 Good afternoon everyone. It's a pleasure to be here. Thank you so much for having all of us. Okay, so my talk is entitled what are the best agents for second line and beyond in the treatment of metastatic clear cell renal cell carcinoma. It's a mouthful. It's going to pay you back right off of Dr. Harrison's talk. So Dr. Harrison did a beautiful job of covering what we use front line. I'll go through all the other agents that are approved in kidney cancer and sort of how we think about them and stratify them in terms of what to do next. Sorry I just forwarded a bunch of slides. These are my disclosures. So you guys have heard a lot of this background already but as you know there are several different subtypes in kidney cancer. The most common of course is clear cell kidney cancer which makes up 75 to almost 80% of what we see. So most of these drugs are very well studied in clear cell disease and so that is the date I'll be presenting today. And we've talked at length about the associated BHL mutation in clear cell kidney cancers. And again there's two distinct patterns here. There's the familial genetic BHL syndrome versus the sporadic BHL mutation that occurs in the majority of clear cell kidney cancer. So what does the BHL mutation do? It basically causes a state where that tumor cell does not have enough oxygenation. It's hypoxic. So there's a lot of different up-regulation of factors that try and grow blood vessels to that area so as to provide more oxygen and nutrients. And so this VEG F pathway becomes a very logical target for our cancer agents. You heard from Dr. Harrison and some of the other speakers today about our different strategies for risk stratifying patients. As you heard there's the Memorial Sloan Kettering score and the IMDC score. And these have become increasingly relevant because a lot of our recent approvals in kidney cancer have been based on that patient's risk criteria. And so this takes into account laboratory factors like anemia. It takes into account somebody's sort of performance status which is basically their strength and function on a day-to-day basis. It takes into account sort of the timing of their diagnosis to the point at which they're metastatic. So this is the Memorial Sloan Kettering score. The IMDC score has a lot of similar criteria with some differences in the labs that we monitor. And that helps us to sort of get in our minds a sense of the biology of a patient's tumor. So is this somebody who we think will behave more indolently with sort of a slower tumor? Or is this somebody who we are worried is sort of quote-unquote on fire where things are moving quickly and we need to kind of get to action very quickly? So as Dr. Wood mentioned we didn't have much before 2006. And gratefully we have a lot of options now. But putting it all together is something that is still very much a work in progress and sometimes the more we know the more we don't know about sort of what comes next. And so Dr. Harrison just covered the data kind of on the bottom right here. So the CaboSan data and the Checkmate 214 data brought CaboZantinib and NevoIPI into the frontline setting very recently. I've just highlighted a couple things to put on your radar. There were two very recent studies that just resulted out that are combinations of immunotherapy and TKI. And so these have not been approved at this time, but approvals may be forthcoming. So just to keep in your radar it has a Lizumab and Bevacizumab as a combination of immunotherapy and TKI as is a Velumab and XCITNib. So a little bit more on the general categories. Of course the VEGF RTKI act on the VEGF pathway. There are seven approved agents in this category and I'll go into each of these. Pizopinib or Votrient, Sininib or Sutent, CaboZantinib or Comedix, Seraphinib, Bevacizumab or Avastin, Lenvatinib or Lenvima, XCITNib or Enlida. In terms of immune checkpoint inhibitors we have Nevolumab or Obdivo and Ipilimumab or Urvoi. And remember Dr. Harrison's analogy these immune checkpoint inhibitors essentially ramp up your own immune system to better recognize those tumor cells as being foreign and something that needs to be cleared from the body as something that's not self tumor or protein. I'm sorry not tumor protein. M2 inhibitors are a targeted therapy. They work on a different pathway than VEGFR. There are two approved agents Avrolimus and Temsurolimus. Avrolimus is approved single agent by itself or in combination with Lenvatinib. And then as I just alluded to there are a lot of combination immunotherapy, TKI, sort of novel treatments that are coming down the pike. And so I actually have a slide later with all six different combinations but that's going to be I think increasingly important moving forward potentially. And then of course you guys have heard about clinical trials. There's all kinds of different novel agents coming along as well. And so probably in a year from now this slide will be incredibly hopefully out of date. Things have changed so much in the last year even so recapping sort of in 2017 in the good and intermediate risk patients we use SNETNib or Pizopinib primarily. And in poor risk patients there was data for Temsurolimus. After that front line we sort of had this basket of other TKI's mTOR inhibitors and immunotherapy to turn to. In 2018 things really shifted with the advent of the data from Checkmate 214. With the data from Checkmate 214 nivolumab and ipolumumab is being very commonly used in the front line setting now. And so how does that change what we do in the subsequent line? That's a new area of interest. CaboSun has meant that more patients are being potentially started on Cabo's antenna up front and then these combo studies as they come out people may get treated with a combination of TKI and IO in the front line. So in the second line here are sort of our major options. And I'm going to go through each of these but SNETNib, Bavisizumab, Pizopinib, ExetNib, Avrolumus, Temsurolimus, CaboSunNib, Nivoipi. So how do we think about these? So Dr. Harrison covered is there a best front line treatment? It depends. Is there an ideal sequence after front line treatment failure? And as IO treatments are incorporated earlier what does this mean going forward? We used to think of kidney cancer in a very linear fashion. If one thing doesn't work we go to the next. If that doesn't work or works for some time and stops working we go to the next. And now with these immunotherapies the question is do we keep this pressure ongoing? If it stops working do we try different combinations still incorporating that or do we not do it anymore? So how do we overcome resistance? These are all things that are trying to be answered at the moment with different trials. So going through the agents. SunetNib is an oral small molecule inhibitor of VEGFR. It also hits other receptors such as PDGFR. Most commonly it's administered as a pill that you take once a day, 50 milligrams. Typically people take it for four weeks at a time and then a two week break. In practical data sometimes there's modified regimens where people may take it for two weeks and be off for a week depending on on their side effects and tolerance of the therapy. And this was approved in 2006. It was approved on the basis of this particular trial where SunetNib was compared to interferon which was one of the early immunotherapies that we used in kidney cancer. You guys have seen a lot of these Kaplan-Meyer curves today. So I won't go into too much detail about it but the way we think about these curves is basically we're comparing two different therapies to each other. So the orange line here was SunetNib. The green line here is interferon. And what we're looking for with these Kaplan-Meyer curves is we're looking for separation of the curves that indicates that one is better than the other. If they're crossing it really tells us, hey, you know, was something really superior here. And then we're also looking for the tail of the curve. Are we extending people's survival for X amount of time because when we see that tail of the curve that means people are living longer. Pizzopinib or Votran is also in a Vajavar inhibitor. Also hits other receptors. And Pizzopinib, unlike SunetNib, is dose continuously typically. So people take, comes in 200 milligram tabs. People take four tablets a day and they take it every day. This was approved in 2009. And again, in the original data, you can see Pizzopinib was superior to its comparators in our traditional Kaplan-Meyer curves. ExitNib hits Vajavar C-kit and PDGFR. It started at five milligrams twice a day. ExitNib has a shorter half-life than most of these other agents, which is why it's twice a day. And most of the other TKIs are once a day. And there's data in ExitNib for dose adjustment up, which is unusual for the TKI. So you may notice your oncologist may mention, hey, we need to go up on this dose or down on this dose. That's frequently done with ExitNib. There's improved progression-free survival with ExitNib when it was compared to Seraphinib in the second line and beyond setting. Nevolumab is a PD1 checkpoint antibody. As Dr. Haas mentioned this morning, originally it was approved for every two-week dosing. However, recently we do have this approval for administering double the dose every four weeks, which is kind of nice in terms of convenience for our patients. It's less trips to the doctor to get the infusion since it is an IV medication. And originally it was approved actually in the second line setting as a single agent. So you heard a lot about the combination of Nevo and Epi in the front line, but originally this was actually used single agent in later lines of therapy. And that was on the basis of this trial, which compared Nevolumab and Avrilimus, which is one of the mTOR inhibitors. And Nevolumab had a clear overall survival advantage over Avrilimus. Now one thing that was really unique about this trial is this quality of life data that they collected. And this is something that is much more frequently being done in kidney cancer trials now, which is really great because we're paying attention to the symptoms and day-to-day effects of these therapies on our patients' lives. So not only did Nevolumab have an improved survival, but patients felt a lot better on Nevolumab compared to Avrilimus as well. It had less side effects. Capposantinib is an inhibitor of Vegefar, and it hits some additional targets called Axel and Met. It comes in 20, 40, and 60 milligram tablets. Typical starting dose is 60 milligrams a day. And it was approved initially also in the second and subsequent line setting after previous TKI therapy. But with the Capposan data earlier this year, Capposantinib became approved in the front line setting as well. So the original data for sort of subsequent line setting for Capposantinib was with the Meteor trial. It compared Capposantinib to Avrilimus in patients that had previously gotten a TKI. Usually it was Pizopinib or Sunintinib. And Capposantinib had a superior overall survival compared to Avrilimus. And then I wanted to introduce you in the Capposan data that Dr. Harrison just presented to you guys. Not only did it show improved progression for survival, but you can look at the waterfall plots, which the idea behind waterfall plots is they actually show you the change in tumor burden. So at the, you know, at zero is sort of where the patient's tumor burden is at baseline. And then on Capposantinib or on whatever treatment when you see bars that go up, that means the tumor grew. When you see bars that go down, that means the tumor shrank. And you can see that a lot of patients really got change in sort of reduction of their tumor on Capposantinib. You see that definitely with Su-102, but sort of favored Capposantinib. Linvatnib targets VGFR, FGFR, PDGFR retin kit. It is approved in conjunction with Avrilimus. When you, they actually did a three-armed study for this agent. So Linvatnib alone was compared to Avrilimus alone, was compared to the combination of both of them. And the combination of the two led to both improved progression for survival, overall survival and response rate. And so this is another therapy that we frequently utilize. So putting this all together, what do we choose? I just named seven different or 10 different agents for you guys. How do we, how do we figure out what to do? In reality, there's not a lot of head-to-head comparisons. And with the rate that our approvals are coming out, there will likely never be a trial that compares everything head-to-head-to-head where we can say XYZ is the absolute best. But in reality, maybe that's not even a good question to ask because patients really end up getting multiple of these. As I mentioned, each of these hit different receptors. So maybe if tumors are resistant to one, the fact that you're hitting other receptors means that you bypass that resistance with one of the other agents. And so really most people have at least several of these agents. We also take into account a lot of patient-specific nuances. And so particularly, for example, with lab functions. In a patient who has liver function issues, we might not want to choose something like Pizzopinib, which can cause a higher issue of liver dysfunction. With sites or volume of disease, sometimes, for example, if somebody's got a lot of bony disease, we have data that Cabo-Zantinib works a little bit better in bony, predominant disease. And so we might favor that. The side effect profile we take into account quite often. So while these are sort of similar class, a couple of agents will have more diarrhea. Some will have more issues with rash on the hands or feet. Some will have more issues with blood pressure. And depending on a specific patient's individual medical comorbidities, we may want to avoid some of those. And so we might choose something different. I'm going to go into a little bit of sort of the side effects of all of these agents. In reality, with kidney cancer, because we have so many options, we think of it as a little bit of a marathon. And so part of our job, and I think a really important part of our job, is to help keep you feeling well as you're going through therapy. We can't afford to let our patients get beat up on these agents because we have second and third and fourth line things we can try. So we have to keep you feeling well on these. So what I tell my patients is that with TKIs, side effects are easy on, easy off. In that you're very likely to have side effects. There's a very predictable pattern of side effects that occur. But we also have pretty easy ways of troubleshooting them or helping you feel better on them. So what do we watch for? We watch for blood pressure. Most patients on TKIs are going to have an elevation in their blood pressure. When we see it happening, we take it as a good sign. The drug is doing what it's supposed to be doing. But of course we want to protect your heart, make sure your other medical issues don't become exacerbated by this. And so we do need to control it and change up your blood pressure regimen potentially. Diarrhea is another common one. I have a whole slide dedicated to diarrhea in just a minute. Fatigue, taste bud and appetite changes, mouth sores and then thyroid issues are really common on all of these agents. And so your oncologist is likely checking your thyroid function intermittently with labs to make sure you don't need an adjustment of centroid or something like that. So diarrhea. I find that imodium is grossly underutilized by most of my patients. We tell people it's okay to take up to 16 tablets a day. But if you're anywhere close to that, we need to be hearing about it way before that is what I tell them. And so if you know for sure you take your TKI and 30 minutes later you're running to the bathroom, I tell my patients wake up, take to imodium before you even start eating for the day. If you're not in that boat of it's sort of more intermittent, you can certainly use it as needed. But don't be shy on the imodium because when you have severe diarrhea that's not controlled, you're at risk of dehydration, you're not absorbing things well, you're going to be fatigued. And so, you know, prevention is really helpful there. Probiotics can help. I will say we, there's recent data saying probiotics are not good to be on with immunotherapy. And so I do recommend them on TKI, but maybe if you're on immunotherapy, maybe don't be on probiotics. Metamucil is actually a really good trick. And so it's funny because we think of metamucil for constipation. But if you take a scoop of metamucil and stir it into something thick like applesauce or oatmeal, it can really help bind up the bowels. So that can be a really helpful trick. And then sometimes we do have to adjust the dose. That is not uncommon. You don't have to feel bad if your oncologist says, hey, we need to go down, buy a little bit on your dose or we need to think about an alternate dosing schedule like take your meds Monday to Friday and give yourself a weekend break. Part of these strategies are to help keep you feeling well. And so oftentimes we do need to rely on dose adjustments to make sure we're keeping your functional status up to par. Hand foot syndrome is also quite common with these. Basically a blistering type rash on the hands or feet. It's particularly common in the feet because it's a weight bearing area. And really here moisturization is the key. You want to buy a nice thick lotion, really, you know, kind of greasy and moisturize the hands and feet twice a day at least. If it's really severe, again, we think about doing, you know, dose changes or breaks. And then we also have prescription strength things that sort of help numb that up to make it more comfortable. Mouth sores and taste bud changes are another one that we see often. A simple home remedy of what I call salt and soda, which is a glass of warm water, teaspoon of salt, teaspoon of baking soda, and just gargling with that multiple times a day really helps to prevent that. And then, again, there are prescription strength things to sort of coat the mouth. The taste bud changes are a lot harder. And I'm sure many of you have experienced appetite changes where nothing tastes quite right. There is a couple things you can do. There's zinc supplements you can take. And then there's something called mberry, which you can order on Amazon. But it makes everything taste sweeter. 50-50 on this. Some of my patients love it. Some hate it. But if you really are in the boat, where things taste terrible, you can try that. Immunotherapy side effects are a whole different ball game. We call them the itises. Itis means inflammation. And so what's this concept in immunotherapy? We're allowing the immune system to ramp up. And if the immune system gets overactive, it can cause damage to normal self-tissue or inflammation in some other part of the body. So immunotherapy, severe side effects are relatively rare. Most of our patients feel really well on immunotherapy. But when they're developing side effects, they're often more subtle. It's not like the TKI's where I said they're easy on easy off. These are much less likely to happen. But when they happen, they can be more nuanced and subtle and sometimes difficult to pick up upon. However, they can be quite serious if we don't catch them. And so you'll notice your oncologists always have their radars up. When you're on immunotherapy, in particularly combination immunotherapy, like the Ipilimumab and Nivolumab, we ask a litany of questions, just making sure everything's okay. Are you having diarrhea? Are you having a rash? Are you having a cough? Are you having change in your energy level? Looking for signs and symptoms of whether that immune system is getting overactive. The truth is it can happen in any part of the body, which is why sometimes it's nuanced, is that it's hard to pick up on. But I'm going to go through some of the more common ones that we watch for in just a second here. So endocrinopathies are basically a change in hormone levels of some kind. So thyroid is a common one. But on Nivolumab and Ipilimumab, one of the things we watch for is actually dysfunction of your pituitary gland where your adrenal function can be affected. And so people feel very, very fatigued. They can have issues with sort of their blood pressure. And so that's a big one we watch for. It's not common at all. But one of those things we don't want to miss. Colitis or inflammation in the colon, causing severe diarrhea, is another one. If it's relatively mild, you know, sometimes it can be sort of managed with sort of supportive interventions. But if people are having more than seven bowel moments a day, that suggests the colon release is very inflamed. And then typically we need to get involved with systemic ways of calming down that immune system. Anytime these immune mediated adverse events happen, we're looking at something like steroids to calm the immune system down. Steroids are a first pass. Sometimes it works. But with these immune related events, sometimes as we taper down steroids, those symptoms can rebound. And when that happens, we sometimes need to reach for other rheumatologic type agents to keep that immune system under check. So don't be shocked if your oncologist mentions other agents that typically you think of for autoimmune diseases. We often use those in these subtypes of immune mediated adverse events. Pneumonitis or inflammation in the lungs, it's exceedingly rare. However, if somebody develops cough or issues with oxidation or getting winded when they exert themselves, it's something, again, we don't want to miss because it can get very severe. Hepatitis refers to basically inflammation in the liver. So every time you go in for your immunotherapy, your oncologist is probably checking your labs. And part of that panel we check is going to look at liver function tests to make sure there's nothing like that going on. The three in red at the bottom are the ones that I hear most often on a day-to-day basis. So I kind of mentioned some of the more rare stuff, but the day-to-day stuff we hear a lot about are sort of joint aches and pains. So people often say, hey, you know, I've always had arthritis, but all of a sudden I feel way more creaky. It's a lot worse. Those are typically managed with lower doses of steroids or other rheumatologic agents, but again a quality of life issue thyroid I've mentioned and then skin rash which can typically be managed with topical steroids. I want to take just a moment to touch on some interesting upcoming data. You have a whole lecture dedicated to novel treatments coming up, but just some of the data that's just coming down the pike. So combo IOTKI treatment, and then as we use more of these immunotherapies in the front line, what happens to the response to these TKI's in the second line and beyond? And so there are currently six, actually probably even more now, trials ongoing combining different IOs and TKI's. And what this chart is showing is this is these gray bars are showing the disease control rate. That refers to the tumor is either stable or shrinking. And you can see in all of these combos that we're hitting somewhere between 80 and 100 percent. So almost all these patients are deriving benefit from these combinations in terms of it being stable or shrinking, which these are pretty unprecedented numbers in single agent TKI's or single agent immunotherapies. So the combo does seem to be effective. These trials, of course, I mentioned these front to the bevacizumabitazolizumab and exit nimbavillumab just resulted out. And so we do have data to support them. But one of the big questions going forward is what's this going to do for an overall survival trend in the coming five and ten years? And it's just too early to know that still, but a very promising sort of area that we're all excited to see what happens. As immunotherapy is used more in the front line, we were all kind of wondering, does this mean TKI's are going to be just as effective in the second line? This is unpublished data, but we just took a quick look at our cohort of patients at MD Anderson. So we had way more than this, but we had 42 patients who were treated with upfront IO in the context of a clinical trial before it was approved. When all the immunotherapies in the front line were in clinical trials, there were 42 patients we collected that had either stopped deriving benefit or had progressed or had adverse events and then went on to receive a TKI. So that exact scenario of front line immunotherapy, second line TKI. And really our patients did really well on it. They had minimal issues with adverse events and when you look at the water flow pot, every single one of the patients had reduction or stability in their tumor burden in the second line TKI. So you know it's early days in this setting, but it does suggest that the TKIs have not lost efficacy by not being used front line, that they're still a valid very good option in second line and beyond. So looking ahead, thankfully we have a lot more options than we used to. Combination options are exciting, but we also have a lot to learn about when someone becomes resistant. How do we sequence these things? What's the optimal sequence? How do we better select who's going to respond to TKI? Who's going to respond to IO? Who's not going to respond? And sort of tailor individual therapy. The standard of care will continue to evolve, which is a good thing, but it also means that each time that changes, it affects what we do down the line. I think, personally, tell everybody in quality of life our huge here, and that's a big part of what I deal with on a daily basis with my patients in clinic is we have to keep you feeling well to keep getting to the next best treatment. And predictive biomarkers, as I mentioned, are going to be key in terms of right patient, right treatment. There's so much work being done on it, it's a huge area of controversy and interest, and so hopefully in the coming years we'll be a lot smarter about what we're choosing. I really want to take a moment to thank our patients and their families. You know, you guys show a tremendous amount of grace and courage and hope on a daily basis, and that's pretty amazing in the difficult situation. And so you guys are a true inspiration to us, to keep working and trying to improve things. Families as well, caregivers being absolutely a vital part to keeping our patients happy and healthy. Thank you to the KCA and also to my mentors and friends at MD Anderson. I wanted to highlight a couple of my, I have their permission to show their pictures and everything. This is Bruce, who we were not sure we'd be able to get him to surgery. Here he is after a very successful surgery. He's recovered and eating a Texas-shaped pancake. This is Mike, and he, six years ago, was diagnosed with advanced disease and is doing amazing on his current therapy. His scans show no sign of cancer. He's a professional race car driver and has won six or seven major series. He's also in the World Poker Tournament in Las Vegas every year, and so he's really enjoying every moment to the fullest. This is Maria, who right around the time of diagnosis of advanced disease with a very rare tumor type, not clear cell, but was found to be pregnant. She is doing okay, but her baby is now nine months old. Happy, healthy, cutest baby you've ever seen. And then a very, very special shout out to Nick Harmon, who's here today, with his wife, Kim. Nick joined the Texas Game Wardens in 1985. He retired just earlier this year after 33 years of service. I wish I actually showed you guys more pictures, but he was out on the Bay rescuing sea turtles while on active, you know, treatment for kidney cancer. And when Nick got diagnosed, one of his buddies told him, well, you just need to get bit by a radioactive spider like Spiderman, and you'll be, you know, fine. So Nick really took that to heart. Every single, he's going to hate me for sharing this, but every single clinic visit, he comes with Spiderman boxers or Spiderman t-shirts. And so, you know, we're going to keep working to find that magic spider bite. So thank you guys all very much.