 Okay, so I'm going to cover all of these topics hopefully in the next half hour and we'll try to see if we can stay on time. So what do we, so you've had your kidney removed, some of these were questions that were raised, so I'm going to try to cover these important topics. What's the best therapy after the kidney is removed to prevent the disease from coming back? So these were some of the questions that you had addressed about stage one, stage two, stage three, if after you've seen Dr. Son, he's removed the kidney, is the, what do we do next? If we don't see anything visible by scans, should the kidney be removed if somebody already has disease that's spread to the lung? We are going to talk about that. What is the first, we have seven drugs, how do we pick the best drug when you come in for your first diagnosis? If that therapy fails, what is the next best second line therapy? When should high dose intraleukin-2 be used? What about combinations? And then we'll touch a little bit about rare histology subtypes and finally close up with what's new and upcoming. So the first two address about adjuvant, so that's what it's called, so it's very common in patients with breast cancer today to have their breasts removed and have no evidence of disease and undergo treatment for six months with chemotherapy, hormonal therapy, and radiation. Is that common in kidney cancer? So we already heard that especially for patients who are at a higher risk for the disease coming back, such as T3 or T4, or patients who have lymph nodes that were removed, we know that these patients have a higher risk of the disease coming back. But to this date, no therapy has actually shown to be effective in preventing the disease from coming back. Because we have really not had good therapy up till 2005, people have tried using high dose IL-2 and they gave it to half a group and the other half were watched. And in fact, there was worse outcome to the patients who got therapy. So today the standard of care is observation. But what do we have by way of trials? These are all the clinical trials today that's looking into this question about is there any value added by giving a drug early on before the disease actually shows up. It makes sense intuitively, but have we proven that in clinical trials? So I have listed seven trials up here. It's not exhaustive, there's probably two more, but just so that you know, thousands of people. So this is the start date. It started in 2004 and we have trials still continuing in 2013. In fact, we have a trial here at Stanford with another drug called axitinib, which I don't even think here with axitinib. So these are all looking at more than you can see large number of patients ranging anywhere from 300 to about 1500 patients are being enrolled in this trials to answer this question. Yes. That's what I mean. So it's not all inclusive. There are a few that I want to say every drug that we currently have today for metastatic disease is being tested in this setting. So do I have any results to show to this date? So the first one is this trial called the Assure Trial which started in 2006. That's the first one where we actually have a readout. What was this trial? They took patients with anybody who had stage one and higher. So stage one, stage two, stage three, but they shouldn't have any visible disease that was seen after the kidney was removed. Those patients were taken and were randomized to either a placebo for one year, sunitinib or suraffinib for one year. This was a blinded trial and you'll hear more about all of these from Sujata when she talks about clinical trials. But I just wanted to give you a little bit about the readout. This is the first trial for which we have any results. All of the rest are ongoing. The patients may have all been accrued. But you have to wait so many years before you know whether there is a benefit or not. So here's the first trial. Like I said, it's called the Assure Trial. It took patients with non-metastatic kidney cancer. They underwent surgery and then they were randomized to one of these three for a total of one year. After that they were followed and you want to see what happens to these three groups. So there is an independent group that evaluates these results and here are the results. Unfortunately, this was a completely negative trial. So here is the disease-free survival and here is the overall survival. And you can see all three arms are blended together, which means that there is absolutely no difference by either taking a placebo or taking one of these drugs for a total of one year. So what went wrong is that the drug is one year, two shorter period of time. Is patients with stage one their risk you heard from Dr. Son? They have a 90% cure rate. Did we take two patients with two lower risk to actually show that there was a benefit? So there are many questions that we continue to want answers and we don't have those answers yet. So there's really value added to continue asking these questions. So to go back to your question the current standard of care is after your kidney is removed watching is what we know best outside of a clinical trial. So we continue to urge people to participate in a clinical trial but we really don't have any information that early on just taking these medications help. So that's the first question in terms of adjuvant therapy. Now how about kidney removal in stage four? So the scenario here would be that 30% of patients who I first described to you who already have disease in their lung or their lymph nodes or bone and that's the first time they know that they've been diagnosed with kidney cancer. Is there any value in removing the kidney? You don't do it in other disease so if a woman has breast cancer and for the first time comes in with a tumor in her breast and already has disease in a liver we are not focused in removing her breast we focus on giving her systemic therapy because in some ways the tumor has already escaped and what's the value in removing the primary. And kidney cancer is slightly different because throughout the last two decades what we have learned is that removal of the primary even in patients who have stage four disease is beneficial. Why do I say that? It's based on these two trials looking at not a large number of patients but anywhere from 100 to 250 patients one group just got immunotherapy with interferon and the other group got surgery followed by immunotherapy. So these are all patients with stage four disease and you can see that there is some value added to this group who have their kidney removed and then went on to having systemic therapy. So the standard of care really has remained that if somebody is physically fit and can tolerate a kidney removal, kidney removal followed by systemic therapy was the standard for the last two decades. Now the question is we have a lot of these drugs that are so good right we never had all of these before so does that same dictum hold true today? So the one that I showed you before were with interferon which we now know is not even used nobody gets interferon. How about with these new drugs will this paradigm continue to hold true? Can we be removing the kidney in every patient who walks into the door with stage four disease? And I think identical to the interferon data there is this trial called the Carmina study where they are going to take 576 patients with stage four disease and they are going to be randomized to either kidney removal followed by sunitinib or just sunitinib alone. So this trial will give us definitive answer as to whether all patients with stage four disease should have their kidney removed first prior to starting on systemic therapy. The alternate trial is okay kidney should be removed but what's the appropriate timing? Should I get my kidney removed first and then go through systemic therapy? Not all patients can get a robotic surgery like Dr. Son described. If you have an open surgery there is a long recovery period and if something has already spread to your lung is it good for you to wait 12 weeks or 6 weeks whatever it takes before your recovery to go on systemic therapy? So this trial in Europe is asking the question that should we do drug therapy first and then give it a certain period of time and then do kidney removal or should we go with kidney removal followed by drug therapy? So these are all important questions. We don't have answers today but we are continuing to explore these questions. So till you get these yeah that's okay maybe you can write it down so that we can remember. So in the meantime let me continue. So for patients till we get the results of these randomized trials how do we know the answers to such questions? This is a large international database where all of us are providing information about what we do in the clinic every day and this is run with an international database from Canada and they have looked at 3,245 patients and of those patients 1,600 so finally the numbers came down to about 1,611 patients, 676 had no kidney removal whereas 935 had their kidney removed. So now I'm going to show you some information about what was the outcome between these two groups of patients and what they found was that actually in this this is not prospective meaning we already did this and now we are looking back that has a lot of bias because I would not have picked let's say somebody comes in in a wheelchair I'm not going to offer that patient kidney removal so already because these have been done this is somewhat a biased data but this is what we have. So if you look at the group who actually had their kidney removal in this international database it seemed that the patients had a better outcome their median life expectancy was 21 months compared to if you didn't have your kidney removed was only about 9.5 months so there are some hints that perhaps even today if you can get your kidney removed that would be a better outcome. However, not everybody had benefit okay so there was some risk factors that were looked at what was the performance status, what was patients hemoglobin, what was patients calcium, what was the platelet count so these are all we look at normal prognostic criteria and if you had all 6 any patient with 4, 5 or 6 risk factors it appears that they didn't benefit from kidney removal. On the other hand if you are completely fit and you had none of these risk factors it appeared that doing a kidney removal so this is no cytoreductive nephrectomy and this is the group who had their kidney removal and you can see that these are all showing that it's statistically significant so it appears that not everybody needs their kidney removed but there may be a certain group of patients who may benefit from having their kidney removed. What's our approach at Stanford? Again we pick patients who are not at an urgent need for systemic therapy so let's say there's just one or two small lung metastases that's a good patient to have their kidney removed first get that out of the way and then we can start with systemic therapy. Patients who have a good performance status meaning that this disease is not bothering your everyday living activity to be functional. Patients who have no symptoms we in general believe that liver and bone disease is more aggressive and needs systemic therapy first before kidney removal and you know most patients have if a large like one of the scans that Dr. Son showed if you have a 13 centimeter tumor and a few millimeter spots in the lung obviously it makes sense to get rid of the burden of the disease by having your kidney removed. So we don't again we pick and choose and we hope that the results of the randomized trials will help us make a decision better in the years to come. Yes. Can you cancer for 10 years? You can take the mic so that people can hear your question. I've had kidney cancer for 10 years and I've never taken any chemicals so in my particular case where I have had metastases but mine's very very slow growing with this be something that would be recommended to a trial. Obviously 10 years is a long time you know you've done so well without any therapy to prove that therapy is going to add any benefit for you now would be tough to do because you have done so well without any help. So I think this is exactly why we need clinical trials the behavior of kidney cancer is so different and different individuals the minute we see spots in the lung we are not just jumping to therapy because there are patients like you who could do well without any treatment at all and we would much prefer that you don't get the toxicity from any of the treatments and you're leading a great life without the help of these drugs. Okay so moving on to what's the best first line therapy oh sorry again I've listed all of these drugs should we be picking Sunitinib, Pozopinib, Hydrocentrylucin-2, Temserolymus, Bebasisimab plus interferon. All of these combinations have been tested and have shown benefit in a patient with a new diagnosis of kidney cancer. Which one do we pick? How do we know what's the right drug for you? So some of the factors that aid and treatment the way I think about in clinic when I'm seeing a patient is we think about the patient characteristics you know how old is a patient I tell patients it's like going to a restaurant and picking off a menu you know what's your food allergy that's how you pick what you want and I think we pick treatments similar to that how how much treatment can you tolerate so do you have diabetes how about high blood pressure so those are the patient characteristics and then we look at the tumor characteristics we know that a lot of these drugs today have been approved for clear cell kidney cancer does the same apply for non-clear cell how about sarcomatoid histology so there are things that we look at from the tumor characteristics to help us choose a therapy and then finally drug characteristics what's the toxicity profile of the drug and how will your body tolerate it yes I'm going to show you a slide at the end so hold your thoughts on that one so these are the things that we decide about how to pick and again you know the two big classes that we have today are the Vegef inhibitors and the mTOR inhibitors and we pick we think a patient a good Vegef can candidate would be someone who has a good performance status because some of these drugs have more side effects so you want to be starting off in a good position to be able to tolerate these medicines and they have a much higher chance for tumor shrinkage so do you have a need for rapid tumor shrinkage is it is it is the tumor they're causing your breathing to be altered then we want to be acting more quickly and then I already spoke about comorbidities and then here are some of the non-clear the mTOR inhibitors we have some if somebody has diabetes this is not a good class of drugs so there are different ways to think about it so this is overall all of the I told you that all of these are choices suit a Sunitanib bevacissima plus interferon Pizopinib and Temsero Limus these are all choices and these are the trials you can see that this was compared to interferon and shown to be superior okay how much superior the respond tumor shrinkage was 50% compared to 12% the likelihood of progression was 11 months with Sunitanib versus five months with interferon and then Pizopinib was compared against placebo and again shown to be of benefit so we have all of these choices and to date you know maybe Dr. Gruber will help us in the future by analyzing individual tumors to help us make better treatment choices but this is what we have today and we have some of the earlier slide that helps determine these decisions about which drug to pick so each one of these rows here all five they go on and range between giving you an extra five three to five months it looks like is that the right way to read this I think so this is progression free survival and what that means is I mean overall I'm looking at the last I'll tell you that I'll come back I'm sorry second so progression free survival tells you that if you've been on the drug how long is it likely to be of benefit how long can you stay on it before the disease gets worse that's what progression free survival is overall survival ultimately is what we really care right we want people living longer from these drugs the problem the reason why these don't look that different is we have seven drugs now so every one of these patients who went on this drug for instance sootent subsequently went on to receiving six other drugs so it's and including that patient who was on interferon right so remember this trial looks at Sunitinib versus interferon the patient who progressed after interferon went on to getting Sunitinib so that's why this overall survival doesn't look that different the FDA approved these drugs on the basis of progression free survival which was a lot more meaningful compared to overall survival did that answer your question okay it's real simple I go on and have a chance of either screwing with this stuff and getting 26 months and not screwing with it and get 21 months that's why interpret that right well that's why I'm telling is wrong that's the reason it's wrong is because that the reason you only see five months difference is very tough it's not meaningful because the benefit that this patient the one who had 21 months right normally if they had not received any other drug and just got that interferon and died would have been more like 11 months because of the availability of other drugs that patient went on to getting a lot of other drugs so it appears that the magnitude of benefit got shrunk down but that's really not true because they received all of these other agents that were available I have to determine whether not to participate in this stuff one and I got a choice I can go on and either not mess with it or I can do it it's not what number do I look at to show me in general for the two trials how many more months it buys me overall total yeah what is the number is it an OS a PFS a QPRP whatever what is the number what is the month thing that shows me the answer to that question yeah I think it depends on individual diseases and it depends on individual drugs in this trial you know back in 2006 there wasn't a drug for kidney cancer so that's why we were able to do a trial like this that looked at Sunit and a versus interferon and subsequently people have gone on to receive a lot of drugs that have prolonged their lives so I know in the for the audience it seems it's hard throughout as I'm going over the trials don't look at this number because that's very misleading it doesn't mean that if you have kidney cancer today you're only going to live 26 months that's not at all what things are we have patients who go from first line to second line to third line to four line we still don't know the impact of overall survival of all of these existing drugs I know based on a database that we have of close to 2,500 patients that a majority of our patients are living far longer than 26 months so but this is how the trial gets done this is how the FDA and regulatory agencies look at these trials to help approve it as a member of the audience that number is a particular interest to me of course so I think probably I'm not speaking out of turn here probably to most everybody else here too so if you had a mechanism to present that I think it really be appreciated and maybe suggest I might talk about that in her talk to yes since interferon has never proven to be very effective why do the studies always compare a particular drug with interferon because back in 2005 when we didn't have anything for kidney cancer you have to compare with something and interferon was what every patient coming into our door would get so you have to compare with that standard in fact there was a lot of concern about this drug was open a being compared to placebo which was challenging you know how can you give a patient just placebo but at that point there was no drug that was shown to be better so when you don't have anything you have to compare like the woman up in in who just said that she's been through 10 years without any drugs so placebo might not be a wrong thing for certain groups of patients so that's how those trials done today we cannot compare with placebo because especially for first line because we know that there are five great drugs it would be unethical for us to do a clinical trial comparing placebo but 10 years ago that wasn't the case so this trial then went on to asking the question okay there is Sunitinib and there is Pizopinib which drug should I get and this was a trial called the compares trial and it asked the question for somebody with new diagnosis of kidney cancer should they be going on Pizopinib or should they go on Sunitinib so this was a randomized trial patients with new diagnosis of kidney cancer who had had no prior systemic therapy were randomized to either Pizopinib or Sunitinib and what they were looking for here was not to show that one drug is superior to another drug all they were showing is is it no worse than the other drug which might help us choose one drug or the other what are the results and you can see again here that it's not that different so the trial was positive in that sense that you have a choice of either one of these drugs and both were about the same so that's the next step telling us now we are not comparing it to placebo we are not comparing it to interferon we are taking two good drugs and we are comparing one or the other to see if we can give either one and this trial proved to us that whether you went on Pizopinib or whether you went on Sunitinib the outcome was about the same and they looked at a variety of side effects yeah that says that 20 after 36 months three years 20% which is that where that level is right now our progressive free right yeah 20% of the patients can still take the drug continuing on the drug okay yeah that's what I want to understand yep thank you so that's the first line so really your choice could be either to choose Sunitinib or Pizopinib how about second line what do we have for second line and we have again you know if you had let's say you had a drug called Pizopinib you could have chosen Sunitinib or the other way round is high-dose intraleukin 2 an option now how about Tensirolimus, Bevacissimapilus interferon, Axitinib, Suraffinib, Everolimus which one to pick and these are all choices that we have again you have to go back to the first slide that I showed you about patient characteristics disease characteristics and the toxicity of the drug that helps us choose one drug or the other but these are the we all go through a national comprehensive cancer network puts out guidelines that helps practitioners choose one drug or the other and for patients with second line if you have had prior cytokines like interferon you could get one of these drugs if you have had a prior VEGF like either Sunitinib or Pizopinib you could get either Axitinib or Everolimus when I say you could get what does that mean it means that we have level one evidence by way of clinical trials which have taken this exact group of patients and that's how they studied it and showed that there was a benefit for giving let's say Axitinib after you've had Sunitinib there is evidence to show that you can give Everolimus after having had Sunitinib or Pizopinib and obviously you know we want to continue encouraging clinical trials so here is the summary of the second line that there being two trials now one showing that after you get Sunitinib if you had Axitinib it was marginally superior compared to Surafinib and these are the numbers again these are tough as a patient sitting in the audience to sort of say hey am I only going to get five months on this drug I think it's hard to apply that to you as an individual these are good for us to prove benefit and again you know I'm not a statistician but I'm a clinician taking care of patients and I know that patients get far more benefit than this than just showing this five months that we have up here how about hydroxyl 2 anybody have has had hydroxyl 2 okay so there's just one and the reason why there is just one in an audience like this is because it's a harsh therapy it's remarkably tough to deliver this what is hydroxyl 2 it's I'm sorry my yellow doesn't light out too well so hydroxyl 2 is an immunotherapy and it's probably the toughest treatment that we give today what happens patients gets admitted to the hospital they are in the hospital for one week they get this medicine intravenously and it causes havoc to your body it really does it makes your blood pressure drop down you have fevers you have chills you have rigors you're feeling terrible your mind is all altered your liver function is abnormal I mean every organ in your body gets messed up and the way it gets messed up it's really like a storm inside your body it's like the worst flu of your life and what we are really doing is stimulating your immune system for it to go and do the thing but sounds really good but you know it comes with such a high price that it was approved in 1992 and through the late 1990s there were a lot of people who died from this therapy too so over the years we have become very selective about who we give this treatment to and why do we do it because among all of the treatments that I'm going to show you today this is actually the only one that results in a complete response meaning there are patients who have disease that's gone to their lung is gone to the liver but 7% of patients can be cured by taking this treatment that sounds really great because that's what we want all of our drugs to do we want not just for the tumor to become smaller but we want to get rid of it so that you never have to worry about this disease for the rest of your life unfortunately all of the drugs we have today while they are remarkable in prolonging lives and giving you benefit we haven't seen any cures with that with the current drugs other than high dose interleukin 2 so it only happened in about 8% of patients and how do we pick this 8% is there a great way for us to just say if you're going to be in that 8% then it's worthwhile going through all of the side effects but to this date prospective trials have not helped us identify a biomarker or something in your tumor that helps us say hey you're going to be in that 8% just go through all of the side effects it's worth it so how do we pick we really end up picking based on patients who are young who are otherwise healthy who have the ability to put up with these side effects so how about combinations in kidney cancer you have all of these seven drugs why can't you just combine two of this wouldn't it be better than just one unfortunately we have tried that and those results have all been negative to this date combining two of these drugs have just been so hard to do because of the side effects so we've really not been successful that the current standard to be negative trials and the standard is to do these drugs sequentially so taking two and mixing them together is no better than just giving each one after the other and that remains the standard okay and then I'm going to quickly talk about new agents and pathways watch out for this drug this is a new drug called Lenvatinib so Lenvatinib is in the class of TKI's and targeted drugs and we now know that the reason why a drug becomes ineffective is because your body develops resistance to it and resistance happens in a different pathway and Lenvatinib is a drug that blocks the VEGF and also blocks a pathway called FGF and it's the car it's this pathway that makes this drug successful in kidney cancer so it's not yet FDA approved it was just presented at our national meeting and they took patients with kidney cancer who had had one prior therapy and were randomized to either this drug Lenvatinib or Eberolimus which is a finitor or the combination of the two and what they did show was that the drug by itself and in combination was superior to Eberolimus by itself in all measures that we looked at what were the measures progression free survival in objective tumor shrinkage and in overall survival so for the first time we learned two things that there's a possibility of a new drug which is always exciting for our patients so Lenvatinib second for the first time we have shown that perhaps combining the two drugs might not be that much of a stretch for the first time we might be able to combine Eberolimus with another drug and show superiority compared to either one of those alone so this is probably going to go through a phase three and it may be available in the next several years finally I want to close in with the topic of immunotherapy so the buzzword in not just in kidney cancer but in a lot of cancers today is immunotherapy with a pathway called checkpoint inhibitors or PD1 PDL1 inhibitors and I know it is on trial there are many patients who are already on it but it's not yet FDA approved for kidney cancer we are very hopeful that this drug will become available perhaps at the end of this year there was a large trial that took patients with kidney cancer who had had one prior therapy and were randomized to either this drug nivolumab or Eberolimus and we have just had a press release that came out sometime two weeks ago showing that nivolumab was superior to Eberolimus so that trial will be presented at a meeting will be presented to the FDA and hopefully by the end of this year or perhaps early next year nivolumab will be added to the list of all of the drugs that we have for kidney cancer so I want to talk but there are other immunotherapy trials I'm going to quickly wrap up because we're going a little bit out of schedule to talk about non-clear cell kidney cancer so that's a large it's about 25% of patients don't have clear cell and they have non-clear cell kidney cancer what's the best drug for that group of patients it's a small number of patients so we don't we haven't had dedicated trials just for that group of patients in all of the earlier trials that I've showed you there was a portion of patients who had non-clear cell so for instance in the Temserolimus trial which had close to 1500 patients 75 of them had non-clear cell histology and these were the numbers that we showed that Temserolimus was superior compared to interferon similarly in the Eberolimus trial which included close to a thousand patients 92 of them had non-clear cell and again it appeared that there was some benefit to Eberolimus so we never had a dedicated trial just for patients with non-clear cell I'm going to show you this trial called the Aspen trial which was the first trial that was just presented last month at our national meeting which asked this question for patients with non-clear cell subtypes what's the best drug so they took patients and randomized them either to a VegF TKI and in this they chose Sunitinib or is the mTOR pathway a better pathway and they randomized patients to Eberolimus and these were the results overall Sunitinib was superior compared to Eberolimus in progression free survival and then they looked at various risk groups if you were good risk against Sunitinib had an overall progression free survival of 14 months compared to 5.7 with Eberolimus for patients with intermediate risk against Sunitinib was better than Eberolimus the one group that really benefited from the Eberolimus were patients with chromophobic histology again that's a very rare type it happens less than 5% of the time but you can see in that group for chromophobic Eberolimus outperformed Sunitinib so what's my take for patients coming in with non-clear cell histology I would give them a VegF TKI like either Sunitinib or Pysopinib but for that patient who has chromophobic histology I might be more pushed towards talking them on Eberolimus rather than TKI I think I'm going to stop there and have some room for questions so my have a couple questions but first is so my wife was diagnosed with stage 4 in October and then had surgeries in December to remove her right kidney and then a mass in her neck and so far the scans have been clear I'm wondering if there has been anything has shown that either Sunitinib or Pysotinib have been able to prevent a recurrence of the cancer so your question is slightly different from the trials that I showed you where just kidney removal and then giving drug therapy without any evidence of disease to this date we haven't proven that yet your wife has one step higher question that you're asking that she has her kidney removed but she also had lymph node removed so it's already spread and it was stage 4 but right now has no evidence of disease is there any benefit in giving a drug early now rather than waiting for something to show up there is an ongoing trial that's asking that exact question but we don't have any evidence or any data to support use of drug therapy in this situation if a drug had completely no side effects then we certainly would be willing but right now till we can prove that there is any benefit we would hate to put her on a drug that might actually lower her quality of life without really any proof that it's going to be successful so the whole question of doing individual genetic testing on tumors is really a very important topic and we feel that the science hasn't really caught up with what we know so Josh Gruber is going to be doing a talk on doing genomic testing and give you some examples but I don't know what he's going to say but I'll tell you our bottom line is we don't completely understand what to do with the results and anytime that happens I think we are a little cautious about doing testing if you don't know what to do with the results but I think we are in the process of learning a lot of information five years from now if I were doing this talk I might be saying something completely different that we are now going to be doing personalized medicine for every patient based on their tumor but today I think it's really part of research and we don't have an answer as you is there any research in regards to low dose chemotherapy as opposed to full on doses like this there are some people who could that's called metronomic you know where you believe that small dosing in pulses is better than just keeping them on like this which drug to use I don't know specifically about insulin but many of these strategies are being done but they haven't really proven to be successful as yet yeah do you have any data on side effects which medication side effects than others than others you know they all have side effects and the thing is it's very different we know that there are certain individuals might have certain snips that predispose them to some side effects so not everybody gets high blood pressure not everybody gets diarrhea not everybody gets mouth source what is it about a given individual that puts you at a higher risk and we think that there are some differences but that compares trial that I showed you that looked at posopinib versus sunitinib the outcome was about the same but the side effect profile was different between the two drugs so overall I think there are side effects and the way we manage these are by dose reducing giving you enough tools to be able to deal with the side effects and there may be times when we even have to hold the drugs to help patients get through it my name is Ravi I'm a data scientist and a statistician I I work with the Johnson and Johnson like in breast cancer research I'm curious if this subjects that you are showing us the stats is it available to us or is it Stanford proprietary that oh no these are all public this is already published information you probably won't have access to the raw data for you to do your own analysis but these are all you know published they are on peer-reviewed journals but you probably won't have access to going over the individual data for each of these patients I'm just curious if I could be of any help oh thank you so much I'm sure we can use your help I'll come back to you after that yeah hi so I noticed that some of the first line was also listed as a second line option but not necessarily the other way around so can you speak a little bit to why that is and how is that determined and can patients go through the sequence out of that yeah I mean I think the level one data comes from clinical trials but in practice if we have six drugs and we have a patient in front of us we are going to be going one drug after the next so that's why the guidelines if you go through NCC and guideline each of these drugs are listed under first line each of these drugs are listed under second line we know now that patients go beyond the second line we have patients who have had the fifth line or the sixth line of treatment and that goes to show that in kidney cancer that you continue to have benefit from one drug after the other and it doesn't mean that if you have had one that shuts the door for you for others any skin come here you spoke about the the trial nevolumab versus tamarola tamarola ever all I ever all I missed second line there was a trial that you started last year I think nevolumab versus Sunitinib and I wonder is Sujata going to talk about how that is progressing or can you speak to those trials so the first the way the companies bring their drug to the forefront is they choose different strategies right so the makers of nevolumab took patients who have had one prior therapy and compared it with what was the current standard so remember I told you in second line you could do everolimus or you could do accident and they chose to compare it to everolimus and after having 850 patients enrolled in the trial you need a certain amount of time to know what the differences between the two groups and that trial completed its enrollment almost a year ago and now we have a readout which says that nevolumab is better we don't know by how much we don't have all of that information and we'll get to know about it in the months to come so nevolumab will get approved but it'll probably have a label that you can only use it in patients who have had one prior therapy now so that's the first thing so also as part of a clinical trial how can we do better so right now the current trial is going to be taking nevolumab and combining it with another drug called epilumimab which is another checkpoint inhibitor it's approved in melanoma so the combination of these two is being tested against our current first line which is Sunitinin and that's an ongoing trial it just opened I want to say maybe four or five months ago and it's enrolling very rapidly so for our patients coming in for first line that's the clinical trial that we have it's randomized again so we don't know if you will get the immunotherapy arm but it's a 50-50 you'll get treatment and you'll get the best treatment we have today which would be Sunitinin or this immunotherapy now for example stem cell transplants or cart cell stuff if you could give your opinion on that well stem cell transplant has been done in the past so we have had a now experience both at our own center here at Stanford and this was probably in the early 2000s where a lot of data came from the National Cancer Institute whereas was an extreme form of immunotherapy right it was in stem cell it was actually allogeneic transplant so you take somebody else's cell and you put it in your body and that recognition that you have something foreign in your body is what was going to work but it was very toxic foreign was bad and not just for the tumor cells but it was bad for a lot of your normal cells so people died from lung infection people died a little bit like it but at least interleukin 2 is not it's not damaging your normal system so one of the problems with current immunotherapy is is there auto antibodies generated that can harm your own body so we worry about pneumonitis we worry about bowel issues so these are all things now CAR T is a very new immunotherapy that has shown promise in leukemias and is showing promise in a lot of other blood disorders the current trial is just about to start for solid tumors like kidney cancer and other we don't have it open at Stanford but it's just about to start