 Thank you. I'd like to thank the organizers for inviting me to speak. That's always a pleasure and Moving on these are my disclosures I've been given the task of discussing one of my favorite topics, which is the role of adjuvant therapy in kidney cancer and So I'm going to give a brief review of what's going on and what we see as coming in the future so The current adjuvant trials Basically are listed here and I'm going to just go through some of the slides fairly quickly If you attended ASCO this year you heard Ari Belda Grun present the results of the orizer trial which was an antibody to carbonic anhydrase 9 that was infused on a weekly basis for six months and Basically was powered to clear cell carcinoma and I mentioned this because those of you who are younger than age 30 that I saw in there may not know that 10 years ago when we were first talking about developing some of these trials that this was a very important backbone for all of the tyrosine kinase inhibitor trials and It's easy to kind of look back now and say oh gosh. I wish we'd done things different Well, that's why we review these because each time we do a clinical trial I think we get a little bit better at designing them so Moving on this trial had a lot of the same risk categories that we've used for the tyrosine kinase trials and There I bring attention to the Inclusion of a kind of a broad group of tumors t1b and up up to node positive disease So this study was unfortunately not statistically significant And was a negative trial in essence, but I think we learned a lot from this The current adjuvant trials are mainly powered to or mainly a veg f tki Trials and I was the study chair of the assure trial which is shown on this slide here Which is a large trial of over 1900 patients that accrued very rapidly in the US and Canada and Include it was powered to clear cell but also included non-clear cell histology and Saw to answer the question of whether a year of synitinib therapy or a year of seraphinib therapy was Superior to placebo and I mentioned that both arms are compared to placebo rather than to one another I'm going to go through these slides quickly because there's a lot of slides the S-track trial Is an industry trial that was also looking at this space was a 500 patient trial did not include t1b disease and But the rest of high-grade disease and looked at a year of synitinib versus placebo The source trial Answered a somewhat different question and Used a similar population of patients to assure with high risk and an immediate risk disease based on but use the Leibovitz prognostic score as part of the stratification and in this trial patients received Either a year of seraphinib three years of seraphinib or placebo and So it addresses an important duration question that some of the other trials don't address and this one Completed a cruel. I think either late fall or early this year So that's something to look forward to as well the Something's wrong with the mouse here I'll move on the protect trial The the mouse isn't working Basically is the next trial and that just finished a cruel last The summer and what that did is address? whether Pazopinib in this space versus placebo was Efficacious and as I said that completed a cruel just a couple of months ago Somebody needs to help with moving the slide Okay here So here's the project to study design and Finally the Everest trial is ongoing and this is a trial addressing the use of mTOR inhibitors with the primary endpoint of recurrence free survival and this trial Initially was somewhat slow to a crew, but a cruel appears to be picking up and is 551 Out of the 12 18 patients as of right now So what I want to use the rest of the talk is to address issues that I think matter for Adjuvant therapy and they're listed on this slide and I want to just move on to some of the other slides So one of these is the design and scan frequency and you can see that one of the good things about These trial designs is that they're all fairly similar So at the end of the day we can go back and really look at this as a large database there are some subtle differences in scan frequency and The current a way and nccn guidelines do not require scans behind beyond five years and so One question I guess is are we going to get the data in as quickly as we think? If people are forgetting to do scans on a yearly basis after year five The other thing that I think is very important is the is the dose duration and IV or oral formulation and these are the veg FTKI trials ongoing and You can see that some of them are using full dose and some of them have been dose reduced and I'll get back to that in a second and Looking at the common adverse events this slide is data that I have from a sure you can see in the first three columns here Compared to what's in the label for advanced disease for sinitinib and seraphinib and I just want to point out that There were some differences we saw in toxicity predominantly in the skin Toxicity and perhaps less in the human logic and these Changes I think affected tolerability of patients so based on What I'm going to show you on this slide, which was a 14.9% discontinuation to a ease but also a 15% dropout for other reasons which are mainly patient refusal We adjusted the dose of the assure trial to start at a minus one dose level for both synitinib and seraphinib and I meant to Yellow the seraphinib one there as well, but that was 400 milligrams daily and the synitinib was 37.5 if patients did not have a Grade one toxicity then they had a mandatory dose escalation at either Cycle one or I mean after cycle one or cycle two and the same was done for source and protect so I think that the modification did affect did improve retention and Decrease dropout for the assure trial and I and communication tells me that the same was true for protect and for source So the strategy works, but the issue is really do we use that dose is the adjuvant dose different from the advanced dose Do we use all of these? Lower grade tumors as well as the higher grade tumors are these sorts of things ultimately going to affect the answers to these trials and Right now we have eight trials ongoing the AGUO is basically a trial in China collecting some more data on seraphinib But the other ones the other ongoing one is the Atlas trial, which I think I yeah I did put in here, which is three years of exit nib and These are some of the proposed studies that we're doing an assure with the Database and what I want to mention with all these trials is this is a tremendous resource with which to I think Pull the data and really you know both clinically and Relatively look at things so we have over 1,300 tumor blocks for a sure We have 16,000 blood samples at multiple time points, and we have 7,000 year urine samples so anybody who's Who wants to do? correlative work in this Can submit a proposal to ecog and I think that this is a nice database with which to validate studies This is what Tim Eisen has reported so far and source, which is the identification of a susceptibility marker Zeb 2 and that is in press so Tim has a nice sample set as well and Just in the last minute. I'd like to just address Since there are new agents available mainly the checkpoint inhibitors and some other interesting small molecules and we now have data from the TCGA as well as from some of the other groups Sequencing tumor and we know that there are some interesting Genes such as BAP 1 and set D2 might these be things that we will be able to Apply to this population in the future and future trial design We previously looked at immunotherapy trials. These are trials that were conducted before the era of TKI They were all negative trials, but it was a different era and one Provocative question is tumor was not present at the time of immunotherapy administration, so based on this in the PD 1 information that's available we have One approach is an approach that we've been developing at ecog which is looking at a neo adjuvant design of Patients with tumors greater than four centimeters who would be Acceptable candidates to have core biopsies followed by adjuvant PD 1 therapy followed by nephrectomy and a control arm in which patients have both core biopsies and if they have high enough risk disease are able to receive PD 1 afterwards and the purpose of this design would be to ask Both address safety and tolerability in the perioperative setting But also to learn some important control issues with core biopsies versus resection biopsies are they representative and to have an internal control of non-treatment versus treatment so this is one approach that we've taken at ecog and another approach that we've been moving forward with ecog is and And and hope to collaborate with the other cooperative groups in this is a phase 3 trial also using an anti PD 1 approach in which we check in in which we Address a question that appears to be front and center Which is do you need to have tumor intact when you administer these agents to really get a good Response and so this is a trial design where patients would get both pre-operative and post-operative PD 1 therapy and The you know it would be either a placebo or an observation arm and so given the time constraints I will end here and just say that we have some really large clinical data sets We have a very large tissue repository and I think there are some exciting new agents out there And as you heard yesterday with the discussion of some of these new chromatin Modulating genes there may be some glimmers of ways that we can refine risk in renal cell and Direct that forward into new adjuvant trials. So I thank you for your attention