 Since we are a little bit ahead of time, I'd like to just take a moment and say that being the outlying speaker today, because everyone else has been based here at MD Anderson, it gives me the opportunity to say that that globally and nationally, the RCC community of doctors is quite strong, very friendly, and we share and work together at a level that a lot of our other peers and other tumor types and other scientists don't have. So we have great relationships, both personal relationships and academic relationships. So it's a very tight community. So hopefully that gives patients a lot of comfort in knowing that the doctors are not fighting each other, that we actually are on the same team to try to cure this disease. And so these doctors you've heard today, I get the chance to interact with at national and international venues. The Kidney Cancer Association has been a pinnacle for us in the kidney cancer world and have been vested in new therapies for kidney cancer back when kidney cancer was not sexy, back when all we had was interferon or interleukin 2 for therapy. So it's great to be here to talk about promising new therapies. My agenda is simple. I want to be, since I am the last didactic presentation today for you, I wanted to provide an overview of the current status of systemic therapy. You've heard the details of the clinical trials by Dr. Taneer. Talk a little bit about the new trials and some of the clinical trial methods that we're doing. You've heard that mentioned briefly by Dr. Taneer, some of the innovative patient preference trials, and then also talk about some new targets in ongoing trials in kidney cancer. So let's just start off here. This is a very busy slide. Don't worry about the numbers. This is just to show you we've got lots of drugs. You've heard that we've got seven new therapies available for this disease. And one of the benefits, probably one of the few benefits of having multiple therapies is that we've got choice. One of the negatives is that we need to have data and we need to have experience to help guide us on the choice. And I think a lot of us have felt in kidney cancer that the rapid development of new drugs in the disease has somewhat outpaced us scientifically in knowing how to best utilize the drugs we have. And so one of the new things moving forward for us in kidney cancer research is going to be trying new trial designs that allow us to compare. Because you as a patient and me as a doctor, I want to know which drug, compared to the other drug, is better. And we've got to do those type of trials. So it's one thing to have a bunch of drugs on the market. But do we really know what is the best sequence of the drugs? Do we really fully understand the combinations of the drugs? And that is something that's going to take years here for us to discover. But what is clear is that we have, of these panoply of drugs, when a patient comes in to see us and they need to start their therapy for metastatic disease, we generally have across the world two drugs that are chosen. And those drugs are synidinib and pozopinib. Those are the two most commonly prescribed agents in the first line setting for this disease, synidinib and pozopinib. And so we've actually done something that we've done across other tumor types too, is we've come up with these treatment guidelines. So it's one thing to have an expert like Dr. Taneer say, okay, you're going to get pozopinib as frontline therapy. But what is Dr. Jones who's out in, you know, middle of nowhere, Texas? What data source does he have? And so sometimes in the patient may not be able to drive to see Dr. Taneer, or they may not be able to drive to see me in Dallas. Well, the guidelines serve as a reference point for doctors to know what experts feel would be appropriate therapy. And what I've shown here is to be not politically correct, because I didn't choose the U.S. guidelines, I chose the European guidelines. These are the ESMO guidelines 2012. But they're somewhat similar to what we have. We use something called NCCN treatment guidelines. And the first thing to mention, a guideline is not an absolute, it just gives you an idea, because we recognize patients are individuals, and we need to tailor the therapy for the individual patient. But as you can see in the first line setting, synidinib or pozopinib, pozopinib has a little asterisk there. Those are the two most commonly utilized. Which drug you get, the trials show us, and we'll review that briefly. It really doesn't matter in regards to the outcome of response. There's a little bit of difference in side effects. So a doctor chooses one or the other, and I said globally, those are the two that are used. And if you have very poor features on your tumor, the way it's behaving, which is extremely rare, about 10% of patients we see are what we consider poor risk. They have advanced symptoms. The intense surlimus is pretty much the global standard for that setting. So how do we select? We select therapy based upon the individual drug, the differences in uniqueness between the drug in regards to side effects that the clinical trials have shown us. We look at patient-specific factors. There's no patient that's the same as the other. So patients have their own unique tumor burdens. They have their own medical histories. Some patients come in with histories of heart failure, heart attacks, strokes, other things that make us choose agents differently. We try to apply the available data that exists, the global data, on therapy for the disease. And we do this to try to get the optimal efficacy. We want to choose the right drug for the right patient that's going to give us the best outcome. And so there's a bunch of factors here, which we've actually spent time in the pharmaceutical companies. Obviously, they spend time maybe sometimes for different reasons. They want to know why we choose what we choose and why patients choose what they choose when it comes to these different therapies. And you can see listed here are the different patient factors that go into it and the different agent factors that go into it. But without a doubt, when we survey both doctors and we survey patients and people respond truthfully, the biggest factor that guides both the patient and the doctor and their choice of therapy when they're familiar with the data is efficacy. So patients want, this is to start off as initial therapy, their first line of therapy, they want the drug that works the best. They're not as concerned about the side effects if they have a drug that works better and shrinks the tumor more. So that is something important for us to know as we're selecting these agents. Another field of research is trying to find, are there ways that we can predict before we give the agent to a patient who is going to respond to the agent? Wouldn't that be great? Wouldn't it be great to be able to take your tumor, Dr. Wood or Dr. Karam cuts out of you to send it for genetic analysis. And then we find out, we get a print-off report, Dr. Taneer gets a print-off and says, this person is going to get Pizopina Votrant, and they're going to have an 85% likelihood of response or a 90% likelihood of response. Wouldn't that be great? You could hand that to your patient. That's the future. I think everyone in this room knows that we are doing genetic analyses now of tumors, and it's not going to be much longer. I'm hopeful that in my lifetime for sure that I would be able to be able to do that. And that's the hope for cancer, is to individualize therapy to that degree. So, I've told you, started off that we have seven of these drugs, and we have to commend pharmaceutical companies for doing something that's tough for them to do, and that is to risk it all, where they actually take on another drug. And so that's what happened in the comparison trial that Dr. Taneer mentioned to you. There was the two most commonly used drugs globally, are synidinib and posopenib. And we have a trial which can be faulted. Now, in our academic lectures, in our meetings, we kind of ripped the trials apart, and there's no perfect trial, but this was a trial that was designed to show that posopenib was as good as, not worse than synidinib. Wasn't designed to show that it was better. It was just to show that it was similar or equivalent to. And that was this particular trial, and what you see here is overlapping curves. I mean, it doesn't take a scientist to know that these drugs are pretty similar in their activity. So that allows us, Dr. Taneer and myself, to say either drug is probably gonna be okay for you, either drug is gonna give you the same likelihood of response. But what Dr. Taneer said is that these drugs are a little different. Even though they hit the same targets, they do so in different ways, and with that comes different side effects, and there are certain side effects, the ones that are in the teal killer up here, that are favoring synidinib, and there are a group of side effects that favor posopenib. And as you can see, as I started off, every patient's different, you could imagine there may be patients that are going to do better with one drug over the other based upon these type of side effects. And so this is what we as doctors utilize when we're choosing agents. Another kind of, this is the, when I was mentioning that I wanted to talk about novel trial designs, this is it. This is the first time I'm aware in cancer where we've done a patient preference study. Now again, academically in behind closed doors, scientists will argue about the validity of these trials, but certainly it was from a patient's perspective, this was a home run, because it allowed patients to have a voice to do a trial where a patient could actually vote as part of the trial results, whether they liked one drug or another, based upon side effects. And that's important to know when we have drugs that are very similar in their activity. If drug works about the same, it's important to know which one's better for the patient intolerance. And so as Dr. Tenier mentioned, I won't go through the details of the trial, they looked at both the doctor's impression of benefit and side effects and they looked at the patients. And we were able to show that actually the average person seems to favor posopenib in regards to side effects better than synidinib. So that important stuff to know and there was the breakdown that Dr. Tenier mentioned to you, 70% preferring posopenib, 22% synidinib. Again, with a lot of scrutiny on this trial, this was not a perfect trial, but at least it gives you an idea that there are differences between the drugs. That's first line, what about second line? Well, we recognize we're not curing anyone. Despite these unique cases, and I have them in my own practice, I have patients on frontline therapy, synidinib and posopenib for seven, eight, nine, 10 years. I mean, amazing lengths of time, but that's not the average person we see. The average person is going to have progression on one of these therapies at some point. And then the decision is to move on to the next therapy. And our goal as doctors is to give our patients all of as many options, as many of the available agents as possible to hopefully get an additive benefit of prolonging survival as long as possible. And what we are trying to figure out is what's outlined here, contribution, is each of these different therapies we give patients, we're trying to understand how much each of those therapies add to the overall survival. But our goal is the same, give as many of the therapies as possible to our patients. And I will tell my patients when I first meet them that that is our goal. So that they understand that it's unrealistic to think that synidinib or posopenib is gonna be the only drug for them. That's what we start off with. And that we have all these other drugs that we are going to sequentially use to drive survival as long as possible. And we've got all these drugs again to do this. And two of the ones that have been most, most putatively most commonly used as next drugs outside of a clinical trial. With a caveat, Dr., you know, M.D. Anderson and Baylor Weymatt, we are big clinical trial centers. So our patients are going on trials, but for the average patient who's not on a clinical trial, they're going to be getting one of these drugs next. And whichever one they don't get next, they get that one after. So we sequentially use these drugs and the two most commonly globally used drugs now as second line therapies are either the affinity or everolimus mTOR inhibitor or exidinib, which as Dr. Tenir mentioned, was the second generation powerful VEGF inhibitor. And so at the end of the day, this is my, this is finishes my review of what you've heard so far is our goal is, we want to achieve long-term survival and that we recognize in 2014 is going to require careful selection of agents for each individual patient. And I can tell you, I can speak in general terms, this is generally what I do first, second, third, fourth line, but that's a generality. And it changes based upon individual patients, it changes upon the individual patient's response to the therapies. So the way they respond to the first line therapy may influence my choice of therapy in the second line setting. The side effects you can imagine, when they have a side effect in the first line therapy, that may influence my choice in the second line therapy, et cetera. So we do, even though we make general statements about how we're going to use the therapies, we do want to tailor that to individual patients. Okay, busy, isn't this a nasty slide, right? Tough slide, I borrowed some of my slides from Tony Tueri, who's one of our colleagues at Harvard. So if he's watching on the video cast, he'll recognize some of these slides. This slide, very busy cartoon, is depicting the sites of action biochemically in the cancer cell and the microenvironment. So we've got up here synidinib, seraphinib, posopenib and exidinib, which are predominantly working at the endothelial cell. That's the cell that makes the vasculature. And then we've got the mTOR inhibitors, which are going to be working down here in the mTOR pathway. What we recognize cancers are so complex, I mean major complex, PhD level complex, that there are a variety of other targets to potentially, to hit, to potentially affect kidney cancer growth. And one of them that's been looked at here is in this red blocks is growth factor receptor for MET. You hear about MET, which is a growth factor receptor in FGFR, fibroblast growth factor receptor. Those are two targets that novel drugs for kidney cancer have been studying. And the first one to talk about is cabozantinib. Cabozantinib is a MET inhibitor. It also inhibits VEGF. And this drug, cabozantinib, has a brand name of Cometric and has received FDA approval for thyroid cancer already. But our colleague, Tony Twerly, who's trained with me at Cleveland Clinic and is now heading the kidney cancer program at Dana-Farber and Harvard, I did a trial in patients with refractory kidney cancer including patients with a subtype of kidney cancer which doesn't do well with therapy, a psychomatoid type of clear cell kidney cancer. And he was able to show in a refractory setting, so third, fourth, fifth line setting that there were good responses, confirmed partial responses of 28% on patients. There was only 25, mind you, in this smaller trial. 52% of patients having stable disease. In a median progression free, that's the length of time the patient's able to be on the therapy with control of over a year. So an exciting drug. And they included in this trial some different correlative studies. And this was radiographic responses using volumetric scanning. And just to show you, this was the baseline of one of his patients on the trial. And then after eight weeks of therapy, showing dramatic response. And this is important, because this particular patient you can see was a heavily pre-treated patient. Patient who's already had four lines of therapy. They had synidinib. They had a traditional chemotherapy drug called gemcytabine, which is a chemo drug which is used in kidney cancer. They had the mTOR inhibitor affinitor, which is commonly used second or third line. And they had this drug which you name might not recognize as Ramucerumab, Ramucerumab. I don't even know if I pronounce it right. But it's an Avastin or Bevacizumab like drug. It targets VEGF receptor two antibody. So this patient's been treated with drugs that should work in kidney cancer. And they're getting this as a fifth line therapy, showing this degree of response. So obviously a lot of excitement was generated by this trial. And so this has resulted in CaboXantinib being studied in two major phase three trials. And if these trials are positive, the drug will move to FDA for regulatory approval. These trials are ongoing as we speak. In the cooperative group, the Alliance CLGB cooperative group, don't tell me why they come up with these names, but that's a group of cancer centers generally through the Midwest of the United States is doing a randomized phase two trial comparing the CaboXantinib drug with upfront Synidinib at the traditional schedule four weeks on two weeks off. So this is gonna be in a frontline setting. And then probably the big trial that will result in regulatory approval though is in the second line setting. And that is the Meteor trial. Nizer, are you doing this trial here? Yes, you guys have this available to you in Houston. I'm also doing it in Dallas. This is a major phase three trial. This is the regulatory approval trial for CaboXantinib versus Everolimus. And patients have had to have had progression after frontline VEGF targeted therapy. The primary endpoint is progression free survival and secondary end points overall survival. So that's exciting. As you've heard already, there are different types of kidney cancer, right? So clear cell is the predominant type, the one that we know the most about. The second most common type is the papillary type. And the papillary actually to be more sophisticated and more complicated, there's actually two types. There's a type one and a type two. The type one hereditary papillary renal cell cancer is associated with a met abnormality, met gene. So just like VHL was a gene associated with clear cell, met is a gene associated with papillary renal cell cancers. And we have developed inhibitors that inhibit met. So met is involved in other cancer types too, but in kidney cancers, what we're interested in, there was a drug for red nib, which is a dual inhibits VEGF receptor and inhibits met receptor was studied by our friend, Tony again in patients with papillary renal cell cancer showing significant evidence of benefit. This is what we call a waterfall graft. And so what's going down negative here is the amount of tumor shrinkage that's seen. So you can see the majority of patients are having some degree of tumor shrinkage when they get this drug in their papillary renal cell cancer. And it's a minority amount that actually has tumor growth. And they showed a progression free survival of almost 10 months, which is not bad in comparison to other drugs that we use for the disease. So again, an exciting new drug pigeon hold for a rarer type of tumor papillary. What about biomarkers? We talked that we don't have any predictor markers in the future there with maybe genomic sequencing and looking at the tumor, but we're also looking at biomarkers. We're looking at ways and chemicals that we can test that we could determine whether or not a patient's responding to a therapy and how long they'll respond. And there's a variety that we've looked at. Unfortunately, none of them have been validated yet, but we continue to search for these. These include things for interleukin-2, high-dose interleukin-2, trying to find ways we can predict and who's gonna benefit from that. VEGF targeted therapy, there's a list and MTOR inhibitors. So this list continues to grow and is ongoing. As I end now, we've talked about, I think Cabo-Xantinib, which is probably, most would agree, is one of the major drugs that's on the horizon. It's an oral drug, similar to the Sutent-Votrient family in regards to it being an oral drug with similar side effects, but inhibits C met. The Ferretinib drug is for a rarer indication. The next big group that is really on the horizon is the immunotherapy you've heard about in detail. So just briefly, there's a couple of vaccines that are being studied. Vaccines that are being studied in patients and the refractory setting in the vaccine types of therapies that are being studied in patients as adjuvant therapy. And this is just a phase two study looking at one. This IMA-901, which has 10 tumor-associated peptides and these tumor-associated peptides are supposed to stimulate the immune system to fight the cancer. And they were able to show, in patients that actually develop immune responses to this peptide, a significant benefit. And these were patients with advanced RCC who had prior therapy with both interferon and alukin-2, TKIs, which would be like the synidinib-pozopinib, and had documented progression, that when they gave them this type of therapy and the patients had an immune response to it that they were able to have benefit. This has resulted in a phase three trial that I have not seen the results of yet, looking at this in combination with Sutent. So people say, why would you take an immune stimulator in combination with Sutent? Well, part of the story that you haven't heard about is that Sutent itself, besides inhibiting VEGF and blocking blood vessel development, is an immune modulator itself. We haven't spent a lot, we don't fully understand it well, but it is clear in labs around the world that Sutent can affect the way the body's immune system is response to the cancer. And so there's been a lot of immunologists that have worked on this. One of my mentors at the Cleveland Clinic has published on this. And so the thought is that maybe you could use this stimulator of the immune system, this 10-peptide vaccine, if you will, and combine it with Sutent and hopefully adjust the Tregs in the tumor and make them more responsive. There's another trial. This is a autologous dendritic cell vaccine. I don't know if you're doing this, Nizer, I'm not. You are. So this is the ADAPT study that is a similar type of thing where you're combining the therapy, sequencing it with Sutent. Again, for the same reasons that Sutent does have immune modulatory effects on the immune cells, the tumor-associated immune cells. And then finally, as I end, you've heard this eloquently mentioned already, that the break on the immune system is this interaction between PD1 and PDL1. And there's energy, which is when your immune system, you're allergic, you don't have reactions to normal immune stimuli, or on the other extreme, you have autoimmunity. And I'm sure you've heard of immune-related diseases like rheumatoid arthritis, SLE stuff. So there can be situations when your immune system just attacks everything. So the problem with the PD1, PDL1 is that's the break. And so we're trying to design therapies that will take off the break that the cancer puts on the immune system to take it off so that the immune system can work, but at the same point, not throw someone into autoimmunity where they're having the immune system attack the body because that produces bad side effects. That would be similar to what happens in bone marrow transplant patients. And so there's been a lot of work into this. The PD1 inhibitors and the PDL1 inhibitors, these are them shown here on the slide. From earlier studies, this again is from my friend Tony's presentation at 2013 ASCO meeting. You can see with the nivolumab, which is the BMS compound, that this is a spider graft, and anything going down negative here is a response. It's the degree of tumor shrinkage. You can see the majority of patients that got this PD1 inhibitor, this checkpoint inhibitor, they were having benefit with tumor shrinkage with kidney cancer. And then you can see one of the PDL1s, also about 50% of them having some response to the therapy. So both of these antibodies to those checkpoints that are the brakes of the immune system are demonstrating benefit. One of the interesting things is that we can actually test the tumor for expression of PD1, PDL1. And so when they look at PDL1, the problem is it's not perfect. It's like PSA testing, it's not perfect. So it's unclear whether this will be useful for us, but clearly if a tumor is expressing PDL1, those are the people that are getting their responses to a PDL1 inhibitor, versus if you don't express the PDL1, you're not. So you remember what I initially said when I started the talk, the future would be able to do a test like this on someone's tumor and determine who is going to benefit from the therapy and who is not before you give the patient all the side effects of the therapy. And so this is a step in the right direction again, but it's not perfect. It's unclear whether this will move forward. And then there are several phase two trials of NIVOLUMAB. This is an ongoing trial, phase three trial. It's on the verge of closing soon. It closed already. I thought it closed in Decemberish time period, December, January, but the results will be forthcoming within the next calendar year most likely of NIVOLUMAB versus Everolimus as a second line therapy or third line therapy. So patients could have had one or two prior VEGF therapies and get this as a second or third line. So whenever you see phase three trials like this, where you have the experimental drug comparing it to one of the standard drugs, that should tell you that that is a registrational pathway. And if they beat it, if they win, they potentially can get the drug approved. So that's what the NIVOLUMAB, the PD-1 inhibitor, the PD-L1 inhibitor, which is the roast product. We actually have open, I don't know if you all do, but it's a frontline trial and it combines the PD-L1 with Bevacizumab, that's one arm versus Sutent, the other arm, as a frontline therapy, and it's a phase three trial of that particular agent, that trial's ongoing. So you can see, to summarize, we've got Cabozantinib, which is a phase three trials ongoing, which is a very exciting drug that has high hopes that will become approved and on the market. Then you've got these two agents, the NIVOLUMAB, phase three trial, already completed waiting results, and you've got the upfront, which I can't pronounce the name of that particular drug, it's the ROSE PD-L1 antibody, which is ongoing. So again, three new drugs, which have real hopes in the next year or two to hit the market. So as I end, I think I'm up with time. Chris is standing there. Thank you, thank patients, thank the KCA. Thanks for your attention.