 Morning. Thanks all for coming. What I'm going to do over the next 20 minutes or so is talk a little bit about some of the agents that we use for kidney cancer and then talk a bit about some of the ones that we are using in the front line, some of these agents that are approved in the front line setting and one agent that's kind of coming down the pipeline in the front line agent. I think it's important for us to talk first about how do these drugs work and I know that many of you are seasoned patients and you've heard this stuff before but I think it's always good to review. So there's really three major classes of drugs that we use for kidney cancer. The first is a blood vessel starving or anti-angiogenic drug of which we have a number that are approved. Su-Tent and Votrient are very good examples of it. Cabometics is also an example of it and the second major class which you're going to be hearing about from Dr. Gow are the immune modulating drugs and there is the old-fashioned one, Hydro-Center-Lukin II or Pro-Lukin and then there's the new-fashioned one, an example of which is Nevolumab or Updivo. And the third are M-Tor inhibitors, a mammalian target of rapamycin inhibitors. And when we are treating cancer increasingly we're realizing that what we're doing is we're treating an organ. We're not treating just the cancer cells. Actually for the large part we're really bad at targeting the cancer cells directly and so a lot of the treatments that we use are either just kind of tickling the cancer cell and slowing it down but not killing it or working indirectly through other cells which we can either decrease their function or we can increase their function. So these anti-angiogenic or blood vessel starving agents do exactly what those words sound like. They will actually target those blood vessels. In a cancer blood vessel cells themselves are actually not cancerous. They're normal cells. They don't have mutations generally speaking but what they are is there are new blood vessels that have been generated that are young and immature and are addicted to factors that the tumors are actually producing. So because they're addicted to this and they're more vulnerable, if you block that then you can actually damage those blood vessels and not the normal blood vessels in our body for the large part which is why these drugs actually work. Because otherwise if we were going to be using blood vessel starving therapies and our aorta and our veins and arteries and the normal parts of our body were to break down this would not be very therapeutic but because it's affecting the blood vessels of the cancer the tumor organ itself then we are we are targeting that. And so this tumors as they grow one cell, four cell, eight cell, sixteen etc. when they're really small you can actually get nutrients to the middle of the tumor without any major problems but as they grow beyond a certain size you can't get the nutrients in the middle anymore and that's when these blood vessels start forming. So in that regard these therapies probably only work when there are blood vessels in the tumor so just micrometastatic or one circulating tumor cell or one tumor cell that's lodged somewhere in a lung or other organ in the body probably won't work that well but once you have those blood vessels it will work better. So the immune agents that Dr. Gao is going to be talking to you about they work rather differently. So we've known for the longest time that kidney cancer is an immune responsive cancer where in some cases we see spontaneous shrinkage we've seen that interferon and interleukin-2 kind of work but they don't work as well as we want and part of the reasons why is because our immune system as you're going to be hearing has a set of checks and balances. You probably know of or have heard of or have friends and family members who have lupus or rheumatoid arthritis. Those are examples of our immune system run amok and so we don't want that either. We don't want our immune system to be overactive but we don't want it to be underactive either. So the therapies that Dr. Gao is going to talk about they actually will help the T cells, the immune cells that are sort of in between the blood vessels and the tumor cells to wake up, recognize the cancer cell and eat and kill the cancer cell directly. The third class of drugs are the mTOR inhibitors and these are if the if the cancer cells themselves are a runaway bus with with the gas pedal on full what they do is they basically take the foot off the gas pedal and they slow down the bus but they don't actually stop the bus or you know bring it to a halt. It slows down the rate of change. So they're they're probably the weakest agent of the three although there's a subset of a small percentage of individuals who derive major benefit from these. So that's sort of a little bit of a background of the different classes of drugs we're using. The one that's most exciting really and where there's the largest growth or in the immune therapies and there's a far more immune therapies out there now already than we can even design clinical trials for and that means that we're going to have to think differently about how we design clinical trials in the future because now what we're doing it's basically we design a clinical trial around you know let's think imagine a pill and it's surrounded by a whole bunch of people and we're basically trying to apply a whole bunch of people to that one pill or in drug. In the future when we get smart enough we can characterize an individual's tumor better we will then take that patient and essentially do experiments with saying all right characterize the tumor and then come up with therapies that are that are really personalized and specific to that person's tumor and as the tumor changes because it's always trying to escape what we're doing we can then alter in a smart way the therapies that we're applying that hopefully is going to be the way we treat people 10 years from now. So again without taking away from Dr. Gall I'm sure he's going to show far more beautiful slides than this I'll skip these just so that I don't I don't steal his thunder. Couple of definitions nephrectomy is as you've heard removal of kidney adjuvant therapy is therapy that we give after we don't see any evidence of cancer like after a surgical removal after the nephrectomy. Metastatic is stage four when you've had spread to other organs in the body. Randomized trials mean that basically you have a study where you have a bunch of people and you then basically divide them into two or three whatever you divide them into these two groups and then you let a computer flip a coin and decide which drug one group gets versus the other group and so that's basically how we figure out when we do trials to make sure that these trials are done in a fair manner and we are a fair testing of the drug. Double-blinded sounds kind of scary but this means that when you do a double-blinded randomized study this is when you don't the doctor nor the patient knows whether or not they're on the experimental arm or whether they're on the standard arm and then study phases phase one studies we're basically trying to figure out what the best dose is what's not toxic. Some hints of effectiveness phase two is when we move on to figuring out whether a drug shows some signal for a particular group of individuals and phase three is when we're actually proving that that drug is useful for that group of individuals. So let's now talk about treatment for metastatic disease in the frontline setting. Here is a table which I'm going to all ask you to memorize because I'm going to hand out a quiz after just kidding. This is basically the table of the drugs that are currently available for kidney cancer both in the frontline setting which I'm going to focus on to see first-line therapy and then second-line therapy and then you see in the second column there is risk, good or intermediate risk and poor risk. I'm going to explain what that means why when we're talking about risk factors and then I'm going to focus on the approved agents Sunitinib and Pozopinib or Su-Tentin-Votrint and I'm going to introduce cabometics or cabazantinib as an experimental agent in the frontline setting and I'm going to briefly talk about Torosel. So what are risk models? It's not whether or not you're acting risky or more or less risky but it's whether or not your cancer has higher probability of resulting in shorter survival versus longer survival. And so these risk models are statistical creations where you take a couple of different factors, you take things that seem to be associated with better or worse outcome for example short time from diagnosis to treatment, low hemoglobin, high LDH, high calcium, less feeling wellness and then you put those together and you can come up with these models that say that if you have none of those risk factors you're going to have the best survival if you have one to two of any of those risk factors your survival will be somewhat lower if you have three or more it's even lower. And what we're looking at here is we're looking at what are called Kaplan-Meier curves. I guess those are the statisticians who develop these and then you have years from diagnosis and then you have proportion surviving so x-axis is years from diagnosis, proportion surviving is the y-axis and as people pass away the lines go down and so you can see obviously the blue line is the one that has the best outcome again not great. This was back in the interferon era. We have another one that's called the IMDC or we also call it HING criteria after Danny HING who's a wonderful statistician and kidney cancer doctor who lives in Canada and this is a slightly different risk model where we basically take out LDH what you saw in the other one and put in high white count and high platelet count as being other negative risk factors and here again you can create these and you can show different survivals as a function of these risks. Okay so now you guys are experts on what how these drugs work and why when we talk about risk stratification or risk models what that means. So some of the key questions we want to ask are once you're diagnosed with metastatic kidney cancer do you have to start treatment immediately? You heard a great talk from Dr. Wood about you know taking using surgery to actually render people free of disease but what about watching and waiting even when you have metastatic disease might sound crazy but let's look at some of the data. Is there a best frontline TKI and you know with with all respect to the pharmaceutical companies and and that the answer is probably not although we can take really good drugs and make them work somewhat better for patients and then I will not ask is there an ideal sequence after frontline treatment failure that's what Dr. Taneer is going to talk about but then I'm also going to talk about m-tor inhibitors or specifically toroselabit. So what about what we call active surveillance so if you have a patient who's diagnosed who has metastatic disease can we watch and so Brian Rini one of our colleagues at Cleveland Clinic designed this study and took 52 individuals who had asymptomatic mean they're symptom-free they didn't have any pain from any of their their metastatic sites and had no prior treatment and watched them basically every three months and determined how long it would take for them to really need to start systemic therapy systemic therapy meaning active therapy and the answer is that it took about 22 months for the good risk they also then stratified between good good and intermediate and sorry good risk patients and then intermediate and poorest patients and if you had good risk features you could wait almost two years before starting therapy in this trial versus in the unfavorable group they have to start sooner because you know maybe symptoms of rapid rapid growth of disease etc etc so this is something that we can do for some individuals. Just a slide of the NCCN guidelines so this is basically a guideline that is formed to basically the committee of doctors around the country who basically you know say what's the what's the therapy that we give in the front line setting or on the second line setting and here's kind of a laundry the laundry list and basically it's a set of recommendations for therapies that have some data and we see that Pazopinib and Sunitinib are category one and bevacizumabin interferon is also category one and then Toricellar-Temserulimus is category one for poor prognosis patients and category 2b meaning somewhat lower level of confidence for people who don't have poor risk features and you see high dose L2 for certain selected patients exitinib and best supportive care but let's talk about the two that are most commonly used first of all Sunitinib resutent and this is an oral anti angiogenic or blood vessel starving drug the official way of giving it is two is four weeks on and two weeks off although we have data that we have presented at GeoASCO and we're gonna be presenting at ASCO that show that that if you give people this drug two weeks on and one week off it looks like the number of grade four toxicities goes down or higher grade toxicities or side effects goes down and at least in our small study it shows it suggests that people get the opportunity to get a better response and stay on the drug longer and have better survival so the data are not super duper strong with regards to changing the schedule but if you ask any oncologist who treats kidney cancer around the country you can find that the majority of them have moved from a four week on two week off schedule to a two week on one week off schedule so the other drug that we we give a lot of is Pozopinib or Votrant and I'm gonna show some slides about why that drug was approved but Votrant is a drug that's also an oral agent and it's given daily and the standard dose is 800 milligrams per day that was FD approved in 2009 Sutant was approved in 2006 and then a study was done comparing them head to head and this study is actually a little bit interesting and it was called a non inferiority study this has nothing to do with inferiority complexes or anything like this but it has to do with the design of the trial this the hypothesis whenever we do a trial we're testing a hypothesis the hypothesis that was being tested is that Votrant or Pozopinib was not inferior to Sutant previously treated patients so it was pretty much as good as is another way of saying it although more technically you can't say it was as good as just that it wasn't inferior to this is a big study 1110 patient that were randomized between Sutant and a four-week on two-week off schedule versus Votrant in a standard 800 milligrams schedule and here again we have those Kaplan-Meier curves the one on the left are the is the proportion of people who did not have the disease start growing and the one on the right is the overall survival curve and again you know over time is on the x-axis the y-axis is then the number of people who are still in that happy state of either not having progressed on the left or are still surviving in the right and you can see that these two curves one for the Votrant and one for the Sutant are pretty much overlapping all right so you have to pick and choose between these two which one would you choose while it's kind of co-crepepsi it's pretty much the same here okay now the side-effect profile for these two agents was somewhat different in that you saw that there was some and what we have here is we have what are called forest plots and and these basically are just sort of showing favoring Pazop and ever Votrant in one direction and favoring Sutant in the other direction and then you have the list of the things that they looked at and you could see that some things were actually better for Sutant for example Votrant makes her hair turn white doesn't happen with Sutant weight decrease seems to be more common with Votrant and also Votrant irritates the liver more but there were some other things that that Sutant did more of and it did it changed the blood count somewhat it seemed to to cause that taste alterations more so there were a couple of things that Sutant did that Votrant didn't now remember this is in the four week on two week off schedule and you know we never we didn't do a follow-up 1110 patient study of Sutant in a two week on one week off schedule compared to Votrant probably this would have equaled that weak-lized out somewhat and the other thing that's missing from this is actually a whole result this is a shortened list there's actually a list of a whole bunch of things that are in between that are actually pretty much the same between the two drugs so fairly equivalent so Torah cell now let's talk about that this is remember in the mTOR inhibitor that's taking the gas pedal off slowing down the cancer cell growth therapy this is IV given weekly and it's FD approved for in for advanced kidney cancer in May 2007 and it was FD approved on the basis of a randomized phase 3 study between Torah cell versus interferon versus interferon plus torso interferon who uses interferon anymore not many people so you know these are stuff but that was the the drug to be in 2005 or so so this trial demonstrated that in that group of individuals this group of individuals had poor risk features okay remember the memorials that that that was those risk categories that I talked about and in this poor risk group Torah cell did better now Torah cell has not been compared to contemporary agents and so Dr. Taneer and our group have a study that's currently open at MD Anderson where we're comparing Torah cell to to Votrant or Pozopinib so there were we're trying to ask the question of whether in that poor risk group of individuals there are better drugs out there and so this is a trial that's looking at that in poor risk patients so let's in the last minute or two talk about kabazan to never kabo matics and dr. Taneer is going to talk about this a fair bit more this is another pill form therapy it's an anti-angiogenic or blood vessel starving agent it's given 60 milligrams per month daily you can dose reduce it which actually because this drug can cause a fair number of side effects we often do and but you can often find the right dose for people with it and it was FD approved for people who had progressed after like sootent or Votrant or therapy other other drugs like that so it's now FD proved in the second line setting not in the front line setting but there was a smaller study that was done and that's been published testing whether or not this drug is better than sootent in the front line setting and this was a smaller study it was about 150 patients the primary outcome measure was time until disease progression or progression free survival and these patients had either intermediate or poor risk features as well there weren't any of those good risk patients in here 80% were intermediate 20% were poor risk and a lot of words here bottom line was that the progression free survival for Votrant and for sorry cabometics was better than suit Sunitinib okay a couple of things so first of all the Sunitinib was given enough four week on two week off schedule in this it was not given in a two week on one week off schedule number two there are a lot of people who came off the study early on in the sootent arm but not in the cabometics arm kind of suspicious a little interest I mean not suspicious in that there was any malfeasance but you know you if you're on a clinical trial and you get on the regular drug and you're told well you're gonna get the you're getting the regular drug and you're gonna have to keep on coming back to you know whatever center that you're you're you have to come to frequently you know some people say I don't want to do this so there were a couple of things that were a little bit you know in favor I guess of cabometics in this trial but the bottom line is it still had a cabometics had a better progression free survival then sootent these data are now going in front of the are being analyzed independently and we're gonna see whether or not with additional scrutiny these data stand up and cabometics becomes a frontline standard of care for intermediate and poorest patients we'll see and and I'm hoping that's going to be the case so in summary at this point in time still sootent or synitinobinpizopinivirvotrient are the mainstays of therapy in the frontline setting Torosel attempts really miss is basically on the list as an option for poor risk patients we're getting more drugs that are either being tested against Torosel like Votrient as well as cabometics that are sort of being tested in that poor risk setting so maybe we're gonna have new options for that and and that we don't have enough time to really talk in greater detail about other things that are coming down the pipeline in the poorest setting but that's essentially the summary and thank you very much for listening