 I'd like to thank the organizing committee for inviting me to talk on really second line and greater, so the refractory patient population. And as you all are aware, this is kind of the area in kidney cancer, which has seen the most rapid growth of new data over the past 16 months. So I've got now just nine minutes and 40 seconds to go through five trials. So let's move forward here. I wanted to remind us that overall survival is the key. We've heard that from earlier lectures here. Our patients want to live longer, and it seems like we accomplished that with sequential use of therapy. And I give you Tom Powell's slide from his talk at ASCO, which illustrates this quite nicely. We must remember that we must think beyond first line. We spent a lot of attention on first line, compares us out there, all these trials that we've done in first line, but we must remember that patients spend 30% or less of their time in the first line setting. And so really, sequential use of agents is what is driving the survival. And we really need to understand the contribution of the second, third, and fourth line as we're making treatment selection. And I want to make an appointment, a statement that I would beg you all to try to find how many patients in your practice has actually made it past fourth line. It's quite a minority of patients. Therefore, our choice of agents that we use in the second, third, and fourth line actually really matter. And I'm just like the rest of you. I used to tout to my patients, I want to give them all lines of therapy. I think that I could give them eight lines of therapy. And it didn't matter the order. While I'll tell you today, I really think it does matter the order. And what separates us out from other types of physicians is the ability for us to use evidence-based medicine. And for now, after these trials that have been presented over the past year, we now have evidence that supports the role of different agents. So we do pick winners now in the second, third, and fourth line setting. So let me share with you that data. And so our colleagues have tried to categorize different categories of progression and what would prompt us to want to switch therapies. And I think we agree with these. There are different categories of patients we see. Some patients will keep them on the front line therapy. Others will switch right away. And this is a publication from Bernard trying to put words to these different categories. So as we jump into second line therapy, I'd show you the ESMO 2012 guidelines, which, like NCCN, try to categorize based upon degrees of evidence. And if we focus to the second and third line, you can see in the second line we've got in the post-TKI setting, which is probably the most relevant globally right now. We have exidinib with a category 1A because it was a pure second line trial. And everolimus actually not given the same high degree of recommendation because as we'll explore, was really not a pure second line trial. And in the third line setting, we see everolimus, which would be appropriate. But what is not been updated is the gold results. And I would argue that seraphinib should now be listed as an equally option in the third line setting. So these are the trials that we're going to review that established this second line and beyond setting. We anxiously await for the switch results, which hopefully will come out at ASCO GU. So the two real areas are do we switch to another TKI, use this concept of VEGF suppression through multiple lines? This would be answered somewhat by the phase three access trial, or do we move and change mechanism of action to an mTOR through the phase three record one? So mTOR versus placebo was the topic of the phase three record one trial that was back, presented back in 2008, resulted in regulatory approval of everolimus affinity around the world and was published in the Lancet. And as you can see, stratification was based on prior VEGF receptor TKI one or two. What's not obvious in this slide is that patients could have had multiple lines of therapy. Patients were stratified also by MSKCC risk group. And you can see the randomization there, two to one to everolimus versus placebo. There were planned interim analyses. The second interim analysis was positive. So it became the final analysis. Patients were allowed to cross over from placebo to everolimus. Primary endpoint was progression free survival. We saw a clear separation of curves. And on the final update, a 4.9 month advantage to everolimus over placebo, no overall survival was deemed. But that may be from the crossover. And what, you know, before we would look at this data. And this data served as the means of marketing this agent as a second line agent around the world. And it actually, on market use, was the most commonly used second line agent. But until we had other agents to actually use with data, we didn't really scrutinize it. But as we've scrutinized the data, we've come to realize that actually there was only a minority of patients on this pivotal trial that were in the second line. In fact, the majority of the benefit, the majority of patients driving the benefit were actually in later lines of therapy, third, fourth, fifth, et cetera. And so that brings us to question then what really is the role of using everolimus second line. Should we be using it then, or should we use it later? And so this new data we're talking about is Exidnib. And Exidnib was received regulatory approval in the United States back a year and a half ago and in countries around the world based upon pivotal trial presented by Brian Rini and subsequently published in the Lancet. And you remember, Exidnib is one of these potent TKI's. So the hope of it was that it would provide us greater efficacy and less toxicity. And if we look at the progression free survival on this pure second line trial, it was in favor of Exidnib and the intent to treat overall patient population. 6.7 months versus seraphim of 4.7 months. Primary endpoint was met. It gets regulatory approval. If we look at the subsets, and really the two subsets we can actually draw conclusions are about are the cytokine pretreated subset and the synidinib pretreated subset. The other two, the TEM and the BEV, are two small numbers to really draw conclusions. And then we see that the bulk of data, the bulk of evidence driving Exidnib's benefit was really in the cytokine group. But there was still benefit of a more potent TKI in the second line setting over seraphim, but only a 1.4 month benefit in progression free survival. And when we looked at subsets across there, most of the subsets did benefit indeed from Exidnib, the more potent TKI, over seraphim. And if we look at partial response by resistance, stable disease, they all were in favor of Exidnib. Toxicity was what we would expect with seraphim. And what was key to us, I think, with Exidnib was what it wasn't necessarily overly easy to give. It was actually, it had its own side effects. And it was a differentiated side effect to profile versus seraphim, same with hematologic adverse events. So I need to move quicker because I'm running out of time. So based on this, Exidnib should be considered the reference standard as second line. Well, here comes Intersect. Intersect was a trial designed to hopefully get at the question of mTOR versus VEGF-TKI that we now scrutinize four or five years after its original design that it wasn't the ideal VEGF-TKI or mTOR, but at least it gives us some idea. And this was a randomized trial in the pure second line setting. Patients had prior synidinib. They could have had clear cell, non-clear cell. Prior nephrectomy was not required. And they got randomized one-to-one between TEM or seraphim. And what we saw was a progression free survival, although numerically in favor of TEM serolimus, no statistical difference, so the primary endpoint was not met. Shocking to us doing the trial was it actually a profound benefit and a secondary endpoint of overall survival, 4.5-month difference in favor of seraphimib and brings to point, you know, why is this? Now, we can scrutinize it saying we don't really have a full set of the post-progressive treatment. In fact, only 10% of the data, and it looked balanced in the 10%, but nonetheless that could have been an influence. But I would argue that the degree of difference between these two arms is beyond that. There's something potentially there we don't fully understand. And then record three trial presented by Bob Moser recently at ESMO was a trial looking at sequencing of synidinib everolimus, everolimus synidinib, and I think a point to mention here is going back to what I originally mentioned, we lose patients through attrition. Look at the number of patients in the front line that got therapy. Look at the number of patients in the second line that get therapy, 50% less. So your choice of therapy matters. Patients won't get all of the therapies. You want them to get. If we see this, we see a benefit in favor of synidinib in the front line setting. In the combined PFS, although crossover to synidinib and second line setting tries to salvage some, we see synidinib everolimus as being the better sequence. And in conclusion, and that is exactly what Bob said, that synidinib sequence followed by everolimus is supported by the preliminary overall survival results. And it's really questioned the role of everolimus. So in second line setting, Nick, and in sequencing questions are summarized right here. VEGFTKI, after VEGFTKI is becoming the new standard, I think the preponderance of the evidence based on access, inter-second record one, support that data. There's no direct comparison of exidinib and everolimus. We saw in subset analysis that the majority of patients on record one were actually in the third line or greater. So that brings us to third line or greater. What are the options? Well, up until gold trial, it was just everolimus. And again, based on this data that the majority of patients were third line or greater. The median progression free survival in the subset of patients who had prior synidinib and seraphim in the setting suggested a PFS of everolimus of approximately four months. So there's data in support of its role as a third line. If we look at recent GUASCO, the Italians attempted to look at a retrospective study looking at their patients. And if you look at the last two bottom two areas, you can see that in the patients they have identified that had sequential therapy. There was TKI, TKI-MTOR, which was suitent seraphim of everolimus. And TKI-MTOR, TKI, which was suitent everolimus seraphim. And if you look who did best was when you moved the TKI-MTOR inhibitor third in this retrospective study. And I think the prospective data somewhat supports this too. So here comes as I'm ending up running out of time, Nick. OK, as I end up going on the phase three trial of dividinib versus seraphim, which was recently presented at ESMO, this pure third line trial. And what was the hope with dividinib? Dividinib's hope was that it was a VEGF inhibitor, plus it inhibited FGF. And we know FGF is overexpressed or upregulated during the times of resistance. Maybe we could overcome resistance. So there was a lot of hope with this trial. Patients had to have one prior VEGF inhibitor. They could have had one prior MTOR. Patients were allowed to have cytokines, however true. So it was not a pure third line. But randomization was one to one to the dividinib on a 5-2 schedule versus seraphim. And what we see is superimposable progression free survivals, negative study for the primary endpoint overall survival superimposable. But what it does, folks, is it gives us an approved drug. And in some countries we have a broad label with this approved drug, with the PFS. The PFS is 3.6 months with seraphim. If you look at the subset of patients on the record one who had sous-tent seraphim of Everolimus, PFS was four months. So I give you two drugs with essentially equivalent progression free survival. So there are two options for us as we move into the third line setting. So my question for you is VEGF, VEGF, VEGF MTOR? Or not? OK. And so if we look at the waterfall graphs, again, the majority of benefit with both of these agents in stable disease. So in conclusion, it was a negative study. So finally, as I end, re-challenge with synidinib, the last group of data that we've had. Many of us, this data comes from studies. We pulled data from multiple institutions, retrospective data, on our experience of giving synidinib when we've run out of other therapies. And we found efficacy. And we've published this data. And you can see based on the patients enrolled in this trial, there were a variety of different therapies utilized. We found that the length of time off of synidinib front line predicted better benefit when you went back to synidinib later. And generally, greater than six months was better than less than six months. Boy, we've heard that six-month phrase before. So there's a variety of new anti-ingenesis. Bob Figglin's Schoenfeld Lecture is a good summary of where the field is going. I think we're looking for things beyond. And I just implore you, let's apply evidence-based medicine. Our community oncologists do not. We need to educate them. They will use whatever drug they want to in sequence. We actually have evidence that there are certain drugs that have proven benefit to be used in sequence. And since we never get our patients beyond fourth line, it seems, let's make sure we choose wisely in first, second, third, and fourth line. And with that, I'll thank you very much for your time.