 Thank you all for being here today. So really what I'm going to be talking about in the next 30 minutes is going to set the stage for some of the various treatments that we're going to be talking about later on in terms of the context of what targeted therapies are. And at the end, a little bit of a dovetail into Dr. Gow's talk into what they're going to be, what's going to happen with these in combination with immunotherapy. And also Dr. Taneer's talk with regards to how we use these in non-clear cell renal cell carcinoma. So I'm going to use the phrase as kidney cancer, renal cell carcinoma, and RCC interchangeably throughout this talk. So they all kind of mean the same thing here. And I'll be defining subtypes of renal cell carcinoma where necessary, although most of what I'm talking about here really is clear cell, about clear cell renal cell carcinoma. And so, you know, our paradigm in 2016 for how we treat renal cell carcinoma once it's spread to other organs in the body really is that we start off with a treatment A where we have good evidence that this is going to be helpful in individuals who have not received prior therapy. We then move on to treatment B in the context of what patients have received previously and move on to hopefully treatment C and D and E as we move down the line. And how we actually sequence these is obviously an art in the science and of itself. But I'm going to talk a little bit more specifically just about the information we have about some of these agents. So I'm going to break, we're going to break this down into what I would call anti-angiogenic agents or for the large part TKIs or kinase inhibitors. And these are the kinase inhibitors that have been FDA approved or about to be FDA approved in renal cell carcinoma with some, with a bit of a question mark here. But the ones that I'm mainly going to focus on this morning are sunitinib or sutentpizopinib or votriant, exitinib or inlida. I'm not going to talk that much about bevisizumab or seraphinib because we don't use them quite as much and I only have 30 minutes. And I'm going to talk about chometric or cabazantinib which, and also lenvasinib, I'm not going to talk about for the interest of time. The other major sort of targeted drugs I'm going to talk about are these mammalian-targetive rapamycin or mTOR inhibitors which we have two that are approved, temserulimus and everulimus. And then Dr. Gao is going to talk mainly about nivolumab and other immune therapies and there are two FDA approved immune therapies for renal cell carcinoma nivolumab and HIDOS interleukin-2 or IL-2. So what is targeted therapy? It's a buzzword. It's one that we use a whole lot. And it's really a fancy way of describing a drug that can block a specific function within a cell, mainly by interacting with some other molecule. You know, you will, antibiotics are a form of targeted therapy. They target a particular molecule within the bacterium and kill the bacterium. So are some forms of anti-cancer drugs like receptor tyrosine kinase inhibitors or TKIs or the mTOR inhibitors or that we are using. So what is a kinase inhibitor and where are the ones that we're currently using working? So what I have here is I have an image of a tumor. And when we think about treating tumors, it's really important that we realize we're treating an organ here, right? We're not, you know, there are the cancer cells, but once you get beyond a certain number of cancer cells, those cancer cells then start developing their own ecosystem, their own organ, where they have lead vessel cells that start coming in and feeding it. They then have the stromal cells. And you also start getting immune cells that come in there as well. And this whole thing kind of interacts in ways that we're gradually learning and is actually critical for us to learn and how we actually design studies where we can actually look under the hood of how the cancer is working is critically important. So the kinase inhibitors are working on particular proteins that are on the surface of cells, and this could be on the surface here I'm pointing to, an endothelial or blood vessel cell, or it could also be, or we could also have targeted therapies against something that's inside the cell, that actually does work inside the cell. And so then this little kind, this receptor actually, for the large part, these are proteins. And the protein is basically a string of amino acids, which are the building blocks of proteins. And they form very specific shapes. And each protein, if you have a string of several hundred amino acids, one type versus a string of several hundred or a thousand amino acids of another type, you get something that kind of clumps together in these very beautiful shapes in very different ways. And that very different shape then confers different activity. What then happens is we can then get that protein, can then be regulated. So you have, let's say that this protein here is on the surface of a cell and some kind of other molecule comes along and interacts and touches this protein. And that will then allow this protein to get modified in a way that it'll get activated. And what I have here, a little P with a circle is a phosphorylation, which is a very common way for a protein then to get activated. And that then gets that protein to start then talking to other proteins and turning those proteins on. And what a kinase is essentially a protein that actually can activate other proteins. And so what we want to do in cancer is we want to inhibit the activation of some of these bad proteins or these proteins that shouldn't be activated. And that's going to decrease the behavior of the cancer. And so what we have here is we have now what's called a small molecule. And the reason it's called small is relative to the protein, which is small already, but this is even smaller, as you can see by its size. It's a chemical structure now. It's not made of amino acids. It's a chemical structure that's been designed to basically fit into some of the peaks and valleys, mainly valleys, of this protein that then jams that protein and prevents it from working. So when you take Suthent or Votriate, basically where you're taking these, you're taking a chemical that's been carefully designed to interact with very specific proteins that help the cancer grow. And in the case of Suthent or Sinitinib and Pozopinib and the other TKI's, these are usually VEGF receptors. These are receptors in the surface of the endothelial cells. So basically you're starving the endothelial cells. Clear cell renal cell carcinoma is the one that actually produces the most of these blood vessel cells that we can then target with these drugs. And so what I have here is I have the different major subtypes, and you've probably seen this already a few times this morning. And we have clear cell over on the left, which has a mutation in the VHL gene. And the VHL gene creates a protein. And again, we see these cute little things that look like something that maybe your kids or grandkids would draw. But what they are is they're actually depictions of how these amino acids actually form shapes. And this is the one that the red is the VHL. And the VHL forms this very special protein that does stuff inside the cell. And what VHL does is it actually regulates other proteins. And in the case of VHL, one of the key things it does is it regulates HIF. And if you have low oxygen levels in the cell, the cell will basically say, hey, I need more oxygen. We need more blood vessels. And VHL sits back and is very polite and allows HIF transcription factors to actually then allow the transcription of very important proteins for cell blood vessel growth like VEGF. And VEGF then actually will activate the VEGF receptor, which is one of these kinases that I talked about. So that's what happens in low oxygen levels. In normal oxygen levels, what happens is you get VHL then grabbing onto these HIFs and essentially degrading them, preventing them from doing their work, okay? And you get degradation of HIF alpha. But if you have a mutation in VHL, it replicates the low oxygen levels. The cell is basically crying wolf saying, hey, I need more oxygen. It produces all of this VEGF. You get more VEGF receptors on the blood vessel cells. And that's what we block with drugs like Sunitinib, Pzopinib, Exitinib. And here we come back to our organ now. And you can sort of see what happens. You have the tumor cell that we see here. You see now there's VEGF being produced. You get these VEGF receptors that basically get activated by the VEGF. And you get more blood vessels inappropriately, all right? And this has resulted in a whole bunch of drugs that have been FDA approved, including, like I mentioned, Sunitinib, Pzopinib, Exitinib, Seraphinib. Are the kinese inhibitors, these small molecules that I'm talking about? Just a bit more background before I start delving into some of these. Disease aggressivity for renal cell carcinoma really is something that's important for us in terms of how we can talk with patients about what the prognosis is, what the likelihood is of surviving one, two, three, or four years independent of therapy. And this also is beginning to allow us to think about how to categorize patients from a therapy perspective, okay? And we've observed that different patients' disease is more aggressive than others. We've created relatively simple tools to be able to obtain information, to be able to categorize individuals. And these tools are called risk models. And so the first one that was developed was back in 1999 and 2002. There were publications that came out of Memorial Sloan Kettering Cancer Center that created a risk model that used real simple stuff, the performance status, which is how well is the patient feeling overall. The calcium levels, the hemoglobin levels, the LDH, which is a blood level of sort of a liver enzyme. And also whether or not they needed to start treatment within one year of their initial diagnosis. And using these, they were able to actually categorize people into people whose survival ended up being somewhat better, which is in the blue line here, or somewhat worse, is what we see in the black line. And this provided us some guidance in some of the clinical trial designs. And then there was a slightly newer one, which was then used, generated, out of a population of patients who had actually been on these targeted therapies. It changed a little bit. We got rid of LDH and we added high white count and we added high platelet count, but it's the same sort of thing. And if MD Anderson had done one, maybe we would have been identical to this. Maybe one or two other factors would have come in or come out. But you get the idea here. And this also was very useful in categorizing people into different risk categories. This is sort of independent of therapy, but like I said, as we start learning more and more about the cancer biology and also about the drugs we're using, we're more and more going to have strategies for these different risk groups, because these risk groups are telling us something or hinting at information. And so what we really need to do is really need to bring this knowledge out of the shadows into the clear light of day so we can really understand what the biology it is that makes these curves happen. Here's an overview of how the drugs that I sort of put in sort of semi-table or sort of in list form before into a table. And I'm going to delve into this table a little bit. So we have first line therapy, you know, that first line and then the second line therapy. And we have using studies, clinical trials where several hundreds of people got drug A versus drug B, we could then show drug A was better than drug B. With usually the readouts would be time to disease progression or in some situations also overall survival. And we have here, Sunitinib or Sunitinib, Pozopinib or Votrient. We have Bevisizemeplis interferon in first line therapy for people who have good to intermediate risk features. And then we have in people who have poor risk features, we have high level or high quality data on temps or lemus. We have some alternatives here. Also in the second line setting, we'll focus on what vast majority of individuals in 2016 or individuals who have been on it, some sort of prior VEGF receptor or VEGF inhibitor, one of these kinase inhibitors. And here we have Affinitor or Everleamus. We have Exitinib and we have some new kids in the block. Nevolumab that is FD approved and Kevazantinib, as I mentioned, is kind of coming down the pipeline. So let's talk a little bit about some of the data that have actually generated that table. That table isn't just something that somebody woke up one morning and said, hey, I'm going to make this table. It's based on trials that were done with hundreds of people where we ended up getting these data with very robust end points which we believe are clinically significant. So let's talk about Sunitinib resutent. It's a small molecule inhibitor. It's that little red thing that's jamming the protein from behaving. And it's officially given 50 milligrams by mouth four weeks on and two weeks off, although we have data now in retrospect suggesting that two weeks on and one weeks off actually ends up being better tolerated and looks like it's probably not worse from an efficacy perspective. And there are actually several clinical trials. It was at least one prospective meaning sort of moving forward, testing that this alternate schedule is better than the old-fashioned schedule. So schedule is actually important. It's just an important little point here. This was approved way back, like 10 years ago. And it's still one of the most commonly used drugs in the frontline setting. Why was it FDA approved? Well, it's because when a 750-patient study was performed looking at individuals who were on Sunitinib versus people who were on what was back then, the standard of care, which was interferon, hard to believe. But that's, you know, and there are some people who benefit from interferon, but it's pretty clear here that basically what we have here is the probability of not having progressed on this axis here, the number of months that the people were on the drug. And then as the line curves goes down, these are called Kaplan-Meier curves, obviously as it goes down, that means that your disease has progressed. You want the line to stay up. Perfect would be, this line would just be going across here, people never progressed when they're on that drug. So this is definitely less than perfect, the green line. The brown line is better. And the progression of free survival was higher. The other thing was that then they looked at overall survival in this patient population. But what had happened already here was that a lot of people who were on interferon in the frontline setting, all of these people had not previously received any therapy, they then got onto a drug like Sunitinib or Pozopinib or something like that. And then in overall survival, they kind of might have gotten rescued. So the overall survival curves were not separated as much. So let's talk now about Pozopinib or Votrient. So this is another one of these small molecule inhibitors that blocks this protein, this kinase on the surface of blood vessel cells, VEGF receptor. And it's given 800 milligrams per mouth day continuously. We've done less playing around here with schedule, although a lot of us in the clinic, when a patient is on Votrient, it starts feeling kind of worn out. We often recommend, hey, why don't you take a break for a couple of days instead of lowering the dose first? And oftentimes that lets the body get better and feel better, and we can recover faster from the treatment. This was after you approved a couple of three years later. And so this was after you approved in the basis of another one of these randomized studies. So this is basically people who had not, either had not received prior therapy or had received some sort of old fashioned immune therapy before. And computer flips a coin, they either got on Pozopinib or they got on placebo, basically a sugar pill. And then they looked to see how long people took till they progressed. And what it showed is this was the overall study population here on the left that clearly Votrient or Pozopinib allowed people to not progress for a longer period of time than people who were on the placebo. And over here we have people who had not previously received any therapy and we see that those curves spread over even further. And what's, you know, before you say, well, that was kind of unethical to put people on placebo when we knew that had a reasonable idea these types of drugs worked, they then actually got to cross over to the Votrient when they progressed. So they actually, it was kind of a Votrient first versus Votrient second kind of study. And for that reason the survival curves were essentially the same. So let's move on to Toracel or Temsarylimus. This is an IV molecule that's given weekly and this was FDA approved in 2007. It was a little bit different. This was a study where individuals who now had poor risk features. So remember I talked about those risk algorithms, they had to have at least three of those negative features. Actually there was another feature they added, a fourth one, so they actually had six instead of five. And people had to have those risk features so they had more aggressive disease. And they were randomized between interferon which was the standard back in the 2000s and Temsarylimus plus interferon or Temsarylimus alone. The primary endpoint here was overall survival. And although it's a little bit hard to see here, you see this is the green curve, these people did live longer and it was kind of modest but if you then look at the numbers you see that it was an 11 month survival for people on Toracel versus seven months. And this was already definitely looking better than the five month median survival that we've been seeing with poor risk patients back in the 2000s. So not great but certainly better than before. So should we use Temsarylimus in all poor risk patients? What we don't have is we don't have good data to really ask the question of whether some of these targeted TKIs that we've been talking about are useful in that patient population. And so Dr. Taneer and Dr. Zerita who Dr. Taneer is here in the audience is gonna be talking next has a study that he's the principal investigator on testing whether or not Toracel and Votrient are as good for this patient population. This is a randomized study, we've enrolled more than half of the patients and we plan on getting up to about 90 people on this study. So so far I've talked mainly about first line treatment. So you come in, you either had an effect to me several years ago, you now are found to have metastatic disease or you have both at the same time and Dr. Wood or Dr. Karam or Dr. Mateen perform an nephrectomy and you're then ready for treatment. So you get that first line treatment and then let's say you progress. What do you do in the second line? So remember back in the table that I showed, I showed a Phinitor or Everlimus, I showed Exitinib or Enlida, I showed Nevolumab or Updivo and I also showed Kebazantinib or Kometric and so I'll talk because that's my talk about the targeted drugs here. Dr. Gao will talk more about the immunotherapies in that situation. So a Phinitor or Everlimus, this is an mTOR inhibitor. So it works somewhat differently. It actually blocks a protein inside the cancer cell itself. If the cancer cell is kind of a bus that somebody has stuck the accelerator on and the bus is moving too quickly, what the Phinitor does is essentially it slows down the bus. It takes the foot off the accelerator, it slows the bus down. It doesn't actually stop the bus or crash the bus, turn the bus to the left or right. It basically slows down the trajectory of the disease of the cancer cell growth to some degree and this obviously provides some benefit. Torus cell is another mTOR inhibitor. We saw that provider and its survival advantage, especially in rapidly growing tumors. So a Phinitor in the second line setting was tested and it was approved in 2009 and it was approved on the basis of this study. This is a study that looked at people who had previously by and large received either Sutek or Nexivar and they were randomized between a Phinitor and placebo. And there was crossover allowed. So if you were on the placebo and you progressed, you were allowed to get on the Phinitor. And the progression free survival was definitely in favor of the Phinitor. So here we have this Kaplan-Meier curves again. So remember, this would be ideal if we just had a line across like this all the way straight down would be the worst possible and we're trying to strive for that straight line here. And you can see that here the Phinitor is definitely doing better than the placebo. Progression free survival of about five months versus two months. And the overall survival once again because of the crossover was no different. So that's why it was approved in 2009. Exitinib or Enlita is another drug that was FDA approved for second line treatment for renal cell carcinoma and this was FDA approved in 2012. And this was on the basis of another study where you had people who had progressed either on an immune therapy. This was done in Europe where they were still using a lot of interferon and stuff or a TKI, I like Sunetinib or Pozopinib for the large part or Bevisizumab. And they were randomized between either getting Enlita or Exitinib or Serafinib which was one of the first FDA approved drugs for kidney cancer, another targeted drug. Again for the interest of time, not gonna talk about it. We don't use it that much for kidney cancer anymore although it's still a decent drug. But what they showed is that the yellow line represents the group of patients that were on the Exitinib and they clearly did better. Their disease progressed later than the people who were on Serafinib. Although these are not massively different. And if you then start parsing this out and looking at individuals who had previously been on Sutent and then moved on to receiving Enlita, their progression free survival was about five months. They're not that different from Exitinib, sorry, from Affinitor. So it's pretty clear that anti-veget therapy in these Amptor inhibitors themselves are a great advance. There's no question we're improving survival with these drugs. Things are very different from 2005. But some people never respond. Most people end up having to go onto second or third line therapy and we need to do better. So what are some novel treatment approaches we're doing and then let me just focus in on some of the agents that we're currently using. So there's some new inhibitors that I'll just mention and also there's also a Met and Axil inhibition that I'm gonna talk about. And there's a bunch of other cool new things that we're not gonna go into in great detail. Just a shout out for this concept. Remember back in the beginning slides, VEGF, if it's broken, HIF goes crazy, you get too much VEGF. Some finally people are developing drugs to start blocking HIF, which is an interesting concept. We don't know yet whether it's better than the targeted TKI's, but it is something that we now finally can do. What about Met and Axil and what on earth is Met and Axil? Well, so remember I was talking about these various receptors and we focused mainly on VEGF receptors where there's another two receptors called Met and Axil which are on the surface of the cancer cells as well as on the blood vessel cells to some degree and these seem to enable metastatic behavior, bad behavior by the cancer and blocking these makes a lot of sense. We know that Met is found on chromosome seven and basically we know that for example in popular kidney cancer when we look at chromosomal gains and losses in the tumors that Met is probably amplified in these patients so we get more copies of chromosome seven thereby more copies of Met. The same is true also in clear cell kidney cancer so this is a good strategy. We also have data that shows that people who have higher Met expression in their tumors don't live as long so this is something that we really wanna focus on and so this drug Kebazantinibracometric is a drug that's not yet FDA approved but we have some pretty cool data on and this is an inhibitor of VEGF receptor kinases as well as the Met and Axil kinases and the owners of this compound did a study where they took 650 patients who had previously received a TKI and they were then randomized between Kebazantinib or Kometric and Affinitor and the primary endpoint was progression-free survival and what they showed was that there's definite improvement compared to Affinitor everolimus in progression-free survival. In individuals who had previously just received Sunitinib as prior therapy the progression-free survival compared to Affinitor was even better so looking pretty promising and then the overall survival initial analysis that was reported in the summertime suggested there was this trend and this was unprecedented now in the second line setting at that time there was a trend towards improvement in overall survival and in the meantime this has now been shown to be conclusively positive so cool drug, some caveats, toxicities. All right so this is a drug that actually can make people feel pretty tired the diarrhea could be pretty terrible in times and it's a drug that we're learning we're gonna, if it gets to FDA approved we're gonna have to learn how to use because it's not gonna be a totally easy ride for the patients but we're gonna work on making it a better drug. So in summary, here's the overview that I've gone through we have these targeted therapies or TKIs where we have these little chemicals that can basically jam these receptors that are overexpressed in various aspects of the tumor organ. We use these in the front line setting drugs like Sunitinib and Phizopinib or the mainstays, Hemserulimus for poor risk patients we have clinical trials figuring out whether we can do better for the poor risk patients with these targeted therapies in the second line setting we have Affinitor Everulimus with Exitinib and we also have Cabazantinib. So what's the future gonna hold for these therapies? You're gonna hear a lot about immunotherapies a lot of buzz about immunotherapy are they just gonna take over and we're not gonna have any targeted therapies? Absolutely not. These drugs have a place they're gonna still have a place we are not curing everybody with immunotherapy and our strategy over the next five to 10 years has to be to figure out to look under the hood of the tumor organ figure out what we need for which patient at what time integrating immunotherapy with targeted therapy so we can actually get more people towards a cure. These agents at the moment still remain the frontline standards of care for renal cell carcinoma. So we have clinical trials with other agents like immunotherapies but we don't have anything FD approved in the frontline space. These drugs clearly help individuals and what it is and what we need I think the help of the patient community is to help us devise these new strategies. We need to get not only smarter drugs we also need smarter clinical trials. So examples of these combinations a trial that Matt Campbell one of our colleagues is gonna be the principal investigator on this is Exitinib plus Avalumab phase three study coming soon. We've got also a study that JJ Gow is gonna be talking about as a principal investigator on and this is a study that's ongoing of Nivolumab versus Nivolumab plus Avalumumab versus Nivolumab plus Bavacizumab. Try to say that fast five times and that's ongoing at MD Anderson Cancer Center and stop there. Thank you very much.