that's the difference between sort of average numbers and averages for the group and how it's going to affect an individual patient. The other way to look at it is this hazard ratio, which is a little more abstract. We always talk about medians as well, because it's a concrete number. It's an interval we can get our head around. Hazard ratio, what the hazard there is, in this case, is risk of dying. So if the hazard ratio is 0.73, what that means is that, instead of looking at a median, so a median is exactly the midpoint. So it's a comparison between the midpoint. A hazard ratio compares the lines across their whole length. Basically, what's the gap between these lines, not at any one point, but at every point along those lines. And a hazard ratio of that means there's a 27% reduced chance of death with this drug at any point in time. It's another way of thinking about the data. Again, it's actually, frankly, probably a more accurate way, because it takes into account all of the data, not just one point. So different ways of thinking about it. But nonetheless, this was really one of the first times that a drug had been shown to improve survival and kidney cancer. And it was the first time in this particular setting, to my knowledge. So this drug was approved almost exactly a year ago. I think it was November of 15. And it's commonly used as our second drug. Again, that's how it was studied. I mentioned there are different ways to look at effects of drug. Another one is called progression-free survival. So overall survival is obvious. Progression-free survival means how long do patients live without getting worse, without having their tumors get worse by a certain amount. So this is a little more interesting. So again, these numbers aren't nearly as impressive, right? So progression-free survival, or we commonly use the acronym PFS, was about four and a half months for each drug. What's a little bit interesting here, and I think we're still sorting out in clinical practice, is you can see these curves are really overlapping until you get to about 12 months, and then they start to split. And that may be for a variety of reasons. One is immunotherapy can have a bit of a more delayed effect than, say, drugs like Sutent and the like, which have a more immediate effect. And the other, and I think I have slides on this later, is part of what these drugs do is induce inflammation, right? We're trying to induce inflammation against the tumor. And so that can make tumors look bigger on a scan, when in fact that's actually a good thing. They're bigger because of tumor cells, excuse me. They're bigger because of immune cells, not because of tumor cells. And so some of these people who quote-unquote progressed and got worse actually didn't get worse. They were actually getting better. And that's just that our scans aren't perfect, right? When we look at a scan and we're looking at a nodule on there, there's no arrows that say, well, this much is tumor cell and this much is immune cell, right? It's just a white blob, right? You've all looked at scans with me and others, and you can see they're relatively imperfect. And so that's probably what's going on here as well. The other side of the coin, obviously, when we're talking about drugs is side effect or risk. So, sorry, this is a really complicated table, but basically it looks at the first three columns are nivolumab side effects, so to focus on that. When we think about side effects, we think about grade. So we grade from one through five, sort of mild, moderate, severe, life-threatening, and a grade five side effect is one that caused death, okay? So we want to see obviously low numbers on this page. This is the percent of patients who experience these side effects as related to treatment at some point while they were getting drug. And you don't really have any context, but I can tell you these numbers are pretty low. So we worry most about grade three and four side effects. Those are likely to be what bothers patients most. That's not entirely true. And if you've had grade two side effects, they're not terribly fun either, but in terms of sort of the more severe side effects, you can see they're really in single digits, you know, one or two percent. And that's really low compared to some of the other drugs we give. So the drug's really well tolerated. Even if you look at all grade side effects, even the most mild side effects, it's really pretty low. What I usually explain to patients is that, again, these drugs are meant to cause inflammation around the tumors, but they can cause inflammation around any organ in your body. And they commonly cause it around skin giving a rash or itchiness of the skin, diarrhea, sometimes lung inflammation, fatigue, sort of a generic side effect. You know, we've seen, I don't think it's on here, but arthralgias, joint pain, sure. It's much lower. I don't think I have any slides on Sutent. We have a little bit of a comparison with this drug, which is probably better tolerated than Sutent. So, but, for instance, this top red box here, these are individual side effects, obviously. The top one is just saying, big picture, 18 percent of patients who took this drug had some grade three side effect. For Sutent, that number is probably 50 or 60 percent. Yeah, just sort of off the top of my head. It's somewhere in that range. On paper, actually, drugs like Sutent cause the same type of side effects, right? Diarrhea, fatigue, hand foot syndrome, right? All the stuff that you're familiar with, but the severity and the frequency is much less, is usually how I explain it to patients. And the mechanism of how it causes it is totally different, but that's sort of neither here nor there. All right, so this is what I was talking about with this sort of tumor flare. So, again, if we have a generic collection of tumor cells here, and if we did a scan, let's say this was a nodule in the lung, a kidney cancer nodule in the lung, and we did a scan and we measured, the way we measured tumors is just unidimensional. So I put a little electronic ruler here and I drag it across and I put it here. Not perfect, but it gives us a rough estimate of amount of tumor. And let's say this was two centimeters for the sake of argument. And then we give some immune therapy, nebola mabor, other therapy. What we're trying to do is induce those T cells to kill the tumor cells, right? By removing the negative, we're trying to stimulate those T cells to fight the cancer cells. But you could see if I put a ruler here and dragged it across and put it here, it would be bigger. It could be three centimeters, right? So that's a 50% increase if you do the math. But in actuality, it's a good thing. And again, there's no way to know this on a scan, but it's just a phenomenon. It doesn't happen quite as often as people talk about. So any of you who've read consents, right, know it's definitely going to happen. You're definitely going to get worse before you get better. That's not the case. It does happen. We're aware of it. But it's just sort of an interesting phenomenon that I think gets talked about more than it actually happens. And this text is really just saying the same thing. So this drug was, on the base of the trial I showed you, approved a year ago in previously treated kidney cancer. You have to have gotten at least one drug, like Sutent, to move on to this drug outside of a trial. And actually from melanoma, I think I showed this last year. So basically what happened is when these drugs, when drugs get developed, they're often developed broadly across diseases. And you do these trials and treat a lot of different people, and then you figure out, G, it's disease A, B, and C that responds, so we're going to continue development in those diseases. So melanoma has always been sort of linked with kidney cancer as a disease responsive to immune therapy. And so this drug was also developed in melanoma. In fact, that was really the first, first drug. And this is just a chart I'll explain it in a second that shows combination therapy. So not only patients got not only this nevolumab drug, we got another drug called ipilumumab, which inhibits a different checkpoint molecule. Not shown on that one schematic slide, but inhibits sort of basically two drugs to inhibit this process as opposed to one. This is what's called a spider plot. So basically each line is an individual patient and it measures their tumor burden over time. So they all start at zero, right? They have whatever disease they have going into treatment, and what we want to see is what's shown here for many to most patients. Their tumor burden goes down, this is percentage, so it goes down by 20, 40, 60, 80%, you know, when they get their first scan, and then it stays there. These little circles are just whenever patients got scans every, you know, 8, 10, 12 weeks, whatever it was in this study. So it gives you sort of a bird's eye view again of how the group did, more than curves can do, because it tells you about individual patients. Again, so a lot of people who had a response, obviously not everybody has a response, and some people who have more stable disease. So they don't have tumor shrink, but they have stability over a period of, you know, this is about a year or so. So I bring it up because this combination has been studied in kidney cancer. We did this trial. This was a trial looking at different combinations of these drugs, just different doses. And the way this regimen is given is two drugs every three weeks for four doses. So there's four combo doses, and then they get nevolumab by itself as what we might call maintenance therapy. And so this was a preliminary trial that showed activity, I might have it here. I don't think I have the activity, but it showed activity, not quite as dramatic as melanoma, but clearly an active combination. Of course, as I have on the next slide here, two drugs are always more toxic than one, right? As oncologists, we love to put drugs together. It's sort of what we do. We love putting drugs together. And in many other diseases, combination therapy is what's led to cure of those diseases. Lymphoma, testicular cancer, there are many examples where one drug is not curative, but two, three, four drugs is. So that's the background of why we do it. This is a similar one of those tables. And again, I don't have the other one up here, but these numbers are higher than what is seen with the nevolumab alone. That's the end in this designation here. So again, getting these two drugs while maybe more effective, we don't know that yet, certainly causes more toxicity. And I bring it up because this large trial was done, has been completed, and we're waiting for results. So basically this said, okay, we know nevolumab by itself has activity. We know in a small trial that if we combine it, there could be more activity, although with more side effects. So let's use this combination as sort of an upfront initial immune therapy combination compared to good old Sutent, which is the standard of care. So this trial was ongoing. We accrued several patients that accrued, I don't know, maybe 800 or 1,000 worldwide. And the results probably should be out in the next one to two years, I'm guessing. And this may change the standard of care, right? Sutent is a standard, not the only one, but the most commonly used standard, certainly here. And again, this is now in patients who are treatment naive, right? So they haven't gotten any prior treatment. They just walk in the door and they're getting their first treatment. And so we'll see whether this combination has advantages over Sutent. But again, in the next year or two, that may really change how we approach, our sort of standard approach to patients. Obviously, this was done in the context of a clinical trial. And then I just have a few slides, sort of rapid fire about all the other trials going on. That one is sort of an example. And it's sort of the leading example, just because of the timeline over which it happened. But there are many others going. And they all have sort of a common theme. So these are all big randomized trials where you take patients and you allocate them, you randomize them into one of two or one of three groups. Sutent is often the control arm, right? It is the standard drug right now. So we use that to say, well, how would patients do on a standard therapy and compare them to how patients do on experimental therapies? This drug now has a much better name. It's called a tessellizumab. Oh, there it is. I think I spelled it wrong. Tessellizumab, it's actually approved in bladder cancer, but being studied in kidney cancer as well. And this trial looked at sutent versus getting that drug by itself versus a combination. The tessellizumab is also called a vastan. It's an anti-blood vessel antibody. It's been around for a long time, approved in kidney cancer. So, again, starting to mix and match drugs from different categories, if you will. Targeted therapy and immune therapy together, alone, et cetera. That was a phase two, which actually will get reported in next February. And then a large phase three is ongoing, again, very similar to the other combination looking at a combination therapy compared to sutent. So this trial is actually completed accrual as well. But it's behind in terms of timeline from the other one. And there are about five of these trials. Two, I guess, are done. Three are ongoing. This is an example of a combination that's going to be in a trial we have coming up. So, and again, it's an example of a combination of an immune antibody. Remember AB, antibody? Pembrolizumab is approved in lung cancer and probably some other things I'm forgetting. But it's also an anti-PD1 antibody combined with accident, which as you may know is a VEGF targeted therapy used commonly in the refractory setting. And so, again, a combination of an immune therapy and a targeted therapy. This was a phase one study. And there was some updated data presented a few weeks ago at a European meeting. This is on just a handful of patients. But you can see the spider plot here. Remember from the other trial, pretty much all patients had tumors get smaller. Super tiny amount of patients. But the response rate to this regimen in the updated data of about 50 or 60 patients was like 70%, which is about twice what we get with, say, a drug like Sudsen. Now, you know, drugs and combinations always look good in their initial data, right? If you treat a small number of patients, and so things generally tend to settle down if you will over time. But that's a really high number. It's as high as has ever been reported in kidney cancer, to my knowledge. So it looks like some of these newer combinations, you know, could have enhanced activity. Now, whether that'll play out into making patients live longer, right, which is the important outcome we don't know yet. That's what we're waiting for these big, large trials to do. And this is a trial that is coming up. Should be open here soon. Again, very common theme. Combination of existing drug plus new drug versus existing drug is one way to think about it. Anti-blood vessel therapy, plus immune therapy versus anti-blood vessel therapy would be the other way to say it. And just yet another example. This is the trial that is just sort of finishing up now, again, but just to give you a sense that there's a lot of work going on here that is probably going to change the standard of care in kidney cancer. So right now it's Sudsen, but it may very well change in the next two, three, four years as these results become available, assuming that there's benefit, right? We don't know if there will or won't be. That's why we do the trial. And then just to tell you sort of what we're doing here on a local level, so this kind of trial is what we call a sponsored trial, right? The company who makes these drugs wants to do this trial and spend the money, which is about $125 million, because they'd like to get this approved, right? So it's a sponsored trial that we participate in. This kind of trial is what we call an investigator-initiated trial. That means we have an interesting kidney cancer in these drugs, and we have an idea, and we're not going to test it in 800 patients, but let's test it in 40 or 50 patients and see. And this is just the idea of giving this nivolumab drug intermittently instead of continuously. So one question with immune therapy. If you think about it, if we generate an effective anti-tumor immune response, just like if we gave you a flu shot and generated immune response, you don't need a flu shot every month, right? You need it once per season, or if you get a pneumonia vaccine, right? It's basically a lifetime. So if you're generating an anti-tumor response, excuse me, an immune response, it should be durable, ideally. And so maybe if we can induce an immune response with this drug that we could stop giving it at least for a period of time. Why would we do that? Well, to spare people side effects, right? So if you keep taking drugs, eventually you'll have side effects, right? And so if we can keep people off therapy, and I won't explain this whole complicated schema to you, but basically it's a way of treating people up front, and then if they have tumors get smaller, to basically hold the drug. And we did this actually with SU-10 and some data that's about to be reported, but basically extending this concept to newer drugs. So this is not yet open. It will be in a few months. And then the other sort of other end of the spectrum, neoadjuvant is a term that means giving drugs before surgery. So this is a study that's just about to open that's basically using some of these new checkpoint inhibitors in patients, not who have advanced disease, but who have localized disease. So they walk in the door with just a tumor in their kidney. They do not have advanced disease. And we're giving them these drugs and cohorts just means different groups of patients treated differently, the details aren't important, giving them before they get their surgery and a little bit after. And this is really more of a scientific study, right? So we can look at the tissue and look at those T cells and get smarter about do we need one drug or two drug or one dose or two dose or, you know, so just different things that we're interested in with the idea that this could have applicability to patients with advanced disease. So we would say this is just a platform to study the drugs for use in other settings, not that ultimately I think these drugs are necessarily going to be used in this setting. They may or may not, but it's really just a way for us to study it and obtain tissue to get smarter. So as I think about sort of the future of immune therapy and kidney cancer, what I hope is that, you know, we'll be able to sort of dial up and down again. We can give more drugs to more patients, but that's going to have more side effects and we're waiting to see if there's benefit. Ideally we could give patients as little therapy as possible, right? We could give you one drug that has barely any side effects. We induce a response and it's there forever, right? In an ideal world. It's not going to be possible, of course, for all patients. But if that one drug doesn't work, then we could add another. And so it takes a lot of years to figure all that out, but that's how I think it's going to sort of play out over the next five to 10 years. Not forgetting about our good old friends, Sutana Xitinibic Center, that VEGF therapy is still the standard of care as we stand here today. It will still have a role. The disease didn't suddenly become a different disease because these new drugs were introduced. So they're additive to what we have there. I don't think they're going to replace. And then I just wanted to mention some other new data that came out. So this was at this European Cancer Conference a few weeks ago. So a totally separate topic. So again, in patients who have non-metastatic kidney cancer, they walk in the door with the kidney tumor in place, they see the urologist, they get it cut out. So for those patients, there's no standard therapy, right? We basically just keep our fingers crossed and hope it doesn't recur. There is no therapy that's common. But there have been a number of trials to test what were, at the time, newer drugs like Sunitinib in that setting. Can we prevent your disease from coming back or can we delay it? And this was a large trial that was reported recently. Again, it was clear cell kidney cancer that confined to the kidney. They got surgery and then were randomized to get either Sutan or placebo. The reason there's a placebo in this trial is because doing nothing is the standard of care, right? It's advanced disease, but in this setting it's appropriate. And more confusing curves again, but basically if you look up here, this is sort of where the main result is, if you can see that, basically giving Sutan in this setting delayed the recurrence of disease by about a little over a year. Let me see if I have anything else in here. Yeah, and these are just the specific rates at different points in time. So, you know, it's not clear whether the drug will get FDA approved in this setting. It's not clear whether people will use it. It can have side effects. So, you tell me, I mean, as a patient, you're saying, well, I'm willing to put up with side effects for a year in exchange for delaying recurrence of my disease for a little over a year. And obviously that's a different equation for each patient. To tolerate it wonderfully is no big deal. If you don't tolerate it well at all, then it is a big deal. So, these data are really hot off the press and we're sort of waiting to see how it unfolds. Importantly, if the FDA approves it, which I think they will, but I don't know. And then how people actually use it in practice. But just wanted to mention it because it's some big, big new data that just came out. So, just to wrap up. So, immunotherapy. Nevolumab currently is approved after at least one treatment, but a lot of clinical trials are ongoing and this will change how we approach patients. There's no question about it. And then just briefly, the suit and after kidney surgery it does delay recurrence. But again, we're waiting to see what the FDA does and sort of that risk benefit, you know, I think is perhaps in question and I'm happy to get your input about it and talk about it. And it's also true that a lot of these immune therapies are now going to be studied in this setting. So, you get surgery and then get an immune therapy and those trials are just starting. So, that data is here as a way. Thanks, I'm happy to take any questions. So, the question was the brand name of this drug is called T-centric. It's this one. It's the Atezzolizumab. This one? No, not that one. This one? So, in kidney cancer it's still investigational. It's not FDA approved. So, you get FDA approval for a specific disease. So, the drug, it is approved in bladder cancer. It is still investigational in kidney cancer pending the result of this trial. Or maybe this trial. This trial might do it, but I have a feeling that the FDA will wait for this trial that's on the screen right now. So, this smaller trial will be reported in February. The issue is that, you know, the question really is sort of a big picture of the development questions. How much evidence is required to lead to drug approval, right? That's a big question. So, 300 patients seems like a lot, but it's really actually a fairly small number of patients. So, I don't know that the FDA will approve on the basis of this trial on the screen. The separate trial, which has completed a cruel, probably will be another probably good two years until it's reported. So, that's the sort of the good and bad news of these kind of trials is that they're big complicated trials. They take a while to do. They take a while to read out, we would say. So, again, drug development is slower than we'd all like, but it's just the nature of having to do these kind of trials to make sure there's benefit. So, I think it's going to be a couple of years. Answer your question. Stunned silence is falling over the crowd. Yes? Right, yeah, no, fair enough. So, a lot of those commercials you see for rheumatoid arthritis and plaxoriasis and all stuff, those are anti-inflammatory drugs. What I've just told you about are pro-inflammatory. So, we use some of those anti-inflammatory drugs to treat side effects. So, they're related and, you know, I don't know if that was your question, like, yeah, why is it exploding, is that the question? I don't know exactly. I mean, I think it's, you know, you just get it, you know, creating antibodies is a science and so, sometimes that science advances and then the science of understanding the disease. So, all these molecules I talked about 10 years ago, I mean, we knew about them, but they weren't even close to being clinically relevant, you know? So, you can know a lot about a disease and not have drugs to treat those targets or you can just not know the targets, right? And so, you know, the advances happen when you understand the targets, they actually matter and you have drugs to inhibit them and that's basically what's happening. Why is it happening now? I don't know, just basically because all those things are connected together. I don't know that, I guess maybe your question is the development of the anti-inflammatory related to the development of the pro-inflammatory? I don't think so, not to my knowledge. I don't know much about the anti-inflammatory drug development story, but I don't think they're related. Yeah. Say that again, I'm sorry. Patient. So, the median age of kidney cancers, yeah, about 62, median meaning half-older, half-younger. Yeah, I don't know about that. It's a good question. I have no way of knowing. I mean, the hypothesis is, well, gee, your immune system is getting weaker over time and that's why, but I don't know that that's the case. Age isn't really an important factor in outcome for patients. So, a patient who's 40 or 60 or 70 can do just as well, vice versa, so that would sort of argue against that. So, it's a good question. I have no way to ask it. We don't have a good way to measure the immune system, right? So, all those commercials of these products that boost your immune system, right? I mean, that's marketing, right? We have no way to measure it. I mean, you can't really measure immune competence. You can measure T-cells. You can measure a lot of stuff, whether it's actually related, you know, to reality is a different question. So, there is no good way for me to measure and say, aha, your immune system has this score and five years later it has this score. I don't know how to do that. All right, come on, more questions. So, for all comers, it's about 30%. If you take everybody who has their kidney removed for kidney cancer without other visible disease, about a third of people will have recurrence, depending on the size and the grade and the stage and if you have tumor cells in the renal vein and depending on a number of factors? Somewhere. Somewhere, anywhere. Yes, just recurrence in general. Yeah, usually not the other kidney. So, yeah, general. There was some more. It's a difficult question for a Sunday, I mean. So, the moonshot is a, you know, it's obviously a federal program, basically to pump money into cancer research. So, I don't know. I mean, I guess this is totally my editorial opinion. You know, money is a good thing, right? We need money to do all these trials. There's no question about it. And so, on some level, more money means more progress, but they're not directly correlated, right? We can pump a bunch of money into something and it fails, i.e., see the public school system. Right? I mean, we can, so money isn't, it's necessary but not sufficient. So, I'm all for any programs that can give money, you know, to fund cancer research and prioritize that over other things, right? I mean, it's pretty early to know whether it's happening or not. You know, I think the initiative is fairly early and I don't know that I know enough to answer that question. There aren't. I mean, you know, we share, we'll share data with anybody. It's not like we're hoarding stuff and keeping secrets here, right? So, I guess it depends on what the specifics are. So, I mean, I think it's a good thing, but a lot, like a lot of big programs like that we'll see at the end of the day if it makes a difference. You know, there is definitely a marketing element to that, right? Calling it moonshot and we're going to do this and we're going to do that and it's great, but you know, for those of us in the trenches, reality is just slow, right? I mean, it's just hard. If it was a matter of writing a check, then great, let's do it, right? But it's harder than that. You got to understand the biology. You got to have the drugs. You know what I mean? So, there's some inherent things that you have to have or you won't make progress. And frankly, a lot of the recent progress with all these agents came well before moonshot, right? So, patients will be living longer with these drugs, having nothing to do with that program. So, it makes it hard to assess the impact, I guess, is my point, right? So, the spider plot where the only published data, the only public data is from a previous trial in like 10 patients or 20 patients, very small, so it's not terribly meaningful. It looks similar to the other ones I showed you, but, yeah, until those big trials are reported, that's when you get those nice charts to look at. Yeah, before that, I mean, I don't know the data. People up too late watching baseball last night? Sure. Sure, my pleasure, thank you. Okay, any other questions? Last chance. Yeah, exactly. That's true. All right, thank you. Thank you. Sure. Thank you.