 Thank you. That was great So we're running a little bit behind. So we're I'm gonna move on and I'm very pleased to introduce Dr. Dan George who is coming down the street from Duke He is gonna talk to us about Adjuvant treatment of I have the ones you sent me But I mean I can use those We can Call it a nervous habit, but I like to keep making changes It should be under adjuvant. Well, thanks folks for coming out and braving the weather Actually, wasn't that bad. I don't know what it was like earlier, but it's mostly rained out. I think you'll be getting home fine But I'm from New England. You know, this is like, you know, this is like late September early October weather for us I'm used to it. Okay, great. Well, and thanks Tracy for organizing all of this and and and Matt and for everybody This has been I think maybe now four years five years been doing this six seven eight eight a long time I'm sorry. I haven't been to all of them But they're this I think this is really a great effort and we're gonna continue to make efforts to get more people out To participate and listen because it's a unique form. It's an opportunity for us to talk a little bit more casually about the The things we do from surgery and as you saw from Dr. Riggs, you know, fantastic opportunity How many times you get a chance to see that and hear him narrate through? You know what what it's like from a surgeon's view Dealing with kidney cancer and I'm I'm gonna talk to you as a medical oncologist at Duke But really just as a medical oncologist and kidney cancer advocate What it's like dealing with patients right after that surgery and particularly for the patients that have that higher risk Procedure like he showed you removing the inferior vena cava tumor thrombus, you know, what do we what do we say? What do we do for patients like that that I think are are, you know And honest facing a high likelihood of that cancer coming back for many of these folks It's more likely than not that the cancer is gonna come back and even even if it comes back slowly Even if it comes back, you know asymptomatic It's still a disease in the metastatic setting the stage 4 setting that we you know We we can control for a long time, but we generally can't cure and and that's a disease You know patients live with for a while eventually suffering from it and many folks dying from it So so it's our biggest unmet need and and although we've developed a ton of drugs for treating and and managing and helping people live longer and live better with Stage 4 metastatic disease We have no therapies for these patients that have Just gone through the surgery dr. Rig showed you for this kind of high-risk disease and it's really been one of the areas We've been working on for a decade So I'm going to give you an update on something that we're excited about because it's a new approval For kidney cancer and give you some context and why it's still Controversial out there when you talk to doctors and and why that might be so just a couple of slides here on the epidemiology of kidney cancer As you know, this is this is a common disease I mean all of you have been touched by it and directly or indirectly and and there's many many more 64,000 cases just in the US and 14,000 deaths and that may not sound like a lot when you compare all of cancer or other things But for patients with kidney cancer, you know, that's a that's a one in four one in five Chances of dying and that's that's too high surgical resection is The standard of care for localized kidney cancer and it's going to continue to be you you saw what what dr. Riggs offered there I mean, it's tremendous and it's he's a big cancers many of these cancers because we don't screen Like mammograms and PSAs we don't have that for for kidney cancer many of these patients presenting with with large tumors And and taken them out really does a tremendous service So that's not going away. That's going to continue to be how we manage a Lot of kidney cancer stage one two and three kidney cancer and then relapse for particularly those stage three kidney cancers is a is a real unmet need and This is the latest sear data. So that's our Medicare data across the country for from 2016 and the five-year survival rate in sear for stage four kidney cancer is 12% Now we may do a lot better than that in academic centers For patients that are motivated and resourced but the fact remains is that for many patients in the population This is still, you know, a very very lethal disease at stage four Dr. Riggs went through this staging. So I'm not going to go through it all But that stage three and really that kind of localized stage four cancer That's kind of gone through Gerotas fashion maybe into a regional lymph node That's still potentially resectable disease and that's all that we're doing surgery on but those are the patients at highest risk For disease recurrence and we know that from this group. This is the UCLA group and they did this international staging Criteria and it was based on the stage that we just showed you The grade which is separate from stage. So grade is what the cancer looks like under the microscope And you can have a really aggressive grade and a low-stage early cancer or you could have a really Advanced stage disease, but it's a sort of moderate to low-grade cancer So they they tend to track together but not always and you can see they the grading system is on a scale of 1 to 4 In threes and fours are the aggressive ones ECOG PS is performance status. That's functional sets. That's how the patients feel and how they're performing Are they completely asymptomatic or are they hindered in some way? Have they lost 20 pounds of weight? Do they have flank pain? Are they limited in some way by this by this disease and a one means? You're still pretty functional, but you do have some symptoms and then they just break it down into the score a sort of a stratification of low intermediate or high risk and the high risk of the ones those are the t3 T4 tumors those are the ones that highest risk for recurrence and and here's the data for that the high risk patients They're only 13 thankfully 14% of the population of kidney cancer patients. Most patients were catching earlier Despite the fact we don't screen for kidney cancer, but the five-year recurrence rate is nearly 60% So this is the group of patients. We know we're worried about they're worried about it We're worried about it and yet the standard of care is to just wait and watch and that's our biggest concern the other populations the intermediate and the low risk We're less as worried about because the likelihood is the cured and there maybe it's a little harder to justify Sort of treatment on people who might most likely be cured, but for the high risk patients That's where you know We really felt the unmet need and this was the case in 2006 in 2005 when the first drugs for kidney cancer were being FDA approved since Hytosal 2 in 1992 so so we were at a new period of time Not unlike sort of where we are today with immunotherapies now Just kind of coming into the field of kidney cancer these checkpoint inhibitors kind of a new revolution if you will in 2006 that was a revolution of these Oral therapies that could block Ingeogenesis and we're excited about them and we were sort of revisiting the question of adjuvant Treatment could we really change the course for these patients? So this is what a typical patient might look like You know in their fifties early sixties more often male than female usually You know still in the prime of their careers and in life and and family and everything might present with a large tumor like this with some abdominal pain flank pain or some blood in their urine and Might have some other medical conditions, but surgery would be indicated. It's a 12 centimeter tumor It invaded through the perinephric fat. So it's stage 3 cancer It's clear cell type, which is the most common type And and is the most responsive to our anti-angiogenic agents and there were no lymph nodes involved So he's a performance that is one. He's a grade 3. He's a stage 3 he's in that sort of high-risk category for disease recurrence and Up until very recently the only standard of care was to wait and watch So we did this a number of studies and I'll show you all of them in brief But one in particular that has led to this approval And they're all based on this endpoint called disease-free survival and that's basically Whether or not a patient has recurred in terms of their cancer now, there's other ways we can define this in terms of Whether it's radiographic recurrence or whether it's clinical recurrence or whether they've developed some other Complication like another cancer or whatnot, but by and large we're talking about that kidney cancer coming back and Long-term disease-free survival is really the goal for our patients if you think about it after you've had surgery Your can't your doctor says I got it all but I'm worried it could come back We're gonna do scans and follow you the primary concern for our patients in that scenario many some of you may have been there is You know hoping this cancer doesn't come back. Yes. You worried about are you gonna live to age 80 or 83? Yes, you're worried about overall survival, but your main concern is Is the cancer gonna come back? Is this cancer gonna kill me? Am I gonna have to do treatment for this cancer, you know in you know for the rest of my life? So that is to me when I talk to patients the biggest concern It's been an endpoint for all almost all of our solid tumor studies that we do in breast cancer and In colon cancer melanoma. Yes, they may also show some advantage for the overall survival of the population But the main goal, you know for those studies have always been based on disease-free survival and all of our adjuvant studies in kidney cancer Are based on that endpoint and so it's been sort of an approval endpoint But we've never approved a drug in kidney cancer for stage 3 disease So this was new this was a new endpoint to really assess It's one of the reasons the FDA called a special panel to look at some of this data So this is the group of patients that we focused on in this study called s-track and I'll walk you through it in a minute This was a study looking specifically at one drug synitinib that was approved in 2006 for treatment of metastatic kidney cancer and We wanted to look at it in this setting in this sort of stage 3 t3 t4 setting or Patients that had nodal disease involvement. I already told you nodal disease is sort of like a localized stage 4 That that didn't require you had a big tumor you could have a t2 tumor if you had nodal disease But there was only a small percentage of patients Thankfully that present like that most of the patients in the study were t3 or t4 and most of them as you see Well, you know had some symptoms associated with it This was the study design that we did and there was a lot of assumptions going into this We again decided to choose these this particular patient population not all the adjuvant studies focused on this population We specifically focused on the ui ss risk group criteria, so we included that performance status before surgery we randomized patients one-to-one to the drug synitinib and Versus placebo and we said would treat patients for a year That was pretty common for this other for the other adjuvant studies. What was different for our study Was that we focused exclusively on clear cell was that? We had a blinded independent review decide on whether or not the cancer had come back Investigators obviously are going to be making those assessments as well But we had a separate committee look at this and it's really probably the cleanest way to do a An endpoint. It's not necessarily the clinically practical thing. None of us are going to do that in practice but it is from a Population perspective the most consistent way to make sure that all the cases are judged the same way not You know one investigator judging differently than another so it really is from a FDA regulatory perspective the cleanest endpoint and And we had one other thing which we didn't make a big deal of at the time But we think actually turned out to be probably one of the most important Aspects and that is we wrote our study to say you could lower the dose down one time To thirty seven point five milligrams from fifty milligrams Which couldn't go below that if you went below that you took them off study And the thinking was is that we get down to a lower dose It may have no activity and since these are patients that we have no tumor to judge We'll have no idea of whether or not that lower dose is helping or just hurting So we set a bar and said thirty seven point five milligrams is as low as you go Anything lower than that and and we stop and the reason for that was based on our metastatic Data that suggested that that many patients at those lower doses don't have as much drug exposure Or changes in blood pressure or other measures to suggest a benefit to this therapy, but it was an assumption We don't know that going into the study So so these were the characteristics the patients you can see most of these patients in their fifties These are younger patients on average that that want to do an aggressive treatment like this But we had you know patients over 65 as well You can see mostly male. That's pretty common. You can see our performance status Most of these patients were performance that is zero. This is that baseline. This is after surgery So after surgery the cancer is out the only thing that's affecting you now Is your surgical recovery and 75% of the patients were recovered from surgery? Fully so this is the other characteristics we see and the t3 high are the patients that had these kind of t3 stage 3 cancers That were also symptomatic with performance status. So that was about half of our population so as a sicker slightly sicker slightly more aggressive population than Maybe some other studies had focused on and we did that on purpose because we felt they were the highest risk We also had the the node positive patients in there at about 8% and then you can see most of these were the high-grade 3s or 4s And these were the patient characteristics on treatment and I put this up front because I want people to know this We intend to treat patients with 50 milligrams On and off, you know four weeks on two weeks off For a year. We don't always treat patients for a year You you can see we have to also the mean duration was 9.5 months. So not everybody made it a whole year How about half of the patient had dose reductions to 37.5 and about half of the patients had Interruptions where we had to stop this the drug before they made it out to four weeks and that that occurred multiple times in patients So that's not to be a negative that shouldn't be viewed as a failure That's a personalized approach to how we manage patients We dose everybody the same and we're obviously all different from metabolism to body size to age You have to do that and recognize that we're trying to give patients a full dose that they can tolerate But that's going to be a frequent thing and some people view that as a negative I I don't it turns out the patients that have dose reductions Actually do better live longer in the stage four setting Metastatic saying so we think that that's actually a good thing when we see you know We can keep people on but we have to make those changes There's a lot of different Effects here in terms of what happened to people you can see the the discontinuation for adverse events about 25% so again, can't not everybody can tolerate it for a whole year. That's okay You know if you took it for nine months or six months, and that's all you could tolerate it You still got the benefit associated with this this was the benefit that we saw and You know we we think this is a really Remarkable effect. This was a 25% reduction in the likelihood of this cancer coming back We we treated people for up to a year. That was the treatment period period zero to one year And that treatment effect was beneficial all the way out to five years or more In fact, if you look at five years, we had an 8% absolute benefit in survival And you know it's it's pretty remarkable if you look here at one year the first year We cut down the recurrence rate by 50% and you might say well That's just because you're on treatment But that's good the treatment works it cut down 50% of the recurrences Then the curves start to come together again, and you can imagine some of those were just delays and recurrences We didn't really kill it. We just delayed it and coming back But after two years the curves are still separate and they stay separate throughout the rest of the population Throughout the rest of the period treatment period all the way out They never really cross and it really suggests that there is perhaps not just a delay in recurrence But there could be a real prevention and maybe it's 8% like it is at five years But that's a one in 12 so that means you have to treat 12 patients to save somebody From recurrence that wouldn't would have otherwise recurred. That's not a bad ratio for a drug that is you know Tolerable I'll be it with some significant side effects So that's sort of how we look at this some people look at this data and say well You know there's a delay in the median recurrence from 5.6 years to 6.8 years So you're do treating for a year to delay the recurrence 1.2 years But I really see that as a reductionist view because it's only looking at one time point and it really doesn't take into account All of the data for the whole population I don't know where the patient I'm talking to is going to be on that curve if they're going to recur in a year Or if they're never going to recur the best way to explain this data is to show all of it and the hazard ratio that chance of recurrence of you know point seven six is Probably the best summation of this data Overall, but I like to give patients that five-year time point because I think that's what we're looking at right we want to know You know are there some patients that are cured by taking this drug in the adjuvant saying that wouldn't be cured Otherwise, I don't know that we can say that at five years, but the curves are pretty much flattening out for recurrence That's four years off drug and still an eight percent greater Likelihoods some of those patients are probably going to be cured, but we just don't know that If you look across the subgroups, they're pretty much all shifted in favor of the synitinib arm here and Particularly when we look at some of the higher risk ones So the t3 high or the node positive ones are shifted over even a little bit more It's interesting age over 65 did well, but they're kind of all over the map for aging So I don't try to break it out too much The main point is that everybody was shifted over in favor of synitinib This is the overall survival and a lot of folks have looked at this and said well This is you know not a positive study because it didn't show overall survival Well number one this study wasn't large enough to show an overall survival Secondly only about 20 25% of the patients have passed away So we we don't really know that and the patients that have passed away have mostly passed away from really aggressive kidney cancer that occurred early And probably weren't the ones who are going to be able to cure It's probably the ones that are a little bit less aggressive that we're going to be able to cure It's just too early to judge to whether or not these curves are Separating or not the hazard ratio isn't one it's point nine and it's mostly by the end here So it'd be interesting to see if there's a trend to this But it'll never be statistically significant because that wasn't this power or the size of the study So it's a little bit of an unfair assessment to say this is Negative for overall survival because we just we just don't know that yet And this study probably won't ever be able to answer it But one thing that is clear from this study is that disease-free survival really matters So if you look at this study and the patients that recurred regardless of arm whether they're on placebo or a synitinib and If they recurred within two years, they had about a 40% chance of living five years You can see 164 died within five years 97 Are still alive beyond five years Whereas the patients that lived beyond two years Those page that that that recurred beyond two years those patients had about a 90% chance of living five years or more So just making it two years makes a huge difference in your five years survival And and many of us in the field know this And that's a 15 fold odds ratio That's a huge odds ratio is the positive predictive value 90% This is a really positive signal. We'll need to do this in other studies to confirm But disease-free survival is going to be a really important endpoint for this disease going forward You know, uh dose adverse events were pretty common I'm not going to go through all these things there were a lot of manipulations as I said most patients almost everybody had some Adverse events and 20 had serious ones like meaning you have to go in the hospital Grade three means it's you know, maybe a modification in your medication blood pressure or other things Doesn't necessarily mean you have to go in the hospital But temporary discontinuations were common and permanent discontinuations were 28 These are the side effects we saw what's interesting is the serious ones the sort of grade four hospitalized ones Were not that common which is good. Um, we made dose modifications before things got really severe in most cases And when we did have to stop the most reason most common reason why we had to stop therapy was because of PPE This is that hand foot syndrome the patients get on their hands That was the most common reason blood pressure and fatigue were the others But were less common and I mentioned that because this hand foot syndrome though It's a real hassle and pain for patients is not life threatening. No one's going to die From having skin peeled on their hands. So it's important to recognize What's serious and you know, what's important but not necessarily serious These are the other adjuvant studies. We've got six of them. I mean, it's remarkable We really the field really invested a lot in doing Studies in this setting and I'm going to just show two other ones because they're the only others that have been reported out The ashore and the protect the ashore was a cooperative group study It was three arms of synitinib and seraphina versus placebo Same treatment a year But could be clear cell or non clear cell and took a wider range of patients And then the protect study was also a year like this S-track study was just clear cell And focused a little bit more on aggressive disease included some t2 tumors as well But more overlapping. This was the ashore study design and those were the three arms And again, they had At 50 milligrams four weeks on two weeks off to start About two-thirds of the way through the study. They changed it. Um, they felt that these drugs were too toxic Uh, not enough patients were completing them. A lot of patients were dropping off And so they lowered the dose for the synitinib and the seraphina down to 37.5 And allow for lower they allowed for lower dosing down to 25 And I'll show you the effect of that. This was their overall survive. This was their disease-free survival curve There was no difference between the three arms And then this is the protect study Which was more like the s-track. Um, but it was using a different drug, uh, pazopinib or votrient At its full dose initially and then again about halfway through switched to a lower starting dose because of this And what was interesting in the protect study is their primary analysis was looking at that lower dose But their secondary analysis looked back at the group of patients that did the full dose To start and that's where they saw The disease-free survival benefit was in that group and it wasn't a retrospective. This is prospectively looked at a similar hazard ratio about a 30 percent reduction in the risk of recurrence and again pretty durable out to at least four years So why did s-track succeed? I would say that protect like s-track probably would have succeeded if they'd stuck with it Because dose matters and we know this in our patients in the metastatic setting if you have Doses and and I shouldn't really say dose. It's really dose exposure So if you have a drug exposure above the median You not only have a longer time to disease progression You have a better overall survival and the best way to judge that is believe it or not side effects The patients that get side effects and have to lower their dose are still having a high drug exposure And are probably getting the maximum benefit These are a dose dependent drugs just like chemotherapy and if you lower down chemotherapy too much you lose the effect And I think what happened in assure was that we lost the effect So a third of the patients started at a lower dose and they allowed these dose reductions And we see that there was about a third less dose Given overall 68 versus 96 exposure over the 12 month period. Yeah No did not say good I said the side effects are real and they need to be managed and half or more of the patients Have to have dose adjustments and sometimes multiple interruptions They're good in the sense that they show the drugs are working. Yeah, if you have an elevation in your blood pressure That's a good indicator. It's what we call a a biomarker or maybe a surrogate for benefit Those patients live longer and it doesn't matter which drug you judge All of them in that class if your blood pressures are going up You're hitting we're hitting the targets. We're having the treatment effects And that's been shown over and again It's true as well with diarrhea or the hand foot syndrome, but probably not as reliably measured as the blood pressure But they go hand in hand It could be a sign that that's not enough dose Believe it or not. There's some people that probably could do more than 50 milligrams And and you know with other drugs, whatever their doses are we do flat dosing in everybody That doesn't mean that's going to be the same exposure in everybody Is going to be a big range and some folks it'll be low Yeah They they did a phase one study or those earlier studies to do that The problem was is that there was too high a rate of toxicity In say like the liver now it might not have been a problem for another patient Maybe could have gone up to 1600 but for the general population it was too high to go above that So, you know, but this is where we don't have individual dosing and ideally with a drug like these that are chronic You do that. We don't really haven't really figured out even despite 10 years of Of working with these drugs how to do that yet This is the drug exposure. This is actually what the FDA put together for us for the assure study And 75 of the recommended daily, you know drug was What they used as a cut-off so that would be 37.5 And you can see that You know only about 60 had that in the first cycle and then it goes down to 50 or less So quickly the majority of patients on the shore were getting, you know, less than The exposure this is the s-track exposure And you can see you go out to about cycle five before you drop below 50 of the population So so we think this is a significant difference between these studies We think this is One of the main reasons why we see effect with s-track and not with assure and with the subgroup of Protact that got the full dose The other reason is that the population was very specific It was focused specifically on the t3 and the node positive patients and that The assure population included a lot of others And when you treat patients that have a low risk of recurrence You're going to lower your threshold for tolerance to side effects and that's going to affect how you manage your whole population So it it's important to recognize there are some other ongoing studies now And we're very excited about the immunotherapy field and these are two of them This is one with a tesilizumab versus placebo and another one with pembrolizumab. These are pd1 or pdl1 Um antibodies so they block a key checkpoint and this checkpoint pdl1 Has been shown to be really important and and you know drugs like this nevolumab in particular Have been fda proved in kidney cancer Because it's shown a survival benefit And and we think this is a really important aspect sort of a new way of treating kidney cancer And and one that that we're very glad is being explored and these are studies that are exploring it After surgery There's there is a study looking at the combination of nevolumab and ipilumab after surgery As well and there was recent data that just came out this year Showing a benefit to that combination in the metastatic disease setting Over sutent so to what extent that might be a benefit in the adjuvant setting We don't know but it's certainly exciting And then one that we're in and I know the unc folks are supporting this too Once that we have at duke is the Is the uh prosper study where we're going to be looking at patients prior to resection So before dr rigs does that operation We're going to try to biopsy and then treat these patients with six weeks of immunotherapy nevolumab in this case And then do the resection and then do another six Doses of that Or six months of treatment versus just straight surgery and so that's two that's another approach We like this because it gets the immunotherapy involved before we remove all the tumor to get the immune system engaged And again, this is going to be looking at recurrence free survival and overall survival and safety and tolerability So it's a big study. We're hoping it'll be a positive study Um, and I think these are important studies But I think to end what why why do we want to treat these patients? I think that there's a high risk of recurrence This substantial morbidity and mortality associated with this disease now. I can take out. There's no approved adjuvant therapy Synet nev was approved Last month by the FDA For this treatment based on this s-track data We think that um patients should make an individual decision This should be something we present to folks and let them decide if the side effects are worth it If the 25 percent reduction in recurrence is worth it if they're high enough risk to justify trying this And then I think clinical trials are a good alternative You know, this is something where patients are not sure They want to do that but they they don't want to do it nothing This is a really good alternative to try some of these immunotherapies or you know, uh, very active watch and wait So so that's where we are in kidney cancer today and uh, we're excited We're hoping the next five years We're beyond this that we've got more studies and we're doing even better than synet nev alone But this is a great start. We're very proud of the study we did and the work that went into it We're very appreciative of the patients In this area and elsewhere that that participated in it and uh, and thank you for being kidney cancer supporters That's it Yeah Yeah Yeah, you know, I I hope that the studies will change to allow for Plus or minus suit tent And not do a placebo the placebo was set up when there was no adjuvant And now that there is an adjuvant option my hope would be that you could do pembro versus You know patients choice suit tent or Or observation Because I I'm you know, I'm not sure We can kind of lump everybody You know into the placebo arm and it'd be hard to compare this otherwise to the suit tent So that that would be my hope but I'm not in charge of those studies. I don't know if they'll change So in the absence of that change what I'd say to patients is that look, you know There is a benefit associated with synet nev and there is a toxicity associated with it make that decision First and if you decide no, I don't want to do That level of toxicity for that potential benefit Then you should do the clinical trial But if you put the clinical trial before the standard of care I don't know any other setting that we do that in so to me, you know, I think that you know, but again, this is A subset of patients and they may not you know, the clinical trials may have a broader population of patients who that's not appropriate for So some you can start right there, but for many others, I think you have to start with the standard of care