 Great. Yeah, so what I'm going to do really is Outline the process that led to a concept that we reviewed in February And then some of the comments that were made during that meeting and where we stand now so the As Brian pointed out, you know what this is this is a working group Which is part of the task force which sort of is mandated by the steering committee and then Ultimately the goal is to then run a clinical trial through C-TEP with Hopefully some some major impact on the disease in question and the working group members for the pre-surgical group that We we headed up Are as follows and Hyun Kim who's not here today? I think was was a co-lead this we had a medical oncologist and a surgeon for this pre-surgical Working group and we again tried to get a good representation of a medical oncology Urology pathology statistics Judy Manola was our our intrepid statistician in designing some some some Some constructs for us in this in this process so our mandate was really to sort of take that pre-surgical concept and to design a clinical trial that would answer important questions for the field of renal cell carcinoma and Our our mandate was to develop this clinical trial that really leveraged the pre-surgical approach to either or Improve our use of existing agents by understanding the interaction of that agent with a tumor micro environment and Also to identify deterministic response and resistance and to prioritize novel agents by assessing tissue and clinical response So the advantage of the pre-surgical design is that one of the the challenges that we face is we really don't have good biomarkers of much in renal cell carcinoma in 2013 and what we really need is we really need a certain amount of tissue and you know the girlinger paper and other Ideas and concepts of tumor heterogeneity Dictate that for us to really have something robust we at this point in time really need to have a fair amount of tissue to achieve it and these tissue end points are really rendered relevant by linking them to to meaningful clinical outcomes and Ideally some of the original thoughts that we had were that a randomized design would really again add relevance to these to these end points So when we think about how a drug interacts with that with the the tumor We have to think of the tumor really as as an organ That's that's made up of the epithelial cell the stromal cells and the endothelial cells and and this is a very plastic Environment you have the drug it'll interface perhaps with the endothelium which will modify be modified perhaps by the stroma And obviously the the genomic determinants of the epithelium are going to modulate that as well So it's a very complex and really sort of thinking through the action and reaction Again requires a fair amount of tissue And the other thing to sort of think about and this is something that was illustrated when we were designing The trials is that on the on the top right here? We have you know hypothesis based Mechanistic considerations, you know ideally what you'd have is you'd have some sort of a laboratory observation Which would generate a hypothesis and you would then test that hypothesis in it in a clinical study But practical considerations come into play how many patients of a particular population do you have? Can you access a drug a versus drug B? And so there's a practical overlay to to anything that you you do hear that ultimately results in in your trial It's you know the the sausage making of of science So as we went through this and we asked ourselves the questions, you know, what are the different disease states? What are the different agents and what are the statistical designs that we would use to? Narrow down the the type of trials would be interested in the first question is are we going to be doing a neo-agibent study versus a Metastatic patient study neo-agibent meaning patients that have a primary tumor in place But don't have metastases where we'd really be looking mainly at tissue endpoints We decided that so that we can have a clinical readout. We would be focusing on the metastatic patient population The second question is should we be learning? The biomarkers and the biology of existing agents or novel agents and at the end, you know We figured that novelty would be good We have new agents that are coming down the pipeline and and using this as a means to to learn something about the Biology of both would be really important The next question is were we ready in 2012 and 2013 to power a clinical trial by a Biomarker as opposed to a clinical endpoint and because we don't really have any validated candidate biomarkers that really You know rise to that level this by definition would have to be something that would be powered for a clinical out And an endpoint and then in terms of response is it primary response versus metastatic response Obviously, we ultimately care about the metastases But we make assumptions about the relationship between the primary and metastasis and hopefully get tissue from both so the the next question then is what are the most important questions we would want to answer from a from a trial design perspective which with regards to agents and so one of the ideas that we had would be we would use a Tki, you know sort of as a baseline plus novel agents that might modulate Tki response and resistance sort of a first past the post type of approach The second was with some preliminary data that young Kim had generated Would it make sense to combine an mTOR inhibitor with PD-1 because it looks like paradoxically mTOR inhibitors might actually augment immune Response and the third idea would be Tki plus PD-1 antibody and we we ended up saying that this third Choice would be the one that would be the most pragmatic and practical from again getting patients on trial perspective and and also having really the possibility for answering great scientific questions We then moved into and I don't have to tell you about checkpoint blocking agents You know, these are obviously very interesting We don't know very much about who's benefiting who should get these how best to give them and we thought this would be a great platform to design Trials and so we came up with ultimately because of Judy Manola's input a randomized trial between PD-1 antibody versus Tki asking the question whether or not we can a see whether or not There's differential clinical response between those two arms be are there any tissue factors that would actually guide us to which individuals were benefiting and We had the statistical design of a hundred and forty individuals randomized 70 per arm and We would then be looking at the tissue with a number of different tissue endpoints We had the meeting in Orlando in February 2013 where we discussed this in front of a panel of our peers and The the ultimate thing was that it was defined really as a fishing they it was considered that this was too much of a fishing expedition Yes, it's a clinical trial that you can do but what's the question and so the the trial was then refined and redefined as being anti-PD-1 versus anti-PD-1 plus a VEGF receptor inhibitor and this was based on the hypothesis that PD-1 inhibition Would be good, but perhaps not sufficient. There are clinical data that VEGF receptor inhibitors modulate the microenvironment a way that may augment the utility of a drug like nivolum up that There are negative immunoregulatory cells that are depleted by anti-antigenic therapy that the combination will be superior to the PD-1 antibody monotherapy alone and that there would be things that we would be able to see in the tissue that would be able to guide us to that degree There are a number of of data that are out there that that suggests that things like PD-1 ligand might be a potential Biomarker, but it's in of itself probably not sufficient and there are circulating data on Myli derived suppressor cells that suggest that these are a cell population that may be Modulated by drugs like Sunita nip so the trial was as it stands would be anti PD-1 versus anti PD-1 plus TKI With the clinical objectives to explore whether anti PD-1 antibody plus TKI provides superior response rate progression-free survival compared to monotherapy that the regulatory cell infiltrates are Portend for worse outcome and are modulated by these treatments and whether or not PD-1 ligand Is is associated with and is modulated by the the drug the thing with this is that we don't necessarily have preliminary data to be able to Power this at this point in time and so at this moment what we're doing is we're developing we're generating these preliminary data So fortunately at MD Anderson we have several pre-surgical studies. We have this bevacizumab pre-surgical study We have the Sunitina pre-surgical study and also through the generosity of my collaborators around the country and around the world We have a number of other sets of treated samples to be able to ask the question at preliminarily whether or not compared to untreated controls We're seeing that anti-angiogenic therapy is modulating these different types of cell populations We have TMAs of these and in collaboration with a couple of really great pathologists and an intrepid Instructor in my lab. We're developing the infrastructure to be able to really look at this in a in a meaningful fashion so the problem with immunohistochemistry is quantitation and Doing this robustly. We're using a Vectra multi-spectral imaging system and this allows you to look quantitatively at your signal as well as segmenting cells and defining different cell subpopulations We can look and you sort of look on the left. That's the unsegmented versus the right segmented the percentage of of CD8 positive here. This looks like this is a very reasonable measure Here's a higher percentage. It fits very nicely And we are also doing Fox P3 So these are single stains at this point in time and we're in the process of moving to be able to do multiple Antibodies so we can really define these subpopulations properly some interesting observations We see that there are more CD4 positive cells in renal cell carcinoma compared to normal tissue we see more CD8 positive cells and Intriguingly initial data not multiple antibody We're seeing that synitinib seems to raise the level increase the level of Fox P3 cells in the tissue Which is counterintuitive So the plan really is to complete these tissue analysis to make sure that our hypotheses that we are using to design this clinical trial actually are Are validatable and the next step then will be to design to power the trial and move forward. Thank you