 Great, so thank you very much Tracy for the opportunity to come today. It's really a pleasure I've been here several times over the years, and I do think that it's one of you know our favorite meetings So I think that you know it's been another sort of extraordinary time in the field of oncology and This does in large part relate to recent developments in the amino oncology agents that are very applicable to patients who have kidney cancer And so I'm going to talk about some of those recent clinical trial advances and some of these are Familiar to you already based on some of the other speakers discussions But I'll try to categorize these for you so that it becomes clear What sort of combinations we're actually looking at and some of the mechanisms and rationale for combining different agents And so I think you've seen this type of slide before But I'll tell you when I finished my training and wasn't training there were really only two agents that were being used in patients with advanced kidney cancer I was in New York at the time and my mentor did a lot of work with the drug interferon Which we essentially don't use anymore in the treatment of this disease But that was really the mainstay of therapy and then of course high-dose interleukin 2 and then you can see here that there were the approval of That seven drugs right between 2005 and 2012 and then subsequently More agents that have been demonstrated to improve outcome and survival in patients with this disease So it's really been an extraordinary time Since my training in terms of the development of novel therapies for patients with advanced kidney cancer So in terms of the emerging therapeutic strategies in the disease There are several baskets and there are more than these but these are the main ones The first being the combination of VEGF pathway agents and PD 1 pathway inhibition And you've heard about this a little bit by dr. Amin And then the other one is the combination of IDO and PD 1 pathway inhibition And he alluded to this in his last slide when he talked about the fact that there are different targets on the immune cells that can potentially Be hit by certain drugs to combine with PD 1 pathway drugs to derive more benefit The combination of CTLA4 and PD 1 pathway inhibition I'm going to show you some slides that you've already seen already related to the checkmate 214 and then another interesting approach targeting specifically something called hip to alpha Which previously had been thought of something that was not really targetable So one thing to notice up front is that when we talk about here targeting VEGF and PD 1 drugs Not all of these combined safely and so there are combined toxicities associated with using certain drugs with certain agents and here you can see that combinations for example of Siu tent and Nebulomab As well as Pizopinib and Pembroluzomab We're not tolerable and these have been discontinued in terms of their development There have been other agents. However, that have been tolerable in combinations So for example the drug exit nib in combination with Avilumab Pembroluzomab And interest looking in Nebulomab and then combinations of Linnvant nib and Pembroluzomab CaboXanthinib with Nebulomab and also the drug Apollumamab as well as Bevisizmab and Nebulomab So even though these drugs work similarly these VEGF receptor tyrosine kinase inhibitors and these Immuno-oncology agents work similarly when you combine them you see issues related to tolerability with some agents and not others And that's frankly the reason why we need to do clinical trials and these clinical trials need to happen With the individual drugs and we can't simply extrapolate from one drug to the next So this is one study looking exit nib and Avilumab. It's the javelin Which is the acronym for the name of the study renal 100 And this essentially looked at patients with a clear cell component. These are patients with advanced or metastatic disease No prior systemic therapy for advanced kidney cancer and there was a dose Finding period and then a dose expansion period But these drugs were essentially administered either together or in sequence and remember I like sit nib is a veg F receptor tyrosine kinase inhibitor and Avilumab is what's called an anti-PDL one or one of the immuno-oncology agents and this trial demonstrated That responses were seen in 58 percent of patients And so this is you know a very promising type of response rate in disease control Which includes stable disease was achieved in 78 percent of patients So there's this sense that when you combine these agents you're seeing higher response rates Potentially leading to better long-term outcomes associated with combinations as compared to using either these drugs alone This is looking that the time to and duration of response These are look like swimmers lanes. And so what you can see here is that the Time to the development of the response is actually quite early. This is in weeks. So it occurs at about six weeks So these are early type responses And what's interesting is that if you look at immuno-oncology agents alone The average time to response may be two to three months Whereas when you combine them with these veg F receptor tyrosine kinase inhibitors you see much earlier responses Which is more consistent with the mechanism of action of those drugs and these blue arrows represent ongoing responses So that many of these responses can be quite durable This is looking at a waterfall plot we these are all the responses we use this 30 percent line here Where which we refer to as sort of the true response, but you can see that all of these patients each of these represents individual responses and So here you can see that 34 patients experience too much shrinkage of greater than to 30 percent And it was actually only three patients in this study that experienced tumor growth of greater than 20 percent So again very promising Another study I'm combining exit nib this same that Jeff receptor tyrosine kinase inhibitor with Pemberluse MAP So now we have a different anti PD1 agent. I and so this study Looking at overall response rate here the objective response rate response rate was 71 percent So once again much higher type response rates than we appreciate with immuno oncology agents alone or with these veg F receptor tyrosine kinase in a agents alone and You can see there are complete responses here 5.8 percent and partial responses in the majority of patients as well as patients achieving stable disease and This is just again a similar type of plot. These are individual patients and you can see here that The response rate again being 71 percent and very few patients actually had any evidence of progression of disease Only really one patient So moving on to other potential targets in combination with immuno oncology agents And this was mentioned by dr. Amin in his talk and this is one that is sort of further on in development it's a drug called Epicatastat and Epicatastat is a drug that targets an enzyme called IDO one and so this is a bit complicated but tryptophan is an amino acid and What happens is that IDO? One is responsible for the metabolism or the breakdown of tryptophan which is involved in a pathway called the kind urinating pathway and you can see that with higher IDO levels you see less tryptophan and increase kind urinating and What this actually does is it creates a more immunosuppressive environment? So that the tumor is able to evade the immune response So that drugs now have been developed targeting this IDO one and by targeting IDO one you're unable to break down the tryptophan you don't have the higher kind urinating and You trans you go from an immunosuppressive environment Where the tumor can evade the immune response to one of which the tumor is now? open to immune attack by the t-cells and so this in combination with one of the anti PD1 or PDL one agents is mechanistically something that has a lot of rationale and so There is a trial is a trial that's been done this is the echo 202 keynote 037 study and this is a study that includes a cohort of patients with kidney cancer and Based on the mechanistic rationale of this study was done It combined it with Pembro-Luzumab an anti PD1 agent and demonstrated response rates in 33% of patients and higher response rates in patients that received only 0 to 1 prior lines of therapy So here 47% and so again here are those Those those graphs again individual patients, and it's just demonstrating the response rates This is looking in patients based on the biomarker PDL one in the tumor So you stain the tumor to see if there is high or low expression of this PDL one But you can see that responses were seen regardless of whether you had higher or lower or present or absent PDL one expression Looking at the duration of response once again here You can see that the responses are quite early occurring on the order of about nine weeks And that based on these green arrows that many of these responses continue to occur so that these responses are ongoing and this whole idea of ongoing responses or durability of responses really Consistent with what has been so exciting about the use of immuno oncology drugs And what also is exciting about this combination is that it's actually well tolerated So one of the concerns is that if you take two immuno oncology agents and you deliver them to a patient Are you going to see more in the way of immune related adverse events? So what you're doing is you're essentially ramping up the immune system to attack the tumor Unfortunately, one of the effects of that is that you ramp up the immune system and their immune system then mistakenly attacks organs within the body and cause inflammation in the lungs and the liver and the thyroid in other places But what we've seen here is that there really wasn't an excess in the way of immune related adverse events or significant toxicity So that this was actually quite tolerable So Excitement with a new agent 30 patients good response rate the response rate with nabula mavalone as an example is 25% So it looks like we are doing something different here by adding this agent And then from a toxicity tolerability profile This appears to be well tolerated in you know, again a relatively limited experience And so there is a phase 3 study of this combination that is not quite open yet of Sunit nib which is suit and Dorpazop and a Votrient In the first line setting versus the combination of epicatastat and pembroluzumab And then you've seen a lot of these slides already So I'm not going to show all of them But this demonstrates the combination of anti CTLA4 and anti PD1 PDL1 therapy and so this again Combinations of immuno-oncology agents This has already been sort of done in the field of melanoma and has demonstrated a lot of promise Although with increased toxicity one of the nice things in kidney cancer is that the doses that were used in this study Are actually different than the doses that were used in metastatic melanoma And so that has led to lessen the way of some of the toxicities that we're seeing in the melanoma studies And so this was the checkmate 214 study comparing Sunit nib or Sutin to epilumimab and the Vulimab and I'm not going to go through this because you've already seen many of these slides, but it looked in an intermediate and poor risk population and basically, what it did show here is that The response rates were higher with the combination of NIVO and epilumimab is compared to Sutent There was an improvement in progression free survival with the combination is compared to Sutent There was an improvement in overall survival again in this intermediate and poor risk population And I'm just going to summarize this as follows that Among the intermediate and poor risk patients There was a survival benefit with the combination of NIVO and epilumimab and epi an improvement in response rate an improvement in progression free survival when they looked at all of the patients that included favorable risk patients to There was an overall survival benefit and improved overall response rate Among patients with PDL one greater than 1% expression within the tumor There was a higher overall response rate and a higher progression free survival But again as dr. Amin had mentioned and others among favorable risk patients Sutent was associated with a higher overall response rate and an improvement in progression free survival So it looks like at least for the intermediate poor risk patients by criteria that Dr. Whitting mentioned The nivulimab epilumimab combination makes sense, but in patients with favorable risk disease Sutent would still remain the treatment of choice This just sort of outlines the response rates in the frontline metastatic RCC setting And I think that it becomes quite clear very quickly that the field is really advancing rapidly I mean this is 2016 2017 data here And you can see here the incredible promise in terms of response rates and remember these response rates often translate to Durability of those responses and larger trials will ultimately tell us whether or not their survival benefits associated with these combinations and Then finally agents to watch so this is a novel target. It's called hip to alpha And in fact we have Billy Kim sitting in the audience who's one of our translational researchers And actually did something really the seminal work in this area when he was at Harvard With dr. Kaelin in identifying this sort of as a mechanism in kidney cancer. I and so here What we know is that hip to alpha is what's called a transcription factor and we've heard of this gene I think Mary probably mentioned this earlier von Hippel Lindauer VHL and under normal conditions these VHL Binds to hip to alpha and what happens under those circumstances is that when VHL is normal And there's no problem This ultimately gets sent to sort of the garbage can of the cell which we refer to as the proteasome for degradation And it gets broken down and sort of tossed out but what happens in situations where VHL is sort of knocked out where it is in kidney cancer is that the VHL cannot bind to the hip to alpha and so what happens is the hip to alpha goes into the nucleus of the cell and it partners with its friend hip to beta and then it essentially Translocates to the nucleus and it leads to the development and multiple a multiple proteins that are involved in in the progression of kidney cancer things like veg F and and PGG F and Orthropoetin and others that ultimately drive the cancer and so it makes sense that this hip to alpha could be a really interesting Target and in fact, there's a drug p2977 Which binds to and blocks the function of hip to alpha and and in so doing What it essentially does is where we are right now is we are in a time when we are targeting these sort of Mediators of of the cancer like veg F But this agent targets it much earlier on so you can see it targets it downstream of all of these other All of these other proteins that we're able to target now with these drugs And so I think people are very excited about the ability to finally target hip to alpha, which is something again was felt to be Something that was not potentially targetable in the past And so a lot of excitement in kidney cancer combinations of veg F and PD 1 pathway inhibitors really really Very promising combination of epicatastat the IDO inhibitors as well as others in these immuno oncology agents combinations of CTLA4 and PD1 pathway inhibition with the checkmate to 14 study demonstrating a Survival benefit in the first line setting that most certainly is going to come down the pike quickly and Be approved for the management of patients with advanced disease and then the excitement surrounding the ability to target novel novel proteins that potentially may help to Either alone or in combination Continue to advance the treatment of patients with this disease And so with that I'll stop and I'm more than happy to take any questions if anyone has Yes Right, so it's really an excellent question so progression-free survival Probably is not the best endpoint for a bunch of these different studies So remember Dr. George was talking about disease-free survival as being a reasonable endpoint in adjuvant studies progression-free survival may not be the best endpoint in some of the immuno oncology studies just by virtue of the fact that What you see in these studies is you see Responses that are associated with durability, but those responses are not at least today Occurring in the great majority of patients So it may not ultimately translate at this very moment with all of these agents or combinations through an improvement in progression-free survival But there may ultimately be an improvement in survival in those patients who achieve those responses And so the hope is that if we can drive the response rates up, which we know are associated with durability Then we may ultimately lead to improvements in overall survival and in all likelihood progression-free survival as well So it shouldn't be discouraged by that. I think that you know, we're still sort of You know early in some of those studies in terms of being able to look at some of these endpoints Great. Well, thank you so much