 Thank you, Scott. So I'd also like to thank the organizers for giving me this opportunity to speak here. Please feel free to stop me if you have any questions. You know, targeted therapy is really a huge topic. I'll try to do it justice. I guess the only thing I can say about that is a lot of it is similar and a little bit redundant. So here we go. So I think I really chose to put this as systemic therapy because I think that's really what we're talking about. You know, in a sense, what can we use to treat the cancer wherever it is in the body? And so I think there are probably three major categories. There is immunotherapy. There's the angiogenic pathway and then there's the mTOR pathway. I'm mainly going to talk about the bottom two because Scott's going to cover the immunotherapy next. So this is again a cartoon which depicts staging and kidney cancer. And really when we're talking about systemic therapy, it's what we use here. We have tried to use it here, but so far, you know, it's not really shown success in that particular area that is stage three. Then again, you know, Scott's gone over this. So really what we're talking about is, you know, about 20 to 30% of patients at presentation have metastatic disease and these are the ones who are the targets for systemic therapy. I think when we say estimated median survival 10 to 12 months, that's not always true. I mean, you know, stage four is not one broad brush. And again, I think it's important. That's the average statistic. But especially with therapies these days, that's probably not true. And I think we have a much, much more to offer. Again, I think this slide's been shown, you know, multiple times as well. And the main point I want to make here is most of the therapies that we have are really optimized or probably work best in clear cell, which is 75% of kidney cancers and all the other subtypes, you know, I think therapy is still evolving and we're not quite sure how best to treat the other subtypes of kidney cancer. So going back to the systemic therapies, I just have a couple of slides on immunotherapy and primarily on IL2. You know, this has been around for a long, long time. And I, you know, again, there are IL2 believers and they're non-believers. I definitely fall in the believer group. And the main reason is this study, which led to the approval of IL2, and I've kind of highlighted here on the next slide. So I think the main point here is in people who do respond, you know, median survival is usually years. So I think the downside is it only works in about 10 to 20% of people, but in the folks whom it is right for, and it's not right for everybody, and in whom it works, it's, you know, it's time limited. You're done in three to six months and you can get very, very long and durable responses. I think the onus on us is to find out who are the people who are going to respond to that and hopefully with some of the work being done, you know, here at the university, maybe, you know, three, four, five years from now, we'd be better able to define that subset of patients. Okay, so moving on to the VHL pathway or the Warn-Hippel-Lindau pathway in kidney cancer. So VHL gene product, essentially what it does is it keeps down levels of hypoxia-inducible factor or HIF on alpha. So if the VHL gene product is missing, there's upregulation of this hypoxia-inducing factor, and once that goes up, a host of other growth factors are upregulated, you know, leading to growth of the tumor, and this is kind of depicted here. So the main one here is really VEGF or Vascular Endothelial Growth Factor, and if this is upregulated, you know, basically cells can survive better, they can grow better, they can migrate, and that in turn triggers off many other pathways which basically, you know, keeps on fueling kidney cancer. So a lot of therapy in kidney cancer, and again, clear cell kidney cancer, has been focused on how do we downregulate VEGF. Now this is a complex system, and this kind of just depicts the complexity. So there are three receptors, one, two, and three, and there are at least eight or nine different ligands, and again, as time goes on, these only keep on increasing. And again, the drugs that we have, you know, they probably target some of these pathways and not all, and remember, I'm only talking about VEGF, there's PDGF, there's EGF, there are many, many other growth factors. So it is targeted therapy, but it's kind of more drone-like. That's specific, and there's a lot of collateral damage. So that's the big challenge in using agents to target this pathway. So some of the things that have been done to target the VEGF pathways, you can have antibodies that, you know, that wipe out the ligand. So this is Avastin or Bevisuzumab, or you can target the receptor, or you can target, you know, the signaling modules of the receptor inside the cell. So that's why there are multiple different drugs available that target the VEGF pathway. We don't quite understand why some work better than others. And again, it probably has to do with which particular pathway is operative in a particular person. And even though if you block that, then since there's so much of redundancy in this pathway, the other pathways take over. And that's why I think this is extremely complex. And again, remember, I'm only talking about VEGF, there's PDGF, there's FGF. There are multiple different growth factors which fuel kidney cancer. The other pathway, which has also, you know, garnered a lot of attention, is the mTOR pathway. And then once again, if you see this, you know, it also interacts with hip on alpha. And so the other line of investigation has been, can you combine drugs and can you block multiple pathways? And so far, that's not been very successful. So anyway, these are the different approved targeted therapies for kidney cancer as of today. So on the VEGF side, you have Sunitinib, you have Surafinib, you have Pisabinib, you have Devacizumab, and you have Exitinib. So at least as of today, these are the approved anti-VEGF agents. And again, it's not pure anti-VEGF. As you can see, there are multiple other things or other pathways that inhibit. And then on the right-hand side of the two mTOR pathway inhibitors, there's Temsurolimus or Toricel and Avrolimus or Affinitor. So at least so far, this is the list that we have, which is approved. Now the first one to be approved was Surafinib, next was Sunitinib. And really in front line today, the three most commonly used are Sunitinib, Pisabinib, and Devacizumab. And I think this is also becoming, you know, this is also starting to be used in front line. But currently the three approved are, in first line is Sunitinib, Pisabinib, and Devacizumab not alone, but in combination with interferon. And then in poor risk patients, Temsurolimus is approved in first line. So the other targeted therapy I forgot to mention, I think is extremely important, is surgery. I mean, when you have somebody presenting with dyspigopa tumor, all the drugs that I showed you, you know, in the previous slide, are not going to do anything much. So again, I think we shouldn't forget surgery is an extremely targeted therapy, important targeted therapy even in metastatic disease. So I think if he kind of had a question as to somebody presents with a fairly big kidney tumor, would the options be observation, nefrectomy, systemic therapy, or BNC? I mean, I think, you know, most of us at least, even on the medical oncologist will say it has to be BNC because, you know, the systemic therapy that we have today is not good enough to do anything much for big tumors. And in fact, every time I see a patient who has a big kidney tumor, like surgery is not an option, I'm actually always very nervous. I think the other big thing which helps us decide, you know, who do we give what are different risk models that we have developed. So in 1999, Memorial Sloan Kettering came up with this one. And 10 years later, a consortium based out of Alberta and Canada called the Henk criteria came up with those. And they're really very similar. And the important, you know, the important points on this are the time from diagnosis to systemic therapy. So in other words, the shot of the period between diagnosis and needing therapy, you know, that's a bad sign. So a poor performance status or a compromised performance status, elevated calcium, elevated LDH or anemia. So these are all validated factors which, you know, which basically help us prognosticate how somebody is going to do. And on the Henk criteria on the right, they have a couple of additional things. And basically the important point here is if patients at presentation have none of those factors, so that means a risk factor of zero, they're in a favorable group. If they have one to two risk factors, it's an intermediate risk group. And if they have more than three, then they're in the high risk group. And I think both the Memorial criteria as well as Henk criteria are actually, you know, predictably shown that, you know, the more the number of risk factors, you know, the poorer the prognosis. So here it speaks to two-year survival. So in other words, you know, in the high risk category or the poor risk category that is more than three risk factors, the two-year survival is 3% and in the favorable group it's almost 50%. So again, this is just a guideline at the time of diagnosis or when you're going to start to treat somebody which can help you substratify patients and, you know, be able to advise them on what to do or what not to do. So this is a little bit more on the Henk criteria. Again, you know, this is more recent, so they have more factors at the disposal. Plus there's been stage migration. We pick up patients earlier. So with the zero risk factor group median survival is about 43 months, 23 months, and for the poorest group it's eight months. I think the other thing the Alberta Consortium did was they actually also looked at non-clear cell kidney cancer. You know, we say kidney cancer, but really most of what we talk about applies to clear cell. So for the non-clear cell, you know, as we predict the prognosis is slightly worse for each of those risk groups. So 32 months in the good risk group, 16 months in the intermediate risk group, and then five months in the poorest group. So I think if you kind of see where the landscape of kidney cancer, you know, stands today, most of the progress has really been in the last decade. You know, so prior to 2004, we had interleukin-2, which was good, but worked in a very small subset of patients. Interferon alpha, which has always been controversial, but has been a control arm for all studies. Again, I think it works, but probably not very effective. And then between 2004 and 2012, there were the other six drugs which we already talked about that were approved. So I thought what I'd do is I'd just kind of walk you through, you know, some of the important studies, which kind of led to the approval of agents in this particular category. So I think for the first line I picked Sunitnip, which I think most of us, for most of us that is first line for clear cell kidney cancer. So this is the study that led to the approval of about 700 patients either randomized to Sunitnip or to interferon alpha. So Sunitnip is typically given on a four weeks on, two weeks off schedule. And interferon alpha is administered thrice a week, subcutaneously, continuously. And again, if you, so the first thing to look at is the response rates, you know, about 46% and 12%. Complete response, almost nonexistent, 1%. So most of the responses we see are really partial response or stable disease. Now again, I think the devil is always in the details. So if you go with the resist criteria, if you treat somebody and if the response is less than 30% reduction in tumor burden, that is still stable disease. And if the tumor grows and if the growth is less than 20%, it's still stable disease. So really stable disease is, you know, a 25% change roughly on either side. And again, if you see the majority of responses are either stable disease or partial response. And they are, you know, almost zero complete responses. So I think, again, you know, it's a little controversial, but I think different people do things differently. When to start treating somebody in kidney cancer again is a little controversial. And again, I'm talking about metastatic disease. So if you have somebody with very low disease burden, I think it's always hard to commit them to lifelong therapy. Because essentially once somebody starts on the treatment, you know, they're going to be on this till they progress. Because the majority of what you see is partial response and stable disease. You don't really take them off. So at least personally, I like to follow patients. And if they clearly have progressive disease, you know, I think that's when you initiate. Systemic therapy. Because again, and, you know, like about 10, 15 years ago, we didn't have a whole lot of options for kidney cancer other than surgery or IL-2. And if patients progress despite IL-2, if we just followed them, you know, very often they just be in this stable phase where the disease will hit a plateau and they wouldn't get growth. So at least personally, I don't like to start somebody on systemic therapy when they're in the plateau phase. So this was the, you know, the Russian pre-survival, 11 months on the sunitnebab and five months on the interferonarm. And in most of these studies, I think survival is always a difficult thing to follow. And the reason for that is, you know, we assume after a phase three study that nothing else is going to impact survival. But the truth is, with so many different treatments available, you know, people see other things and it's hard to see a survival difference just given the multiple different agents that are available. Now, again, if you split the patients up based on, you know, the good risk group, the intermediate risk group and the poorest group, again, median survival can be very different. 14 months, 10 months, 3.7 months. And the other important point here is, again, you know, it can vary. It's 11 to 16, 8 to 10, 2 to 10. So I think the biggest challenge with targeted therapy, you know, other than the fact that one is committing a patient to it forever, is the host of side effects. So if you look at all grades, you know, it's almost anywhere from 20 to 50%, but fortunately grade three and four tend to be less than 10%. Now, I think there's a certain commonality in the side effects that you see with targeted therapy. So fatigue is common to almost all of them. GI side effects, you know, diarrhea, nausea, stomatitis is again very common. Hypertension is common. You know, skin rashes, hand foot syndrome, stomatitis, those are again very common. And it doesn't matter which drug you pick from the category. I think these three or four things, the fatigue, the hypertension, the skin toxicity, the GI toxicity is pretty common to all of them. You know, with one, you will get a little more of the other. And again, there's also patient to patient variation. And then, you know, then there are also side effects peculiar to different drugs like the sunitinib, about 10% of patients will have a decrement in their cardiac ejection fraction. I think this is the slide I was looking for earlier. So remember the progressory survival, there was a big difference between sunitinib and interferon. But when you actually look at overall survival, it's about 26 months in the sunitinib arm and 21, 23 months in the interferon arm. So again, sorry, 22 months in the interferon arm. So, and that's probably largely a reflection of patients getting exposed to other drugs. So the other one I picked was temserolimus. So remember sunitinib is approved for first line in good risk and intermediate risk patients. And for poor risk patients, temserolimus is approved. And the study that led to the approval was as follows. So either there was interferon alone, temserolimus alone, or the combination. And this was probably one of the first studies which looked at combining two different drugs. And here again, you know, overall survival was about 10.9 months and progression free survival was 3.8 months. And the combination arm was not better than temserolimus alone. So remember sunitinib is an anti-veg and temserolimus is an anti-M tool. Again, if you look at the adverse events, very similar, all grades, fatigue, asthenia is about 50%. This has a higher incidence of skin rash and mucusitis, but then also nausea, edema, and again some of the GI side effects. But once again, you know, fortunately, when you look at grade three and four, you know, those are the ones that we worry about more. It goes down substantially. But again, I think we can't get away from the fact. If you look at all grades, it's anywhere from 20 to 50%, no matter which category you look in. And again, the major categories are skin toxicity, fatigue, GI, and hypertension. So this is just a snapshot of the different anti-veg agents, you know, that are either approved or are used, either in first or second line. So sunitinib progression free survival is 11 months in first line. If somebody's failed cytokines, meaning aisle two, it's about eight months. Surafnib is about six months. Persopinib is about nine months. And exitnib is about 15 months. And I think probably exitnib is primarily used in second line. But, you know, some people have wound up using in first line just given the, you know, the fairly significant progression free survival here. So how do we sequence these agents? I think first line, there is consensus, but second line, there is confusion. So in the first line, and again, this is controversial, I think the right person I probably would still recommend hydrozyl two. And again, the reason is, you know, if you do respond, the remissions are probably the most durable that we know of any drug. Secondly, it's time limited. And I think that's actually a very important thing. But then on the con side, hydrozyl two is not for everybody. You know, you have to have an excellent performance status, you know, normal stress test, normal primary function test. So there's a fairly rigorous thing to go through before you qualify for that. But again, in the appropriate patient, I do think that should be first line for the reasons we discussed. I guess for the majority of patients who are in the good or intermediate risk category, either of these three is okay. You know, you can either use sunitinib or pisabinib, or if there's a problem with oral coverage, bevacizumab and interferon is not a bad thing to try. But I think most of us would either use sunitinib or pisabinib. If somebody is poor risk, then I think you can either use sunitinib, or I guess most of us would use temserolimus. Now, temserolimus is intravenous, and this is oral. Once somebody has failed VEGF, you know, it used to be evrolimus, which is an mTOR inhibitor, which is second line, but a lot of people also use exitinib. I guess a more cynical view here is it's also kind of driven by insurance. So pisabinib and evrolimus are both Novartis products. Sunitinib and exitinib are Pfizer products. And, you know, more and more, you kind of run into when you ask for approval, depending on, you know, who has a deal with whom. Very often now I get this, have you tried exitinib before you can try evrolimus? But I think it's really driven by insurance. But I don't think either is an unreasonable thing to do, because the truth is, you know, so somebody gets an anti-vegF, or lets a sunitinib, they fail, they go to an mTOR, they fail, they go to another anti-vegF. So whether it is sunitinib, evrolimus, exitinib, or whether it's sunitinib, exitinib, evrolimus, I honestly don't think it makes a big difference. So then there's also third line. I mean, I know seraphinib is here in the second line. Remember, this was the first oral TKI that was approved. So once somebody has failed sunitinib and evrolimus, I don't think it's unreasonable to try this. You know, in the setting of a, I mean, obviously there's a clinical trial available. You know, that would be terrific. But in the absence of that, I think seraphinib is reasonable. Now obviously the other big thing that is emerging are the immunotherapies which Scott's going to talk about next. So people have also looked at combinations. And here are just, you know, a snapshot of some studies. There's been temserolimus and bevacizumab. There's been evrolimus and bevacizumab. And there have been these combinations. And as you can see, there's no difference and there are more side effects. So at least at present, there is really no approved combination. I mean, patients always ask this, but can I just take it? And I think it's important to remember this is not something you try at home. Having said that, you know, this year at the oncology meeting, this is probably the first trial that was reported where a combination may have promise. And this used a drug, you know, levantinib, which is an anti-vegetin in combination with the evrolimus. Now the big difference between this and sunitinib is, so remember we've been talking about vegetin, PDGFR. And if you look at their activities, the smaller the number, the more active the drug. So if you look at sunitinib, it really has no or seraphinib. It has very little impact on the FGFR pathway. And this drug actually has a fairly good impact on the FGFR pathway in addition to vegetin, PDGFR. And this was the design of the study. It was levantinib plus evrolimus. So this is an anti-vegetin, anti-FGFR, and evrolimus is an anti-emptor. So there was a combination, then levantinib alone and evrolimus alone. And at least if you look at the initial data, the numbers are small, 50 patients in each group. The progression-free survival for the combination was 14.6 months. For levantinib alone, it was 7. And for evrolimus alone, it was 5.5. So again, I think it's early data. It's only 50 patients per group. But this is probably the first combination hitting three to four different pathways, for VEGF, PDGF, FGF, and mTOR, which gave a fairly meaningful improvement at least in progression-free survival in this small group of patients. And I'm sorry, I don't have the toxicity data here, but the side effects were not overwhelming. They were the same stuff, you know, the skin rashes and the hypertension and the mouth toxicity and hypertension. But they were no more than what you see with sunitinib alone or passopinib alone. But remember, it's a fairly small subgroup of patients. It's only 50 patients, and that's not enough to kind of make a categorical statement. Now I think Scott's going to talk about this. The other combinations that are going to be tested are all the oral targeted therapies we talked about with a bunch of the new immunotherapy agents or the checkpoint inhibitors. Finally, the other, I think the other important thing that also came up during this oncology meeting was this is the first trial which has been completed in non-clear cell kidney cancer. So everything we have so far is primarily for clear cell. So this is the first one that was completed in non-clear cell, and they compared everolimus, which is an mTOR inhibitor, and sunitinib, which is an anti-veget. And for the longest time, we have believed that at least in the non-clear cells, the mTORs may be better. But again, it tells you to do test this, you don't really know. Here if you see, sunitinib actually had a better progression for survival compared to everolimus. It was a little counter-intuitive. And so at least even for non-clear cell kidney cancer, I think the current recommendations are that sunitinib prolongs survival in both good and intermediate risk over and above everolimus. Now the group of everolimus was probably more efficacious was in people with a poor performance status or the poor risk category, again going back to the way how we characterize patients, and also in the chromophobic subtypes. So if somebody is good or intermediate prognosis and they don't have chromophobic, all those non-clear cells, you know, sunitinib ought to be the first line. So I kind of began by saying that, you know, so all the systemic therapies that we have, whether they be first line, second line, or third line, are really for stage 4 kidney cancer. There's been a lot of effort expended in stage 3. The idea there being that if you could use one of these drugs in high-risk kidney cancer, perhaps you can prevent stage 4 from happening soon. There's been a huge amount of effort expended on that. Recently the first trial, which was about 1,800 patients was reported on. There's actually no difference in survival between the placebo arm, the sunitinib arm, or the seraphidib arm. So at least as of now, we really have, you know, we don't have anything proven to offer in this space. So I think I'll stop there and be happy to take questions for you.