 I'm a medical oncologist and I give treatment to patients who present with kidney cancer early on, as well as taking care of patients where the cancer has spread. So here are my disclosures, probably the most important is I'm the study chair of one of the big trials that I'm discussing, and I just wanted to define what I'm considering locally advanced kidney cancer because I think there's different definitions, but what I'm really speaking about here are either kidney cancers that are based on their stage or local spread are at risk for recurrence, but in general I'm talking about cancer that we're trying to remove completely and what can we do after that. And there's several ways that we try to determine when you have your kidney cancer removed, what's your risk for recurrence, and one of the most important is basically your tumor stage. So that's based on the size of the cancer, whether you have any lymph node involvement, whether it's invading any of the structures within the kidney like the collecting system where the urine drips out or the blood vessels, whether you have any metastases, whether the nucleus in the actual cancer cell looks like it's actively dividing. But we also have prognostic nomograms, which Dr. Abel referred to just a few minutes ago, which are kind of using the stage, using the grade, but also using other things like whether there's dead tissue in the tumor, whether somebody isn't feeling well, whether their hemoglobin is low, and so people have developed these kind of statistical tools that we think in some cases might also give us a better indication than just stage alone. And so what's adjuvant therapy? So I like to say that it's treatment that we're giving to try to eradicate little bits of cancer cells that might still be present in the body, but that are too small to see on a scan. You could also think about it, though, in terms of, and I think we're broadening our diagnosis, there might even be people where you know for sure that you left disease behind, the margins are positive, or you might see a little bit of disease that you can't get to. But the ultimate goal I think should be that we want to cure disease in patients who ordinarily wouldn't be cured by surgery alone. So that's what I think is the overarching goal of adjuvant therapy. And we use the drugs that we use in metastatic disease commonly to, after they've been looked at in metastatic disease, we then look at them earlier and say, okay, it helped in metastatic disease, is it going to help in an earlier situation? And so this, I can't get the pointer to work, but this is, there it goes. There's really kind of three broad classes of drugs that we use in kidney cancer treatment. The most common are what we call the VEGF inhibitors. These are drugs that target blood vessels. There's the immunotherapy. I'm going to show some more detailed slides. And then the mTOR agents, and they're sort of grouped by these different classes and stuff. And let's talk first about the anti-angiogenesis drug. So kidney cancer in general is very vascular. There's lots of blood vessels. And in a lot of patients, there's a gene that's located on the third chromosome called the von Hippolinda gene that is dysregulated. It's turned off and it kind of makes cancers form and cancers be more vascular. So the discovery of this 20, 25 years ago led eventually to the development of drugs that would target blood vessels, target the endothelial cells, the cells that line blood vessels. And this was really an incredible breakthrough. The first of these drugs got FDA approved in about 2004. And these are the majority of the pill therapies that you associated with treatment for kidney cancer. So you may know them by their commercial names. Sinitinib is a sutent. Bevacizumib is Avastin. Pzopinib is Votrient. There's also Enlida. There's a lot of these drugs. But in the advanced disease stage in metastatic disease, these drugs, these are curves showing the top curve means that there are more patients free of disease versus less patients. And so you can see that in each of these cases, these drugs really performed either better than a standard immune therapy which was used and is still around interferon or whether versus a sugar pill. And roughly 80% of patients will benefit from these drugs if they have metastatic disease. And so it really made sense to go back and look at these drugs in the earlier settings. So these are drugs in all three of these categories. But we're going to talk about the VEGF therapies first. That showed a benefit or I shouldn't say have been tested for benefit or are undergoing testing for benefit. And so far there have been seven trials conducted adjuvantly using these VEGF inhibitors or what we call an mTOR inhibitor. Everest is in here. Avirulimus is an mTOR inhibitor. The rest of these are vascular endothelial growth factor inhibitors. And one of the ways that we look at whether a drug is active is we have to look at a time point that's close to the period of time that you're testing the drug. So we often use something called DFS which is disease-free survival or recurrence-free survival which would be RFS. And this is important to talk about because this is a really easy time point to mention. So if you can show that you're delaying recurrence maybe that means you're benefiting from the drug. But I would argue that overall survival is probably a pretty important endpoint and when we get into the immune checkpoint inhibitors later on in what I'm talking about here you'll see why there may be a really good rationale to look at the immunotherapy agents. So let's review the trials that have been completed recently and the trials that one of my slide down at the bottom is not going to show. So there's four trials that have been reported recently. One of them was the Assure trial which I'm the study chair of. There was the Protect trial. There's Estrack and down below this, sorry about this with the science, there's something called the Atlas trial. So Assure was a trial that looked at two drugs, Sutent and Nexivar and there were three groups of patients treated or I should say three arms of the study. So this included some patients with smaller cancers so cancers that were a little bit smaller but they had higher nuclear grade and so there was some risk for recurrence as well as larger cancers including those that involved lymph nodes. We enrolled patients who had clear cell cancer but we all also allowed a smaller population that didn't have clear cell that had papillary or chromophobe or you know some of the other kidney cancers and everybody was treated for one year and everybody had to take all of these pills so in order for it to be a blinded study they had to take pills that were labeled as Sutent, pills that were labeled as Nexivar and pills that were labeled I mean and some of them were placebo so everybody took four pills of Sutent and four pills of Nexivar so they were taking eight pills a day and one group got all sugar pills one group got Sutent with sugar pills of Nexivar and the other group got sugar pills of Sutent with real Nexivar so that's how we kept all of the doctors and all the patients sort of in the dark about what they were getting and we can talk a little bit more about the use of placebo later but virtually all of the trials that have been done with the VEGF inhibitors have used placebo. Protect did the same thing they used but they allowed cancers that were bigger than seven centimeters and they got either Votrient or a sugar pill that said Votrient on it. S-Track used Sutent same kind of category as protect bigger tumors generally with invasive features and got either Sutent or a sugar pill that said Sutent and Atlas which has only had a press release it has not been published yet so we haven't seen the data sort of you know all of the granular details but Atlas was using Exitnib or in LIDA and what was interesting about this one is same kind of patient population is protect but they could get in LIDA for as short as a year but for as long as three years and they also included you know in our country there's been a much higher proportion of white people participating in trials not as many African-Americans not as many Asians Atlas included a lot of people from Asia so it will give a lot of useful information both about duration of therapy you know whether longer than a year or and also just patients of different races so this was the end points and again we show what we call a Kaplan-Meier curve what you what you really want to see here is that everybody's everybody from each of these colors whether it's Sutent, Seraphina or placebo it's all one line you don't really see much separation so we really didn't see a benefit with this trial to these drugs for a year protect there's a little bit of separation of the curve but when you look at the statistics in the long run there was also not a benefit S track when you looked at it there was a benefit and the benefit was statistically significant and what they saw was that the disease free survival improved by about a year so if you took Sutent and you you your cancer took about a year longer to come back if you looked at the whole population and everybody was interested because the benefit the curves seem to be split a little bit longer but look at this this is the overall survival for each of these studies and you can see that in each of these the curves are pretty flat so it's not in the long run making a big difference in how long people are living if they get adjuvant therapy and that bothers us and bothered me a lot because I mean obviously I was very disappointed that the trial I ran didn't show a benefit after 2000 patients participated and you know this one trial basically showed a benefit and the other three trials I should say Atlas did not show a benefit in the press release so we have three really large trials and one smaller that didn't show benefit and one larger smaller rather industry trial that did show a benefit so based on the S track data the FDA in this country did vote to approve Sutent and this is the National Comprehensive Cancer Network is a kind of a governing body that kind of gives advice about how often to scan people and you know what based based on evidence you know what are the best treatments and stuff so they did list adjuvant Sutent but they listed it as a category to be which means that they considered some of the evidence to be lower level basically because there were three trials that said no benefit and one trial that did show benefit so it is available as a therapy but I think there's a lot of us that still wonder you know what what should we do in this scenario and the European Medicines Agency actually voted not to approve so different parts of the world feel differently about the trial results so why did one trial show benefit whereas the others did not so at least because I could I went back and looked at at the Assure trial and we had had we had well over a thousand patients I think it was it was it was close to 1500 patients that had just clear cell didn't have non clear so so this was already a pre-specified endpoint and we looked in and you can see it's kind of interesting while people are on treatment you can see a little bit of separation of the curves but then it really is still negative when when you look at this population and we went back and we looked at we said okay we're going to look at just the group of patients that were entered on S-track as far as stage and clear cell and we still didn't see a difference in ours and then we said well could it be the dose you know ours was the first trial that opened people didn't have as much experience handling the side effects of the medicine could it be that so we went back and looked at different dosing quartiles so the people that got the full dose are quartile one the people that got a lot of dose reductions or interruptions are quartile four and quartile four is sort of you know maybe a little bit of an outlier here but the bottom line is when you look at all these dosing quartiles the dose in our trial really did not explain why our trial was a negative trial for sure so then this is some data on the protect trial which is votrient and again I should say the assured trial and the protect trial both started out at full dose and because so many patients had side effects and so many patients dropped out we lowered the starting dose in each of these to start at a slightly lower dose and then if it was tolerable people could go up on the dose and so protected the same thing and in that population you can see that the people that managed to stay on the full dose there was a little bit of an improvement in disease free survival but if you looked at the whole group I know the curves are split here a little bit but statistically it it did not show an overall benefit but what's really interesting here is in the protect trial which is votrient the company actually did in in about several hundred people I think it was about 200 250 they actually did blood tests measuring drug levels so they did it when they first started early on and they also did another one at eight weeks so the early trough is about four to five weeks the late trough is about eight weeks into the study and you can see that if they had a higher if they achieved a higher dose of votrient in the bloodstream they actually did benefit but the thing that was really complicated is that the drug level did not correspond to side effects and it also didn't correspond to the dose so it was really hard to predict you know there were people these are mainly patients that that had the 600 dosing so three pills instead of four pills but it was very hard to determine if you took those three pills whether you're going to get a higher drug level or not so probably has something to do with the metabolism and unfortunately we don't really have assays to that are well developed to kind of use these and say okay I'm going to check a drug level and you know you should definitely stay on this drug and and and so that's that's really a quandary because some people had really bad side effects and had high drug drug levels other people had almost no side effects and had high drug levels or vice versa so it's really a very complicated story and so you know this is basically what I'm trying to say we went back looked at our data there was no difference even when you went and looked at the eligibility criteria similar to astrak and in protect these drug levels did not correlate with dose or toxicity but if you achieved a higher drug level it did improve your survival rate but of course we haven't looked at this with overall survival so again overall survival is is important and and I think what's most troubling when we look at the veg of inhibitors using them as adjuvant therapy is we really saw a lot of side effects and so grade three means a pretty serious side effected side effect that means you need to stop drug or hold the drug and readjust the dose it could be really severe diarrhea like six seven times a day it could be really hard to control blood pressure so that you had to have a whole bunch of drug blood pressure medicines it could be that you got a blood clot it could be you know a lot of different things but it was something that involved a complicated medical maneuver and you can see that over 56% of patients on all three of these trials had side effects and one of the speculations is that because there isn't a lot of cancer sitting there the drugs are going after your normal cells not after your cancer and so maybe some of that is why people are reporting more side effects or maybe it's also when you're an adjuvant population and your cancer is removed you expect to feel better so these are side effects I retooled slide that Lauren Harshman kindly lent me and I because we have a later one with the immune therapy that I'll show you but these are basically side effects that you can get with these drugs and this is a picture of a hand-foot skin reaction so you can get calluses in the feet or hand sore feet and you can get blisters that show up so that was a troubling side effect on this trial you can get mouth sores I would say my patients probably complain the most about tiredness taste changes or unpredictable bowel movements as sort of the biggest things that really annoy them about these drugs so well other reasons the studies could have been different industry sponsor versus cooperative group the area of the country they were looking at it how how much how frequently we were looking at scans when you know how much help and managing the doses there's there's many things and I'm not sure we're going to ever going to know but fortunately there's a couple of other trials that have yet to report sources looking at one to three years of seraphimib we're expecting that Tim Eisen is going to be able to prevent present this data soon the evidence ever as trial is looking at an mTOR inhibitor which is a finitor and they did measure drug levels so that that should be interesting and then this is a trial for patients who've had metastatic disease removed asking if a year of vortient versus placebo could help prevent recurrence and we think that the results of that will be available sometime next year so what are my choices if I have a kidney cancer about to be removed or just removed that's at risk for recurrence there are four immune checkpoint inhibitor trials which I'm going to talk about there's adjuvant suit tent and importantly surveillance is still a very good option for a lot of people and we usually recommend imaging every six months for the first three years and then yearly for two years and then you stop with the imaging but continue follow-up with your primary care doctor or your oncologist just to look for symptoms so what was really revolutionary two years ago was that Nebula Mab or Optivo as many of you will know from the television commercials was tested in a trial in patients that had previously had a VEGF TKI such as suit tent or vortient and what they showed was really importantly they looked at overall survival and they showed that there was a big improvement in overall survival in patients that got Optivo over a virulimus or a finitor which was a commonly used drug in this space so that led to the FDA approval and that of course led to using these drugs earlier on so how do these drugs work so this is another slide that that Lauren lent me and and what it what it says is that typically in cancer a T cell will sort of hijack viruses or bacteria but what the immune checkpoint inhibitors do is they kind of rev up the immune system and they make the T lymphocytes in your body have a greater potential to recognize things that are foreign and so instead of just recognizing viruses they say oh yeah the cancer looks different from the normal cells let's go after the cancer and so these drugs are you know widely available and approved now and lung cancer kidney cancer melanoma list goes on and on had a cellular carcinoma they're really being looked at in many different tumors types and what I think what the patients love is that we're not seeing as much that the incidence of getting side effects appears to be much lower and then you're seeing these survival benefits not just disease-free survival and this is another drug that that I mentioned because this is in some of the trials and it has now been approved in combination with nivolumab epilumumab also known as your voice works in kind of a parallel pathway to the immune checkpoint inhibitors and it can kind of heighten the response it by itself when it's used in kidney cancer has not shown as much of a benefit but it seems to increase the number of responses at least when it's used with nivolumab the problem is that you can also get a little bit more side effects with it so these are four clinical trials that are open and enrolling and I'm going to talk about each of these this is the prosper trial and what's really unique about prosper is that this is a trial that you would need to go on before your kidney cancer was removed the emotion trial is so this is this uses nivolumab and importantly it's the one-armed patients get nivolumab they get it before surgery for a couple weeks and then they go on to get their cancer resected and then they get another nine months of nivolumab if you're assigned to get the surgical treatment and not nivolumab you don't have to be on a placebo you can basically go straight to your surgery and then be monitored so we really like the design of this trial and we think the patients like the design the emotion trial is looking at a tizolusumab versus it does have a placebo control but what's nice about these three the emotion the keynote which is ketruda or pembrolusumab and the checkmate which is ipinevo or urvoy and optivo versus placebo is that all of these are available to patients after their surgery if they have high-risk disease and are within three months of having their surgery so prosper allows patients who have any kind of kidney cancer it doesn't have to be clear cell obviously you're not going to know because you have a scan showing it these you have to have clear cell but you also this is also open to patients who if you had surgery and your kidney cancer comes back within a year and it's removable you can still go on this trial so it's available all three of these are available even if your cancer comes back within the next year and it's a receptable so digging down a little bit deeper the prosperous trial has to have a biopsy up front and there's a couple reasons for that and that is mainly we really want to make sure it's safe that you actually have cancer and that you have kidney cancer before you get treated now the way this was set up initially is everybody had to have a biopsy there's an amendment going through right now that what will happen is if you have a cancer that's seven centimeters or greater on your scans you you can then enter the trial you can be randomized and if you're randomized to the nivolum ab you still have to have the biopsy but if you are randomized to just go to surgery alone you don't have to have the biopsy because you're going to have a bigger biopsy when your cancer is removed and this has also been modernized now that nivolum ab or octivo is available as a four week dosing this has been changed so that you get one dose ahead of time and this has been changed that you can get the nivolum ab once a month so that also cuts down on the time you have to go back and forth and obviously if you're on the observation arm you get close follow-up scans same as the as this arm you're watched very closely but you don't have to get a placebo and why would you want to get this beforehand well the reason that you might that we think it might be important to get the drug before your kidney cancer is removed is the drug has to educate your lymphocytes about what to go after so if you've already taken the kidney tumor out and you just have a little bit of cancer left over then maybe there isn't enough to teach your lymphocytes to go after it but if you give a couple of doses or one dose before you get the kidney tumor out then you're teaching all the cells to go after hey this is the bad guy this is what we want to go after so that was the rationale for giving a dose before surgery these are two of the other trials the emotion trial just to give you a little bit more detail it's a Tizolusumab on emotion is every three weeks for a year and it's it's clear cell and keynote pretty similar design design kitruda or pembroluzumab I don't have a slide for the ipi nevo but if we go back a couple slides I think what's important here is you're getting these drugs you're getting them every six weeks rather than three weeks and you're getting them for six months not a year that's in but you're getting two drugs rather than one and so what are the risks so I think what we like about immune checkpoint inhibitors is they don't that by and far most people don't have side effects but if you get a side effect it can be pretty scary so you can get some pretty wild autoimmune effects it can affect the pituitary gland which can affect a whole bunch of things like your adrenal gland your thyroid gland or you could also get some very you know unusual side effects like making liver inflammation making the pancreas inflamed getting diabetes I would say by and far the most common side effects are rash and tiredness that's about 15% of the population so still it's 15% versus a 60% getting side effects so I'm going to end here but basically just say my conclusions are the US use of the veg f drugs in the adjuvant setting still is controversial since it's not showing an overall survival benefit but the disease-free survival benefit did for extract did lead to the approval of adjuvants who tend and you just have to keep in mind that there were a lot of side effects in patients on this and so it's not for everybody maybe we will get some more details about who will benefit importantly we have these new trials with these immune checkpoint drugs which we hope will inform us about their role and we hope that they will lead to benefit but it remains to be tested and if you know anybody that hasn't had their kidney cancer surgery yet the prosper trial is is really a good option as well and the bottom line your choices are these four clinical trials adjuvant suit tent or close surveillance so happy to entertain any questions