 I'm going to talk a little bit about, again, addressing from a slightly different perspective from Ben about should kidney be removed in stage four disease. We'll touch a little bit about that. And then the most common question we get asked as medical oncologists is, I've been diagnosed with kidney cancer, what's the best drug that I should get started on? What's the best for slime therapy? My disease has progressed. What's the next best therapy that I should go on? And then high dose intraleukin 2, again, who's the right patient for whom this is appropriate for? Are there combinations? And finally, I'll just touch upon some of the new drugs. Some of our topics are all overlapping. So in a way, it's good that the message will be reinforced as the day goes by. So first is adjuvant trials. That's your kidneys being removed. What is the risk of the disease coming back? And are there anything that can be done today to prevent that, to decrease that risk or prevent the disease from coming back? So high risk following kidney removal are patients, not the T1 and the T2. So small tumors confined to the kidney entirely removed, overall cure rate is greater than 80%. So people who are at higher risk are the T3 tumors, the T4 tumors, if you have no positive disease. And like Ben said, it's been removed, but obviously the risk exists for the disease to come back. So today for breast cancer, for colon cancer, after the surgery is done, patients get additional therapies such as chemotherapy, hormonal therapy. Where are we in kidney cancer in terms of trying to do something like that? Day to date, in 2014, there's not been a single drug that's shown to have a benefit to give it to you in a preventive fashion. So the standard of care is observation. So you get your surgery done and you're watched. But the good news is that we have all of these trials, either the last one is ongoing, but almost everything else is completed. So starting in 2004, there have been vaccine trials. And every one of the new drugs that we have today, while they are approved in metastatic disease, they have been studied now in this setting. So patients have their kidney removed and they have had this drug for either one, two, or three years. And we are awaiting the results of all of these trials to tell us whether giving any of these medicines in a preventive fashion is going to decrease your risk or not. So these trials are pending. There's one trial. The last trial is using a drug called axitinib. And we actually have the trial open here at Stanford. For patients with high risk disease, they would be randomized to either this drug or placebo and we look to see if we can decrease the risk. The second clinical question is what Ben had addressed. Should kidney be removed in stage four? Why do we even talk about this as a concept? So if a woman with breast cancer has tumor that spread past the breast into other organs, they don't remove the breast out. Why do we even conceive that as a possibility in kidney cancer? It's again based on the data that he showed you that two previous randomized trials have shown that for patients with stage four disease, when their kidney is removed, they have a superior outcome compared to keeping the kidney in. Now why would this even be true? We think that the kidney itself might be making some proteins that make immunotherapy less effective. So by removing the kidney, you're actually making your systemic treatment work better. That's one hypothesis. The second is it's just the burden of disease. If you have a 10 centimeter tumor in your kidney and about a 1 centimeter up in your lung, the surest way to decrease your burden of disease is to get it removed surgically. So just debulking will it add to having less volume of disease to deal with and therefore your drugs have to do somewhat less work. So these are the two trials previously randomized with support, the role of kidney removal, but what about the new drugs? And this is the trial that Ben showed you earlier. This is asking the question for patients with stage four disease, should they get their kidney removed and then get drug therapy? Or will they just do well with drug therapy alone and what's the role of kidney removal? The trial is ongoing and we are awaiting the results. This is the second trial he shared a similar slide, asking a slightly different question. It's not asking whether the kidney should be removed. It's more asking what's the timing of kidney removal? Should you get kidney removed and then get drug therapy? Or should you get drug therapy first? And then reassess what's the appropriate timing for kidney removal? So we do that in clinical practice as well. So till we know that answers, what do we go by? We are part of a big consortium that puts together patients' experience that we have collected over the last several years. And this is a paper looking at close to 3,500 patients. This is not randomized, it's not prospective. This is what we have done in the past. And now we are looking at what has happened to this group of patients. So off those 80% of patients had their kidney removed. And there are patients who don't have their kidney removed. So 676 patients have their kidney still in place, and 935 out of the 1600 have their kidney removed. And we are looking at our results in this group of patients to make some sense of whether the kidney should be removed or not. And here are the results. It shows that for this group of patients, the kidney was still in place. And you'll see this hazard ratio for those patients who got their kidney removed. Now, all of this has bias, obviously, because this is not prospective, it's not a selected group, but just some data for us to go by as to why we still talk about this idea of kidney removal in patients with stage 4 disease. So there are some prognostic factors that we look at. One Ben mentioned was the performance status. We look at other things in kidney cancer, such as having anemia, having a high calcium, having elevated platelets. Some of these things have shown to have a worse outcome. So in this paper, we looked again at the various prognostic factors. There are a total of six bad things. And if you had one, patients had a much better outcome with kidney removal compared to patients who didn't. So this is who have not had a cytoreductive nephrectomy, and this is the group who had their kidney removed. And you can see that for patients with one, two, or three risk factors, having the kidney removed, patients had a much better outcome. Now, for patients who have four, five, or six risk factors, they didn't have such a big benefit from having their kidney removed. So those patients, perhaps, would have served better by getting drug therapy first, and then reassess whether the kidney should be removed. So here is our approach at Stanford. We sort of don't say everybody needs to get their kidney removed. We sort of pick based on individuals. We pick patients for whom there is not an urgent need for systemic treatment. So what do I mean by that? Patients who are symptomatic, who are really fatigued, who have a hard time dealing with this disease, it's going to be tough for them to derive a benefit from that surgical removal that we think about giving them drug therapy first. Good performance status is really a key. You want people who can withstand that surgery. We want people, we think liver and bone disease may have a worse outcome, and we want to give those patients drug therapy first before we readdress surgery for that group. And finally, brain metastasis is similar. We want patients perhaps to get drug therapy first, reassess really what their need for surgery is. And also, like I said, if 75% of your tumor burden is in the kidney, it makes more sense to get that kidney out and then deal with drug therapy. So again, to wrap up that topic, it's mostly individualized. We are waiting for our large randomized trials, but in the meantime, I think in some ways it's your experience and sort of getting a sense of how an individual is going to do before we go on. So moving to the next question then is what is the best first line therapy? These are the choices of drugs we have that have been proven and are FDA approved for use for patients with newly diagnosed kidney cancer that has spread outside the kidney. They include the VEGF inhibitors I had mentioned earlier, Sunitinib, Pozopinib, and Bevacizumab plus interferon. The MTOR inhibitor Temsirolimus has been approved and high dose intraleukin-2 is a therapy that's available for patients with kidney cancer. Which one do we pick? And really unlike other cancers, for lung cancer, for instance, we can take an individual tumor, look to see what specific mutation they have, and based on that mutation, you can give them a specific drug. Our hope for kidney cancer is that's what we would be today in 2014, we have seven drugs. Obviously each drug, there is a specific fit for a given individual, but I think even today we are not there where we can just look at you and say this is the right drug for you. We are not there where tumor analysis helps us pick a drug for a given individual. So the factors that really aid treatment choice end up becoming patient characteristics. What are the tumor characteristics that we know of and also the drug characteristics that help us pick one drug or the other? So what do I mean by that? A good VEGF inhibitor candidate may be somebody who is functioning well where they have, there are a little bit more side effects with these drugs so we want a patient who's got a good performance status and it also causes more tumor shrinkage. So we pick people, if you need to have tumor shrinkage where these large tumors are causing symptoms, then we know that you need a drug that's going to cause tumor shrinkage and that perhaps would be a good candidate for a VEGF inhibitor. We also know that the MTOR inhibitors can make diabetes worse so we want to be mindful of that about which drug we pick for one or the other. Similarly, we know that the VEGF inhibitors can sometimes cause very high blood pressure, may cause cardiac problems. So you want to be able to select based on a given individual's health issues as to which drug. I tell my patients this, that it's like going to a restaurant and picking off a menu. You pick it based on your food preference, your food allergies. In many ways, I think we are fortunate to have this choice of drugs from which you can pick and now we have a luxury of being able to pick based on all of these characteristics. So here is the data really that shows us which drug is good and my take is the following, in general, all of these drugs have a similar progression-free survival. So what does that mean? It means that you can expect to be on this drug for this period of time without the disease getting worse. That's what progression-free survival is and typically our expectation from any of the VEGF inhibitors today are it's about 10 to 11 months. That's the ballpark. In fact, it's around nine to 11 is what we expect. It's a median, which means that's where 50% were. So you could expect more or less, but that's the average. Similarly, what's the tumor shrinkage? So once we give this drug, we expect about a 25 to 40% range where there is likelihood that we give it to you and the tumor is going to shrink. So overall, these are the choice of drugs we have and really it ends up being what ones comfort us in taking care of these side effects, which one is better than the other has really not been completely panned out. As you can tell, each one have been compared. So Sunitinib was compared against interferon. Pazopinib was actually compared to placebo. So the first trial that really compared these drugs, one against the other was this trial called the Compares trial. It took a large group of patients close to 1,000 patients and randomized them to either Sunitinib or to Pazopinib. And the idea here was just to see if they what the outcome of these would be. And overall, it appears that these two drugs have again equal outcomes in terms of cancer outcomes. So the, you can see up here that the two curves are about the same. This is the progression free survival. And again, it's about nine to 11 months as the ballpark that I told you, which means you can expect to go on this drug and stay on this drug for about a year is what we expect the effectiveness to be. And again, here is the overall survival. Between these two drugs, there was no major benefit for one drug over the other. And so it really comes down to what I said in my first slide that you pick a drug based on what we think you're going to tolerate or what the general side effects are. These are the side effects typically of these drugs. They all cost similar ones. They cost an increase in blood pressure. There are diarrhea mouth source. You'll hear a little bit more from Melissa Beaturi later in the evening about how to manage some of these side effects. But the drugs are somewhat in the same class. They have varying side effects. Pazopinib can have increased liver toxicity. Sunitinib may have a little bit more fatigue, but overall, these drugs are all effective and we really don't have a great way today of picking one drug over the other. So that's actually, so we talk about this a lot. What does it mean to a patient to have benefit from these drugs? Ultimately, our goal would be to eliminate cancer and for it never to come back. Unfortunately, none of these drugs are associated with a cure, but what they do is they control. So they prevent the disease from getting worse and they probably prolong life. We know today that compared to a decade ago, patients with kidney cancer are living longer and we have no doubt that it's attributed to some of these drugs. So benefit to us, even though it doesn't mean cure, it means we are prolonging life. We are delaying disease from getting worse. We are shrinking tumors down so that patients don't have any symptoms and we know we are probably improving quality of life. So when we say progression-free survival, that's the delay or the effectiveness for which this drug, the time for which it remains effective. And typically you can expect a year and after a year it's not uncommon to switch to something else, which is my second talk, which is what's the next best therapy? If you have had one drug and it's remained effective for a period of time, but because these drugs don't cure, we know at some point your body is going to develop tolerance and we are going to have to switch to another drug. What should that next drug be? And just like the first question, we don't have an answer for the second one either. So you have all of these choice, which is a good thing. I mean, I think there's good and bad. The good news, I mean, in prostate cancer, we have some remarkable drugs, but we have to pick and choose. You can only get one drug and either that drug works and the second drug doesn't. I think it's amazing in kidney cancer where we actually have all of these drugs and we are able to go from one drug to the next and have patients derive benefit from it. We know that sequence don't seem to matter that much. We could do one drug and get to another drug and have benefit. And I think till we have better biomarkers, we are really not going to be able to pick one over the other. And so for now, the news I think is that all of these drugs are options and we sort of pick one, see how you tolerate, see if you have a benefit from it before we move to the next one. So this is the overall algorithm. There are large national guidelines that help clinicians and cancer specialists guide the treatments. And as you can see, for patients who have had first line, if you have had sunitinib, these are all the choices that you can have. If you have had temsirolimus as your first line therapy, you have data to support use of other VEGF inhibitors. Overall, this table is not very helpful in my mind because it really means you can use any drug, you know? Honestly, because we don't have a great way of picking it as yet. And really that's the bottom line. There are the drugs available. You pick one. There are many choices and I hope that's the message I hope to convey from this slide. How about high dose IL-2? Again, high dose interleukin-2, unlike these other drugs, it is associated with a cure. There is a small fraction of patients who can be cured, but that number is very small. It's about five to 8%. And just like the previous drugs, we don't have a great way of picking who that five to 8% of patients are. So if you have 100% of patients get it, 95 are going to get all of the side effects and only 5% are really going to benefit from it. On the other hand, the drugs that I just showed you previously, they don't cure, but they benefit close to 85% of patients. So that's the risk and benefits that you have to weigh. So what's the data on high dose IL-2? Again, overall partial response where you can get tumor shrinkage is about 10 to 15%, but at five to 8% of these patients can be cured with their disease never coming back. Unfortunately, it's pretty toxic, so you pay a high price for this. Patients get admitted to the hospital, they are in for five days, they have a lot of side effects, but fortunately, most of these are reversible. So we have to pick the right patients. So today, given that you have seven other drugs, we are very selective about who we give high dose IL-2, too. So it includes patients who are somewhat young and who have no brain metastasis, who have normal functioning heart, normal pulmonary function test. So you're really picking your marathons who are able to withstand this treatment. And again, just like the previous trial, we are looking for biomarkers that might help select who that five to 8% is, because then it's truly worth putting yourself to that toxicity, yeah? I mean, and that's the hard part. I mean, your experience is not different from some of the experiences that most people have had. There is a, we call it a capillary leak where there is patients end up having susceptibility to infections like this. But in general, again, for the most part, usually it's when we are very selective about picking the right candidates, most of those only happen during the time that you're hospitalized and we don't get into long-term problems like this. But there is no doubt that's why the treatment has to be selective for patients who can withstand those side effects. Yeah, I mean, I want to reinforce that as well because really this is a very intense nursing issue. So we had to take our time to open that program up here at Stanford and really it's all about good nursing. We had to have people who are trained during that time while you're in the hospital to be able to give it. So there are very selected sites now who do it. But, and I think, you know, you're going to hear from Andrea Harsak next about immunotherapy that's upcoming. The idea here is that in the future, perhaps we'll have immunotherapy that's not as harsh as this and may be applicable to more than just the five and 10% with less side effects. So that's what we are hoping for. Yeah. Nobody knows that there was a very small series that came out about in single institutions experience by giving high dose IL-2 after they have received VEGF inhibitors. And there it appeared that the cardiac toxicity was a little bit more than what we had experience with with just high dose IL-2 alone. So most physicians now in general, if you want to do high dose IL-2, I think it's perhaps best to get it done first and then either it's going to work or it's not going to work and then you can move on to other treatments. So for us, we sort of pick people who we think it would be a good candidate for and do it either front and then it works. Again, you'll know your results within the first three months and then either it works and then you can move on to other drugs. So in general, I think it's preferable to have that discussion up front, get it over with before you move on to other treatments. So I'm going to quickly wrap up that combinations, unlike other type of malignancies where we have been able to combine drugs very easily, that strategy has not been successful in kidney cancer. You can think that we have seven drugs could be not improve our overall outcome by combining these drugs and perhaps getting a better outcome. And that strategy has not been very successful mostly because of the side effects. So when we combine Sunitineb along with Bevacizumab, for instance, horrendous side effects with blood pressure problem. Patients have blood disorders, kidney failure. So it has been a challenge to combine these drugs and some of the larger trials that have combined Bevacizumab with the MTOR inhibitors overall have not shown a big advantage. So the bottom line in 2014 is that we use drugs sequentially rather than combining them together. And again, perhaps with other new immunotherapies that are coming, we might be able to have some benefit. I'm going to quickly touch about what can you expect now that we feel we have made a plateau with these VEGF inhibitors and MTOR inhibitors and are really looking forward to newer drugs and newer pathways and what's out there in the horizon. So I want to just highlight a few things about some of the drugs that you can expect in the next several years. Probably the one that's closest is the PD1 inhibitors. So I'm not going to say much about it because I know Andrea will talk about it in the next talk. The other are vaccines. Certainly those are in development. Some of these are in phase three testing and we may see some results come down in the next several years. So these are all pathways related to the PD1 inhibitors and the phase three trial is completed. So hopefully we'll hear some and the next generation have already started combining these with some of our existing drugs that we have such as Sunitinib and Pazopinib. I want to talk a little bit about this vaccine which is really interesting, which is an off-the-shelf vaccine. So it's basically combining 10 different peptides. So the idea here is that you inject these. These are peptides that we think are expressed in kidney cancer patients. So they just take a combination of these 10 peptides, inject it, that's the first step and by injecting you're going to recruit all these new dendritic cells and ultimately they leave the lymph nodes and the idea is that this will then eliminate tumor cells. So this is called the IMA901, it still doesn't have a name and there's actually, it is in phase three testing looking at close to 350 patients and it's used as a combination. This enrollment is almost completed so hopefully we'll have results of this if not at the end of this year, maybe next year. So the idea here, right. So instead of taking an individual one from your own body, it's like off the shelf, this is what we think there could be 10 different proteins so we are introducing that into your system so that they can then recognize these antigens and perhaps it'll be just like our vaccine that you get for hepatitis or polio or stuff like that. This is actually being used as a treatment so it's a therapeutic vaccine. Similarly, there are other approaches such as this AGS003. Again, these are all some newer immunotherapy that I think is probably what we'll see in the future. I just want to wrap up with one trial that we have up here at Stanford with a similar principle. This comes from one of our investigators here in a lab where they give high dose of radiation to a given site in mice and the idea here is that once they do this high dose radiation it's going to release all these tumor antigens and your lymphocytes and your body now learns about these antigens so we allow them to wait for a few days. So we give this high dose radiation, allow your lymphocytes to acquire memory to it and three weeks later we remove these lymphocytes all these dendritic cells and then we give a drug called cytoxin which is an oral medication to sort of lower the blood lymphocytes and then we give this dendritic cells back again as an IV infusion. And the idea here is that those cells that were removed are going to go back into your body and they're going to multiply about 50-fold higher and go and attack the tumor cells. So there are similar strategies that are being looked at across the country. This is just one such example and these are all ways by which we hope that your body's immune system will then go back and fight the tumor cells. So this is a small pilot trial that we have just gotten started and would be appropriate for anybody who needs radiation, anybody who can tolerate a high fraction of radiation. So I think I'm going to stop with that.