 Okay, I'm coming to the tail end. So my talk is going to focus on adjuvant therapy and kidney cancer. So what does that mean? This is what I'm going to cover. I'm going to talk a little bit about once the kidney is removed, how do we assess risk of the disease coming back? We'll talk about some of the trials that have been done in the past and what the future holds. So first I want to define what does adjuvant mean? It means that we are giving a disease in the absence of any visible disease with the intent to prevent your disease from coming back. So the goal should really be of a good adjuvant therapy should be to cure. By giving you this treatment for whatever period of time, we want your disease never to come back. So just delaying the disease. So for instance, if you give you a drug and instead of the disease showing up now versus showing up a year from now, that's not success. So truly the goal of adjuvant therapy should be if we can completely eliminate the disease. So in general, this has been done in a lot of other cancers. So in breast cancer for instance, it's routine for women to have a mastectomy and then to undergo hormonal therapy and then even chemotherapy and sometimes treatments for up to five years. Why do they do that? We do it as a standard because over the last three decades, we have learned based on randomized trials where a thousand women would get treatment and a thousand would be watched. We know that the women who got treated had an improvement in longevity where we helped them live longer by taking part through these treatments. So we know that from cancers like breast cancer and even colon cancer, if we were to give somebody a treatment, the risk reduction is about 30%. So what does that mean? You have to know what your risk is upfront. So after the breast is removed based on various nomograms and algorithm, you can sort of predict what is this woman's risk of her disease coming back? Then she goes through the treatment and we would say that overall, she has a 30% risk reduction. So just to give you some numbers, so higher your risk, the more the benefit you're going to derive. So if a woman has a 70% chance of a disease coming back, you're able to decrease that from 70 to 49%. But on the other hand, if your risk is really low, let's say you have a 10% risk, then you're only going to bring it down from 10 to 7%. So the relative risk is a 30% risk reduction. Clearly in all of this, you have to weigh in the toxicity. So you may be completely cured, right? So for somebody like that, where we are offering you additional treatments, the toxicity cannot be worse than the disease itself. So that's really important. So I know I've said this, I've shown this a little bit in the past that really life expectancy and survival depends upon the stage. Obviously for patients with early stage disease, so stage one and two are those curves that you see in red and blue. And these are patients who have actually had their kidney removed and a fraction of them are cured, but there are a fraction of patients whose disease comes back, right? That was one of the questions that was raised. That after your kidney is removed, how does your disease come back? A cancer cell must have escaped out of the kidney prior to the surgery being done. That's how the disease comes back. So we know how do we determine risk? So when you come to our clinic after your kidney is removed, how do we determine what is your risk of the disease coming back? I would say that today in 2017, we are not where we want to be and I'll just show you some examples. But what we use today are a variety of things. We look at anatomic things. That's what the TNM classification is. I showed you in the beginning that early stage smaller size tumors have a higher chance of a cure. So we are looking at the size of the tumor. The pathologist gives us certain information as to whether the cancer is invaded into the perinephric fat. If there is vena cava involvement, if there is renal involvement, all of this gives us some information about risk. So if you were to have these risk factors, your risk of the disease coming back is higher compared to if you don't. Then we look at clinical factors. We know that even for a patient with stage four disease, if somebody is wheelchair bound, their prognosis is very different from somebody who is completely without any symptoms. So performance status and having symptoms have some adverse impact. Then there are histologic subtypes. I know sarcomatoid was mentioned today. So there are certain histologic subtypes that carry a higher risk of the disease coming back. That includes the grade somebody had asked about Furman grade. Furman grade, the higher the grade of the cancer, the more aggressive the cancer is. So it gives us some information about what the risk of the disease coming back is. And then now in the last few years, we have started incorporating molecular factors and also genomic factors like some of the things Alex mentioned. So while genomics are not helpful in picking a therapy today, they are helpful in being prognostic. So if you were to do genomic sequencing and we find that you have BAP1 mutation, for instance, we know that we don't have a drug that's going to change it, but people with the BAP1 mutation have a worse outcome compared to those who don't have that mutation. So right now these are all helpful in predicting outcome rather than helping us pick a treatment. So in the past, people, there have been many systems that have been put together because we know that it's not one feature that helps us, but it's really a multitude of things that go together. So UCLA had a system called UISS, which is very commonly used by most urologists and by most medical oncologists when you come to a clinic after having had your kidney removed. And they look at a combination of three things. They look at the T stage. So was your tumor two, four centimeters, seven centimeters? They plug that in. They look at the grade of the cancer and they look to see what your functional status is. How bothered are you by this cancer? Are you really completely functional or is this limiting your everyday activity? So they lump these three factors together and they come up with a risk model with low risk, intermediate risk, and high risk, and you can see how those curves separate. Then there are others who, Memorial Sloan Kettering in New York has come up with a nomogram. So that's called the Catan Nomogram and that looks at size of the tumor. It looks at the grade of the tumor and then it looks to see whether the pathologist tells us whether there is necrosis or dead tissue that was seen in the kidney that was removed. They look to see if there was renal vein involvement, was there vascular invasions? So many models take different things and put them together. So this is the Catan Nomogram and each one they allocate certain points and if you have, let's say you have 140 points, you can look down at the last line which is the five year predicted possibility of being freedom from recurrence. So if you have 140 points it tells you that you have a 0.7. So it's a 70% chance that you will be free from recurrence. So there are groups that use such models to help predict what the risk of the disease coming back is. There's yet another one from the Mayo Clinic where they look at stage, they look at size of the tumor, they look at the grade of the cancer and this presence of necrosis and you can actually go to the internet and you can just put the Mayo Clinic Nomogram and it actually allocates some points. So the point of this slide really is to tell you that there are different nomograms and different risk models that are used. The interesting thing is that they are not all the same. So for a same patient in clinic, I can take all of these characteristics and I try plugging into the UCLA or I can plug into the Mayo Clinic or the Catan Nomogram, each gives you a different number. So clearly these are all not talking together and they're not the same. So our prognostic systems are not perfect. So where just like everything else, there is genomics being looked at in this setting as well. So this comes from Cleveland Clinic where they took 900 of their patients who had stage one to stage three. So these are all patients whose kidney has been removed and they have no evidence of visible disease and they have not gone through any other therapy. They looked at their genes and looked at people who had a relapse and those who didn't have a relapse and came up with some gene signature. So they came up with 16 gene signature and based on this, they were able to come up with a group that's low risk, intermediate risk or high risk just based on the tissue sample. So if you have a recurrent score of less than 32, you would be considered low risk. On the other hand, if you have a recurrent score of greater than 45, you would be considered high risk. What was interesting is what we know today as stage one clinical, 15% of those patients were regrouped as having a high recurrent score and the flip side was also true. 20% of whom we thought was high risk based on our clinical classification ended up being classified as low risk. So I think this is the wave of the future where we will be able to do such genomic signatures to help predict what the risk is. Currently, this is standard in breast cancer. So if you take a woman with breast cancer who has a small tumor and who's lymph node negative, that group typically doesn't get offered chemotherapy. So that group will go through this testing called Oncotype DX, which helps them predict what their risk of recurrence is and they're actually offered chemotherapy or they're offered other therapy because their risk is deemed high enough. So our hope is that in the future, we'll be using things like this in kidney cancer to help predict who exactly is at a higher risk and more important, you can have all of these tests but you need a good treatment to be able to offer to try to offset that risk. So in breast cancer today, they have hormonal therapy, they have chemotherapy that's already been shown that for a group of people who get it versus those who don't, there's difference in outcome. Do we have something like that in kidney cancer? And I'm going to use the next few slides to actually show you that data. What have we done to this date on the use of adjuvant therapy? Again, these are all patients who have had their kidney removed. Their scans show no evidence of disease and we are going to offer you a treatment in the absence of known disease. That's what adjuvant is. So here are the past trials that have been done. So these are all trials that were done in the late 80s and 90s where the only treatment that we had was immunotherapy. So there were patients, half group. So the first line that I have up there is 250 patients. Half of them were randomized to observation and half of them would get interferon and you can see really all of these were failed trials. None of these trials showed that by giving a group of patients interferon in the absence of visible disease really didn't benefit patients at all. So you've seen the slide before Brian showed you all of how the new drugs that we have today that worked. So it's very common in oncology when we have drugs that are effective in metastatic disease to take them on to the earlier stage. So if it works in the presence of metastatic disease could it work when you only have one or two cancer cells rather than a million cancer cells which may happen when you have metastatic disease? So you already saw the slide that these are all the drug treatments that we have to treat metastatic disease. Is there an opportunity to take these drugs and use them in the earlier stage disease to prevent the cancer from coming back? So these are the trials that have been done to date and this list is not completely exhaustive. So you can see up here that the line two is a trial called Assure trial where they have taken close to 2000 patients and they were randomized to either sunitinib. You heard that drug that that's what we use for metastatic disease or a drug called Serafinib which was what was available in 2005 or placebo for one year. And I'll share some results with you but that was a negative trial. There's been a second trial which I've highlighted called the Estrack trial. That was a trial again with 615 patients that took only high risk patients so it really comes down to what defines high risk patients, right? So in this trial they defined anybody who had T3, T4 and if you had lymph nodes at surgery they defined them at high risk and they randomized them to two years of sunitinib versus placebo and I'll show you that the trial was deemed positive but I certainly want us to spend a little bit of time of discussing what positive means and what price you pay for taking this drug for a whole year. And then there are other trials. There is the GSK trial that I've listed, tests another drug called Pizopinib and I'll share those results as well. So all of these trials have been completed and we are awaiting results on many of these trials. So here is the assured trial. So this was again a trial that took patients with kidney cancer. After they had surgery they were randomized to one of the three arms. So this was actually a blinded trial so neither you nor the providers knew which drug you were in. Obviously if you're on a placebo is easy to detect because these drugs have side effects. So if somebody has diarrhea then you know that they're actually getting a drug rather than placebo. But that's what this trial did and you can see up here they took anybody even if you had greater than T1 disease. So if your tumor was five centimeters you are eligible to participate in this trial. So these were the results. Somebody said in the beginning that from the back of the room for a trial to be positive you have to put your finger between the two curves. So you can just see that this trial was completely negative the curves all overlap which means there was absolutely no benefit in taking Sunitib or Surafinib compared to taking placebo in either preventing your disease from coming back or improving longevity. So this was considered as a completely negative trial. There's a huge price that you pay. I told you in the beginning that we have to weigh in with toxicity. So these drugs have a lot of side effects. I think one of the speakers said that grade three and grade four is what matters. You can see up here that 16 to, there were some patients who had a pretty significant grade three and grade four toxicities clearly limiting quality of life. And if you're not deriving any benefit this is not a fun thing to go on for a whole year. Then there was this extract trial which took patients with a higher risk. So unlike the earlier trial which took patients with tumors anything greater than five centimeters this trial was a little bit more stratified. So they took patients with higher risk disease and that was mostly patients with T3, T4. Similar design, you know you get randomized to either Sutent or placebo and you take the drug for one full year. There were 615 patients who went on this trial. What were the, so these were the patients they have to go on it for one year. They took patients who had T3 disease following surgery. You have to be in a good shape to tolerate it. Here there's some separation clearly you can put a finger between the two curves but let's look at what that magnitude of benefit is. So the group who got Sunitnib had a median disease free survival. So without any relapse for about 6.8 years compared to the placebo at 5.6 years. So that's a 14 month difference. Is it 14 month difference? But you have to have been on therapy for 12 months. So a lot of people question is that return good enough for you to go on this drug for a whole year? So technically this trial is considered positive but a lot of us in the field really question are we getting enough return for this magnitude of benefit? You know you have to be on the drug for a whole year and all that you buy yourself is a 14 month difference. Again I said in the beginning that we, I think for an adjuvant trial if you're able to cure you off this disease then it's worth it. But just by delaying your time to relapse by 14 months we don't think that that return is significant. So while this trial is considered positive I think we question the magnitude of benefit that this trial gives an individual patient. And again there's no difference in overall survival. You can see that they are completely emerged. And again like the previous trial there were a lot of grade three, grade four side effects. You can see 12% of patients had a grade four toxicity which means that it was pretty significant side effects. So there were some differences. Why was one trial positive and why was this one the earlier one negative? We think it may have to do with the dosing. There are some small differences about who came into the trial. The earlier trial was very low risk. If you take people with T1 tumors where they have a 90% chance of being cured maybe you diluted the people with that low risk patient population. So the last other TKI that I wanted to talk about is this trial that just was presented three months ago at our annual meeting. It's called the Protect Trial. And this took patients with a very similar patient population but they were randomized to Pozopinib which is the other drug that you heard about this morning Pozopinib versus placebo. And again, there was absolutely no difference in going on one of these drugs after the kidney was removed did not give you the benefit that we were looking for. So Sumit spoke about immunotherapy. We know that immunotherapy has a great promise in metastatic disease. Similar to the things that we have done in the past if it works in metastatic disease would there be a benefit of doing this early on? So after the kidney is removed is there any benefit in us offering you this immunotherapy with the intent to prevent your disease from coming back? So you heard about how these drugs work. This is not new to oncology. This is a trial that was done in melanoma where they looked at this drug called epilumimab which is another immunotherapy drug that's commonly used in melanoma. So they took a group of patients who had melanoma they had their melanoma removed and these are patients who have no evidence of disease. You can see that the blue is the epilumimab group and the red is placebo. And this was considered positive trial. It was statistically significant where the group who had epilumimab there was a five year survival of 40% compared to 30% on the group with placebo. So this is being done in melanoma where they're being offered this drug with an intent to prevent this disease from happening. So melanoma is a little bit ahead of us in kidney cancer in doing these trials but they've already established success in melanoma. So this is being done now in kidney cancer and there are four trials that I'm aware of. There are probably others that are coming but these are the current four trials that are being done across the country. So Genentech has their trial using a drug called Atticelusumab compared to placebo. Merck another company that has a checkpoint inhibitor called Pembrolusumab or K. Truda against placebo. And we actually have this trial here at Stanford. So I've just highlighted that in red. There is Nevolumab plus epilumimab compared to placebo and there is Nevolumab as well. So obviously all of these trials are going to take another two years to complete and you have to wait another probably five years before we actually know the results. So I would say today the standard would be to be observed. This drug Sunitina based on the extract trial is actually at the FDA as we speak where a group of people are looking into that and seeing if the FDA should approve this for patients with kidney cancer. Obviously you need to have a discussion with your physician as to whether you think it's appropriate to go on this drug with all of its side effects. But these are the current plan trials and we hope that what we learn from these trials in the future will help us offer patients a drug before they develop metastatic disease with the intent for us to prevent the disease from coming back after you've had a surgery. So I think that's my last slide and I'm happy to take any questions. Yeah, depends which drug you got. So for instance today with the targeted drugs with the tyrosine kinase inhibitors, it's really like you need to be on the drug for the rest of your life. And we treat this more like a chronic illness. So people live with the disease just like you live with diabetes and high blood pressure. With the immunotherapy drugs, there is a chance that you achieve a complete response where the disease completely goes away. We are in the midst of learning what's the optimum duration. The past clinical trials just kept patients on the drug forever. But in our practice, including in mine, when patients end up having a complete response, we are stopping the drug after one year. And hopefully my rationale would be this is immunotherapy. We have already trained the lymphocytes to recognize these cancer cells. It's like giving a vaccine. You don't get polio vaccine every single time. You get it once and you're done. Your body knows to recognize it if it comes back. You don't get a whooping cough vaccine after your childhood, right? Even though we may be exposed, there may be, you get the flu shot again because the virus modifies each year. But the whooping cough is the same. So I think cancer wax immunotherapy is very similar. Once you have trained your immune system, it should be able to learn and recognize and not. We don't know. I mean, what I'm saying, I think makes sense. But do we have data to support it? I think we are in the thick of things. We are following, we are stopping treatment and watching patients and we have to have a follow-up time to know whether this is really true. We don't know that if somebody's achieved a complete response, if their disease were to come back, will they respond the same way again? These are all some unknown questions to continue. Yeah, I mean, those are all other things people are looking at. Maybe you need a maintenance dose. You know, like a booster shot every so. So these are all some ongoing trials that are being done right now. I think you know, some of the promise, our first look at cure is defined by over a period of time. First you have to achieve a complete response with your treatments that we have. Then the next step is that complete response has to be maintained over time and that's what really defines cure. So I think towards that, with immunotherapy, including drugs like nivolumab, there is a third of patients, those who respond where you can achieve a complete response, a third of them, their diseases, you've achieved a tail at the end of the curve, meaning that we have now got follow-up for more than five years for those patients and their disease has not come back. So I think we are there, but obviously 30% is a small number and we want to see that number get to 80. So that's the first thing with where we are today. With the combination, so people have now moved away from just single-agent nivolumab, we know that you need combined drugs to be more effective. So the next wave of trials is really combining nivolumab with something else. That something else could be another immunotherapy drug like what Sumit showed or it could be some of these Vegev drugs. So when you combine a checkpoint inhibitor with a drug like Axitinib or any of these TKIs, we are now seeing response rates at 87%. So that's pretty promising. We don't know how many of those will be long-term responders. So I think the future, I mean, we are seeing a better response than what we did with single agents. Whether it'll be a cure, I think remains to be seen over a period of time. So it's definitely promising.