 Thanks, Philippe, and thanks everybody for staying. It's a familiar role, the last speaker usually after the hotel checkout. Anyway, this will be on the internet, I guess, so you don't get a lot of jokes on that. So what's on the, we can make a separate bloopers. So what's on the horizon for next year? I'm going to have some kind of forward-looking statements in the SEC sense of the word. And let's have a look and we'll come back next year, see if I'm right. Sometimes I'm right. And anyway, here's a couple slides. We have a firm 6 p.m. commitment. You can move that clock. I'm going to win it. So here's anyway, thanks for staying. There's a picture of my grandmother and my great-grandparents from about 90 years ago. So that's some staying power. We visited Moldova, so that's in Moldova. They did not stay in Moldova. So that was like the last time. I work with drug companies. I like drug companies. They've got good medicines. They brought us here today. So here's some of the ones we work with. Details matter. I've been preceded by many excellent speakers and will not go over some of their good points. But details matter. Here's some of the histology differences. Here's some of the anatomic differences that we might find. And knowing that, it almost seems unfair to just say, well, here we are at the kidney cancer association. You know, it started in the same location in the kidney, so we should treat it the same. Well, they're not the same. Here's some of the risk factors. We know the patients with more problems there have a disease with a different natural history, a faster natural history versus a slower one. Molecular details matter. Sometimes there's a drug which exactly fits onto a particular target. Well, if the target's there, you have a chance. If the target's not even there, then time to move on and try something else. Sometimes we like talking about medicines, but we have good presentations about the local therapies. Local therapies can make all the difference. Clear cell kidney cancer in particular sometimes will have a very irregular pattern of spread. There might be a one problem area. You fix that problem area and you're done. You don't really have to do anything. I have a patient 10 years out presented with a tumor in his leg and in the kidney. Took care of both of those and nothing happened since then. Other times are brain lesions. Kidney cancer can spread to brain, but it just sits there. Sometimes it's much worse. Other times it just sits there. You take it out, move on. Very early on, one of the trials, just looking at an open access program for seraphonib, identified that people with brain pattern of spread, they track just along with people with no brain pattern of spread. I have patients who had interleukin-2 treatment who are a decade out after having had brain pattern of spread and there's no disease left. It's pretty different in that sense that sometimes you don't need a drug at all, just a strategy. Talk about what happens in a trial versus what happens to a patient. I know with my colleagues, many remaining still in the back. We're interested in general concepts, but as soon as we step into the room, we're really only interested in one person. It can be a little bit of a different experience. Here's a cartoon with a bunch of colored spots and you average them together and it looks something like that, but you can't go back and make little mini-means out of the trial. Here's some of these risk factors, which we don't need to go over now just to say this figure, which we all saw before, shows that more risk factors is worse. It's embarrassing to say we're making some progress with it, but the dominant factor on how well people do is whatever they walked in the door with. We're changing that, but these are some of the risk factors which we've had experience with. How many prior treatments has a patient has? Well, pharmaceutical companies love this and the FDA loves this and a lot of times you'll see one L or two L first line or second line or immune therapy naive or checkpoint naive. Well, guess what? Cancer doesn't care. It just depends what you have walking in the door. So it's a good way to organize things, but it's not quite biologic. Here's a nice diagram of looking at two factors, prior treatment or not at good risk or high risk or low risk. The trials as they come along, they kind of carve out subsets of patients and we reach some conclusions and they're good conclusions. They're a good conclusion for the patients within that set and as they get a little bit outside the set, you might be extrapolating a little bit, but you can still say, well, it looks like this drug is better than that one. And then real life comes along, you say we're going to use this trial. Here are the next three patients, they're not in the group. So there's a bit of judgment involved and this is not special to kidney cancer, but just something to remember. VEGF receptors, I think you've had a good schooling on this. The VEGF receptor pathway, what's ahead for that? Well, the old role was a lot of single agent treatments and some sequencing strategies, intermittent strategies. Sinitinib, the dominant drug for a decade, was mostly prescribed at 28 days on or 14 days off. Turns out that's hard to tolerate and many patients wouldn't complete the whole 28 days and then they'd stop and wait a couple of weeks and get started again, but actually more rapid cycling 14 days on and 7 days off seems to be better tolerated and probably works better and may get more drug into the patient. So many of the trials that used the Sinitinib as a comparison, they may have actually handicapped the Sinitinib arm and in real life this didn't matter that much, but on the trials you might have had the Sinitinib losing by a bigger margin than it otherwise would have. Why wouldn't it matter in real life? Here on colleges probably knows this already and would adjust your schedule if you're on a regular treatment, adjust your schedule to make it meet you. This is not unique to Sinitinib, many other of these medications need some schedule adjustments. Here's another cartoon with a VEGF receptor pathway. There's a tumor cell and there's some of the VEGF drugs blocking the VEGF receptor. The money is probably on the endothelial cell, although tumor cells themselves have some of that. Here is Lenvatinib also blocks this, the FGFR receptor. Not all cancers have this, not all clear cell kidney cancers have this, but it may matter for some. Here's Cabozantinib, it blocks C-Met and Axol, and those are actually more dominant targets on the tumor cell. So there is some sense that blocking the VEGF with a VEGF drug may be something that could be salvaged with Cabozantinib. So we're seeing a lot more Cabozantinib in 2019. Talking about immune therapy, we got a good education on that here as well. The immune therapy, the PD-1 pathway was used mostly in isolation, and IL-2 and the interleukin-2, another one also used in isolation. These are proteins on the white blood cell surface, also CTLA-4. And the drug in this case works on the immune cell, and the immune cell has to do what it was born to do, which is attack something, but the drug isn't really attacking the cancer directly. So let's talk about one partner, which I think is going to be a big partner in 2019 and beyond to use the catchphrase, and that's the IL-2 receptor. And it's an odd choice to say that the IL-2 receptor is going to be a big deal in the future because it was a big deal in the past. Interleukin-2, I mean, it's got a really low number, 2, is one of the proteins that white blood cells make to communicate with each other, and there was a receptor on the lymphocytes, T lymphocytes, CD-4, T lymphocytes, CD-8, T lymphocytes, natural kill lymphocytes, IL-2 receptor, and it gets the IL-2 and it changes its behavior. It divides more, it goes to attack more. Interleukin-2 receptor is used in a lot of lymphocyte-based treatments. We talked for a minute about CAR-T cells, so the CAR-T cells are the patient's own T cells taken out of the body, expanded with what? With Interleukin-2, they're infused back in after the patient's own white blood cells have been kind of wiped out to clear the stables, and the patient gets a few doses of what? Of Interleukin-2 to help those lymphocytes to expand. Now, we don't have CAR-T cells that are available for kidney cancer therapy. The antigen matters. Tumor CAR-T cells have been slow to develop as a technology, but that Interleukin-2 receptor is what's on those cells. Similarly, TIL cells, tumor infiltrating lymphocytes, this was initially tested in kidney cancer. The tumor is taken out. Interleukin-2 is put on there, it grows out the lymphocytes, and they have a population of lymphocytes which were at least smart enough to get into the tumor. Then those are re-infused back into the patient, and at the point they're put back in, they're given Interleukin-2. So Interleukin-2 receptor is something that helps support lymphocyte activity, which is what we're interested in. We have some combinations of medications that use Interleukin-2 receptor and PD-1 receptor at the same time. They're listed here. Pembrolizumab with high-dose IL-2. That was a single-arm study. We're finishing that up at the Moffitt Cancer Center. Nectar and Nevolumab. Nectar is one of the engineered IL-2 drugs. I'll show you that. That, together with Nevolumab and ipilumumab as well, that's also an initial testing. And ALKS 4230, an engineered IL-2 also in early testing with the PD-1. So here's a native IL-2. It's just a small protein. It's got a three-part receptor illustrated there with the blue, green, and red, which is beta, gamma, and alpha. And IL-2, a little oval there, attaches on there. The alpha part is a special part. It doesn't really stick into the cell, but it stabilizes the IL-2 onto the other part of the IL-2 receptor. There's two kinds of IL-2 receptors, just the beta-gamma or what the alpha also. The cells we think are attacking the cancer have just the beta-gamma one, called the intermediate receptor. Here's a cartoon showing the native IL-2, which is now pink in this illustration. And you can see it either binds the two-part one or the three-part one with the alpha attached so it stays on longer. Here's one of these, Alchemy's 4230. This is completed. It's a single agent testing in man, and now it's going to be doing combination testing. So it's a phase one trial. Phase one trial, but you're kind of getting a good deal on both drugs. You get the ALKS42, which is an engineered IL-2. It's got an IL-2 receptor alpha pre-attached onto it in a single chain. And this is how they did it, with a little permutation of the protein sequence, which is pretty interesting if you have a Ph.D. in biochemistry, but otherwise it's just a cartoon there. And then that trial is being given together with the Pembrolizumab, which we know already is active in kidney cancer. Here's another one, Nectar. Nectar is the company, Nectar 214. So the sequence of interleukin-2, which is a small protein, has some different amino acids. Six of them are a kind called lysine. And lysine is particularly good for attaching things to it. So in this case, they've attached a thing called PEG, polyethylene glycol. So polyethylene glycol is a big, long molecule. You may recall seeing it on your ice cream ingredients. It uses a thickener. Anyways, it's not toxic. It just sits there. However, it's so big that the IL-2 is effectively a pro-drug. It's like the drug is in there, but it's got these extra pieces. The attachments are not particularly stable, and they pop off. And then when it's down to one or two, that's good enough, and it can fit onto the receptor. So this is in a trial with a dozen different diagnoses. Kidney cancer included, and there's been several complete responses already reported with that. The frequency of complete responses, we don't want to especially speculate on that, is a low number of patients, but they're definitely out there. I have one patient who's done quite well with that. There are at least a dozen other ways to engineer IL-2. Here's one which has only been tested in the test tube. It hasn't even made it to mouse testing. And what they do is they take the lymphocytes out, give them an IL-2 receptor which doesn't fit IL-2. It only fits a special IL-2. Then they give them a special IL-2. It only fits onto there. And what's the advantage of that is you could take your lymphocytes out and only have the population that you want to respond to that. So maybe the CD4 cells, which we have a regulatory function. You don't want them to see IL-2. Well, you could use this special engineered combination. We'll see if that comes out. That won't be in 2019, however. So as far as on lymphocyte targets, and you've seen most of this before, just highlighting the IL-2 receptor there with the IL-2 and the other engineered IL-2s on the left side of the slide and on the right side, PD1 and PDL1. Those are ones we've talked about before. Those are kind of the brakes. And then on the right lower corner, there's the tremilumumab and ipilumumab, which blocks CTLA4, which is part of the priming response. So looking at PD1, happily for me and the time, these are the same slides you've seen before. This is the same key paper here with initial therapy of those two medications together versus a synitinib. And just going through it briefly, we see that the ipilumumab-nevolumab combination was better with some complete responses observed. On the other hand, in the favorable risk subset, which was a smaller subset, it was planned to be a smaller subset, but the synitinib appears to be better for those patients, especially if they don't have the PDL1 protein. So anyway, as I said, the details matter. The evolution of how to pick patients for which of these drugs and the reality is really we're just picking which drug first because if one doesn't work, we're going to take a step back and try the other. And there's a graphic there. And here's the same lines that we saw before with the ipilumab-nevolumab graphs on the right there. Again, a trial we've already seen, the Emotion 151 with the Teslizumab-Bevizizumab, the PDL1, and the VEGF antibody versus synitinib, again with the combination doing relatively well. Here's another one we've seen as well with Axitinib, the VEGF antagonist pill, with Pembrolizumab and just a striking number of proportion of patients who really get their tumors to get smaller. As Jolie just mentioned, we get a lot of graphs with tumors getting smaller and we have to take a step back. Mike talked about this, Mike Harrison, about what do patients really want. A paper which I didn't put in here, we BMS and I worked with them and they took a survey to ask patients what they really wanted and it was a little bit anticlimactic. Turns out patients really want to live longer and you get a graph like this and it becomes an ironic question. It says, if patients want to live longer, how come from the day they're diagnosed to the day they die, all they talk about is how big is the tumor? Well, that's the only accessible thing we have there. So anyway, that's again one of those graphs there. Here's a big question. Here is adjuvant synitinib and Naomi Haas talked about this trial, the S-track trial, the single positive adjuvant trial. We see the blue line, the patients who got synitinib had a lower rate of reoccurrence as compared to the patients who didn't get synitinib, but the overall survival is about the same on both arms. They've updated it. It's a few patients ahead on the sutent up front arm as opposed to the placebo up front arm, but still not a significant difference. So is this 2009 technology playing out or is this 2019? Well, there might be some subsets that do particularly better or it makes a big difference. So this has been looked at in a few different ways. The first was just a generally easy answer, which is that whether it was a T3 tumor or a T4 tumor patient had symptoms or no symptoms or a high-grade ferment or not, it came out to be about the same. So that didn't add much information, but two of the other subset analyses give some hints. So in this one from Dr. Rini as the main author here, we see that there's this 16 gene recurrence score and they didn't have that many patients on it, but you can see that at least in the placebo group, it really matters what your score is. On the other hand, in the treatment group, the lines are closer together. So we already know that the treatment group had a better progression-free survival, but also that the lines get closer together. So at least for the worst group, which would be the red line on the left panel, it probably makes a bigger difference. So the people in the worst group, it looks like it makes a bigger difference that they should really be on something besides observation. Now this is a secondary analysis on a fraction of the patients, but that's at least a hint on that. And then similarly, looking at the markers in the tumor, we already knew that PDL1 seems to be a marker for patients with a higher progression rate. And looking at this here, we can see one line standing out, which is the placebo patients that had PDL1 on their tumor, the blue line on the right graph there. So that's a hint maybe to help us out on adjuvant patient selection. There's three large, very large, very slow adjuvant studies accruing now. Check again, this won't be in 2019. This will be in the 2023-24. We'll make it a readout whether starting those immune therapies very early helps. I have a trial here, and this is just for general interest on how we had set up that trial there. It's finished accrual, and we wanted to get at least 45% major response rate. We've got a lock on 60%, so it does look again that putting those two types of immune therapies together seems to be better than one. Now, with a single-arm trial, we don't want to really make any comparison statements, and we know that picking the patients carefully is probably the best way to get a good response. Here's some art from my trip to Moldova. Clinicaltrials.gov. Clinicaltrials.gov. I guess at least one person in the room thinks it's hard to use. I use it all the time, but I think we'll work with KCA, maybe get some tutorials on that. It's true. I can't know all the trials there are. If you look on this here, it says there are 284,824 research studies in 204 countries. So, yeah, you'd have a pretty psychotic doctor who had a really working knowledge of this, but you can use it to look up some things. Here's one. We could look up. This is a CBA-39 calytheris product, the Glutaminase inhibitor. We had a good presentation on that, and a couple trials combined with that are open. The first two are open. I think the third one is just a planned trial there. Apexinostat. That's an HDAC inhibitor. HDAC inhibitors, probably 20 HDAC trials have been coming on in oncology. A couple have approvals and hematologic malignancies, but they're still waiting to hit the big time for solid tumors. So, this is a combination. Everybody gets Pizopinib. It's a phase three trial, but they either get Pizopinib and nothing, or they get Pizopinib with the new drug added on. So, that is a registrational trial, and it should be a couple years till it grew. The exciting thing is, it's an HDAC inhibitor, which has nothing to do with all the other things we were talking about. So, kind of a new angle on this. Here's another HDAC inhibitor called Intinostat. You might remember Intinostat is a partner drug with IL-2. This was a single-arm trial, which did relatively well. And Intinostat only blocks HDAC-1. Coordination with radiation therapy and other destruction, destroying stuff. That really gets the attention of the immune system. It changes a lot of things in the tumor and in the immune response. And there's about eight different trials in kidney cancer, probably another 20 in other diagnoses as well. So, I think those will mature. We'll get some more standardized protocols for that. Some of the thinking is that getting to a higher dose with a lower number of fractions may be something that really makes the immune system sit up and get stimulated. But those are details that we need to work out. The idea of using combinations with the PD-1 drug and something else, so at least a two-part immune therapy, that's going to be something we see a lot of, not-clear cell type cancers. I hate to always give the not-clear cell type cancers kind of a quick wrap-up, but at least for the first time in many years have several trials are directed at CMET. And these are going to be slow trials to come around, but we may actually get some targeted drugs which really focus on that. So, what's the target a year for 2013? Do we do a defect that's already on there, but I think it'll pop down. There it is. So, I think IL-2 receptor, it's on every lymphocyte in your body. He's got IL-2 receptor. We've got the PD, we're kind of running strong in the age of the PD-1 type trial. And I think that IL-2 receptor, we've been using it as a single agent. We used it in TIL therapy and CAR-T therapy. And I think that we're going to see it have a resurgent, not just as a single agent IL-2, but IL-2 receptor is a partner for these other immune therapies as the immune, the immune era kind of overtakes everything. So, anyway, thanks very much and thanks for the Kidney Cancer Association for organizing this. I want to encourage all of you in your own health but also to the extent you can. You can advocate and work with the association. It's here for you and you can be here for it. And I think Gene's going to give us a couple of genes outside. Good. Thanks to Gene Bureau for organizing and Gretchen will give us some closing remarks. Thanks. Thank you.