 Thank you, Kim, and thank you all for coming out this morning. I really appreciate the chance to talk. And I've got 20 minutes to talk, and then we're going to do a panel for questions. So if you can, write down your thoughts, and we'll cover them in the panel in a little bit. But I'm going to do something that I like to do, that we never get a chance to do enough of. And that's sort of give you my thoughts on kidney cancer. And this question that Dr. Rathmell has posed for us, how do we decide when we're going to start treatment in patients with kidney cancer? What treatment are we going to choose first? So what I thought I'd do is rather than show you a bunch of slides and data, is to talk with you a little bit about how I view patients with kidney cancer, how you all, if you come into clinic, how the physicians are seeing you, and then what we're thinking in terms of what are the distinguishing features of your cancer, of you as a patient, and then how do we think about the therapies in that context? Because the data is fantastic, and it's really a huge guide for us in terms of understanding which drugs work. But it's population data. You all are individuals. Every single patient, to me, is different. And it's important for people to realize how they're different. When they look at that data, or you go online, and you read something about kidney cancer and the survival of kidney cancer, patients get, I think, rightfully nervous. This is a scary disease. This is a lethal disease, especially when it's metastasized. But it's not the same disease in everybody. And it's really important, particularly for people who are just diagnosed with what we call metastatic disease, or disease that's spread. It's no longer in the kidney. It's out of the kidney. It may be in a lymph node. It may be in the lung. It may have spread to bones, or liver, or even the brain. It may have spread to all kinds of places. And those are one of the important factors that I look at. When I see a patient, even before I see the patient, even before we meet, we get the records on you. And we are looking. And the things I'm looking at in your records are, number one, what's the diagnosis of kidney cancer? Is it based just on the scan? Someone has scan. There's a big tumor in their kidney. It's pretty diagnostic. But it doesn't tell us the type of kidney cancer. Did they have a biopsy? Has the kidney been taken out? If the kidney's been taken out, the pathology, what does it show? Is it this clear cell cancer, the most common type, but not the exclusive type? Is it you have some papillary features or some sarcomatoid features? Is it one of the more rare forms of kidney cancer, like chromophobe or even oncocytoma? These are technically kidney tumors, but they have a very different biology than the clear cell cancer, or even the papillary cancer. So these are all factors that I look at even before I see you in clinic. The next thing I look at is, what's the extent of disease? Is it confined to the kidney? Is it something that we think we can take out? Is it something that's spread out of the kidney? Is it spread to lymph nodes? Is it spread to the lungs or other sites? How many areas? And to me, are there any sites of disease that I'm worried about a complication? I think so often people think, well, it's just stage one, two, three, or four, but there's a big difference in stage four cancer between patients who have, say, just some tiny areas that are asymptomatic and not bothering them to parts of the body where it's really symptomatic, particularly things like bone and vertebral body metastasis along the spine or into the brain, or pressing on a vital organ, pressing on a bronchus in the lung, or pressing on a major blood vessel, or doing some other major complicating feature to it. Those are situations where, again, we're gonna individualize care because the care is gonna be focused primarily on that site of management first. It's not to say that we're not gonna use drugs and other therapies, we absolutely are, but the first thing we're gonna focus on in a patient like that is how to manage that site of disease. So that's the second thing I look at when I'm, before I go in the room to see you, is I'm looking at the extent of disease. And if I can, we always request, it's a little bit of pain, the CDs with your images because the reports don't tell the story. I know you all read the reports, but I'm always surprised how many patients I go in the room and I pull it in the CD and I say, have you seen your images? And they say, no, I haven't seen them. It's really, really important to me that you know where your tumors are and just what they're doing. One, it gives you some peace of mind one way or the other of what's happening in your body. And two, it gives you an idea of what you might wanna expect in the future for a symptom and what to look for. So you know, reading the reports, they're not written in layman's terms. They're frequently not descriptive enough. Nobody can write in words what a picture can show you. And so it's so important to me that we go over that. So that's one of the things, and I look at that before I go in the room ahead of time, so I kinda know what we're dealing with. Another thing we look out of the labs, the labs are really important. They're important because they give us some prognosis, some indication of where you are in the spectrum of things. If people have really low hemoglobins, blood counts for their red blood cells, that's a very important prognostic factor. If they've got an elevated calcium level, that's something that sometimes gets missed. It's sort of slightly elevated. It's not something that people associate a lot of symptoms with, but it can be symptomatic, and it's very prognostic. So I look at labs like that. I look at kidney function. Kidney function's really critical for the tolerance of drugs, for just the well-being of the patient. Kidney function's really important. I look at a protein called albumin. It's not necessarily one that shows up a lot, but it tells us, I mean a lot in our prognosis, but it tells us a lot about the health of the patient, your nutritional status, and to some extent, what the cancer's doing is the cancer catabolic tumor. What I mean by that, it's a medical term, but it means the cancer's breaking down your body, that you're losing weight, right? And that's one of the symptoms we can see with patients, but the reason they lose weight is because you lose appetite, you're not eating enough, but you're also hyper metabolizing. The tumor's metabolizing away a lot of nutrients, and it's starting to break down your body's nutrients. And unfortunately, they don't start with the fat. They start breaking down the muscle, and that's the most important part of your body. So to me, I mean, it's a really critical piece here, is really understanding that aspect and if that's happening. And then I look at the doctor's notes. I look at what people have read and said about the patient, what's been going on, what's been reported so far for symptoms. We have patients fill out a little symptom score thing, a little patient reported symptom profile of what we call a review of systems of just what they might be having. And I look at that as well. So that gives me kind of a picture before I even go in the room of what's going on with patients. And then when I'm in the room, the first thing I do is size up, how functional is this patient? Are they in a wheelchair right off the start? Or are they sitting in a chair? Do they stand up when I come in the room? Are they, is it hard to get up? Those kinds of things, sometimes I'm not even necessarily conscious of it, but that's what I'm thinking when I go in a room and I see a patient is how functional. I ask questions about what do you do in your daily routine? Are you, what's your job if you're working? If you're not working, what's your daily lifestyle? Do you walk every day? How far do you walk? What kind of pace do you keep? And things like that. Do you do a lot of activities around the house or you mostly sedentary and things like that? Although that doesn't necessarily show up as a score or a number, it's a really important characteristic for us in understanding how the patient is functioning. And to me, it's probably one of my best indicators, much more so than age or gender or size or anything else, of how you're gonna tolerate a medication is just, you know, if you're somebody that is, you know, just active. Just I like to use the term vertical because my old Hopkins hematologist, William Bell, used to always tell us, are you vertical? You know, that was his term. He's a little bit crass, but at the end of the day it's really true. The patients that are sitting or lying a lot don't do as well as the patients that are up. And now we have, now it's the new thing to have vertical workstations. I'm at a vertical workstation. You know, this is an important part. I think we're starting to realize in our everyday lifestyle, but it's been a really simple concept for a long time. So those are some of the things that I look at when I see a patient. And then the question comes down to, you know, to prognosis, how do we determine that? The other thing, and I forgot to mention, the other thing I look at before I go in the room is the timing of this story. What I mean by that is, is this a sudden story? You know, this patient, you know, a month ago was fine, started coughing, got a scan, and now they've got metastatic kidney cancer. And it's in multiple places. Or is this a story of somebody who had a tumor removed four years ago? And then, you know, on an incidental exam was found to have a nodule somewhere. Those are very, very different scenarios. In one scenario, this patient is already symptomatic, is already spread. The disease almost, you know, from the get-go has, you know, gotten out of the kidney. And that patient has a likely course that's gonna also continue rapidly so that we will likely be thinking of one therapy onto another pretty quickly. The other case is, frankly, someone I'm probably not even gonna treat right away. Now that may come as a surprise to you, but I'll tell you that at Duke, we just did a retrospective analysis, just got that accepted for publication, a recent paper on our retrospective analysis of over 200 kidney cancer patients managed from 2006 to 2008. In a quarter of those patients, we deferred therapy on their first visit. We did not, and what I mean by that is not like it started the next week. I mean, we decided not to start a systemic therapy. Now, we may have done a local surgery, we may have done some other kind of palliative maneuver, but it's a chunk of those patients, and some of them may be gone right to hospice, but most of those patients that were in that group, we decided their disease wasn't aggressive enough that we had to start therapy right away. Now, that may seem a little bit defeatist, but the rationale behind that is that there is a significant percentage of patients with kidney cancer that is like that second case that I described to you, that is slow-moving, is limited metastatic disease. And what we call sometimes oligo-metastatic disease only has a couple of spots, may only be in one organ, and just one, two, or three spots, or really, really small spots, less than a centimeter. And we feel that that disease is not going to change very quickly in the short term, so we'll follow it. And the reason not to start therapy right away is because we believe the therapies will decondition the patient. And again, getting back to what's the most important factor for these patients that is under their control, to some extent, is how vertical they are, how functional they are. And if I'm gonna hurt that functional status, but I'm not really gonna make an impact on the disease because it's not really moving or growing that quickly, then I may be doing that patient a disservice by starting therapy ahead of time. And it's a concept that's not very prevalent out there. It's not in our guidelines. You don't see in our guidelines a recommendation for that. But we all practice it. We all recognize this. Those of us that see a lot of kidney cancer patients recognize that this is not necessarily a scenario where everybody has to start on a drug right away. It's hard if you only treat three or four kidney cancer patients a year to feel comfortable with that, to know that. Again, the guidelines don't really support it, but we recognize that that's an okay practice. And when we looked back at our practice of these patients, they had phenomenal outcomes. They had average survivals of five years or more. And they did get therapy, the ones that progressed. But some of them still, a few of them, still didn't get therapy for several years. Now there've been a couple of prospective studies going on and some of our colleagues at other centers are looking at actually randomizing patients, to starting them right away or watching them who meet this kind of criteria. I call them the very good risk patients. But I think it's an important concept that again doesn't get enough recognition, something that we're comfortable in academic centers where we see a lot of these patients, but in a lot of other places we're not. So that's one end of the spectrum. What's interesting is that's also the patient population who I will talk to about Hytocentralucin-2. Now you may say, wait a minute, you just told me you're comfortable doing nothing for that patient or giving him an incredibly toxic inpatient therapy. And it does seem kinda incongruous that you're gonna say, you can do this, we're gonna defer therapy, or we can do this really intensive therapy. The reason for that is because the reason, the goal of the really intensive therapy is not to slowly control the cancer, it's to try to cure you. Our goal of that is nothing short of trying to get you to a complete remission, no evidence of cancer, and hopefully the cancer doesn't come back. And we've got some cases of that. I don't know if anybody's in the audience that has done that, but we do it still because we do have some cases like that, but it's not that common. But that's the population where we can afford to try that, even if it only has a 5% chance of working because if it doesn't work out, yeah we've taken on some side effects and things that are reversible, will require work to get yourself back into shape and everything, but it's reversible. But importantly, that's a population of patients that we haven't lost ground, if three months later we didn't cure them, the cancer didn't go away, but at least we didn't lose ground in that patient. So to me that's a really important setting where we can consider that still. But this is what we call the good or the very good risk patient. Where most of our patients fall is in this intermediate or higher risk population. Patients that are like the first case I presented, presenting with some symptoms with disease that's already spread and we've got some really important decisions to make and you may have already heard about debulking nephrectomy, we can talk about that. So one of the decisions is, do we take out the kidney in that patient? And we do a multidisciplinary clinic just like at UNC, we talk with our surgeons, we review the case together. And a lot of the factors that I've mentioned to you, how functional the patient is, what symptoms they have, their laboratory values and the sites of metastasis and how big, how extensive is that spread of disease, all factor into that decision. So we use those decisions to decide, can we afford to put this patient through surgery? Is it a big open surgery or is it a laparoscopic surgery? That's a factor too. So all those things kind of factor into whether or not we take out that primary tumor. But we still do a lot of that. And we do it for a couple of reasons. We do it when that's the bulk of the disease and we can debulk most of this cancer. We still believe that's a benefit to this population of patients. And it's been shown in the past, not as much with the newer therapies that are available, but we still believe that could be beneficial. We think that could be beneficial for future immunotherapies as well to have that primary tumor debulked. So with the new evolving therapies, we think that's gonna be important as well. And I think the last thing is that, this local disease, when it's really bulky like that, eventually can cause a lot of problems locally for the patient. And it's harder to do that surgery later on in their course. So if we have a window to do that upfront, to debulk it, to get a better idea of the pathology that we're dealing with, to have a lower tumor burden for future therapies and to avoid future complications, we like to do it. But it comes at a risk and a cost and delay and a deferment of our other therapies. So it's a balanced thing. A second question then for that patient population, what's gonna be their systemic therapy? And I'm gonna tell you something right now that I think is really important to recognize, is that we have some really good systemic therapies for patients that have intermediate or higher risk, more aggressive kidney cancer. But I believe that the way we treat kidney cancer today with a single drug at a time is not the best for everybody. And I believe in the future, we're gonna have to figure out who are the patients that really benefit from one targeted therapy. Typically, these drugs that block the blood supply, that block this protein, VEGF, or VEGF, this protein that helps grow blood vessels for the tumor. And drugs that target that, like Sinitinib or Pozopinib, these are really effective therapies for a big percentage of patients. And we've done some biomarker work. We think there's at least a third of this population up front that really benefit and that's all they need is that therapy. But we think there's also sizable chunk of patients that may get some benefit, but not enough. They still have some poor risk features and we need combination strategies. And I think right now there's a lot of clinical trials going on looking at combination strategies and we think that that's gonna be a future as well. And one of the most important questions in kidney cancer today is how can we do even better in treating these frontline patients? But for the patients that we're not gonna put on a clinical trial or we don't think are that high a risk and we think that could really benefit, we start, but have some of these features, these more intermediate risk features, we start our VEGF targeted therapies. And typically it's one of those two pills, Sinitinib or Pozopinib. And I think they're both very active pills. I'm personally comfortable giving either one. I've probably given more Su-10 and if you've followed it Duke, I probably give more of that drug because we started with that drug and we're comfortable with it. And there's one thing I do like about it and it's an intermittent dosing. So it gives patients an opportunity to kind of recover from any side effects that they see in longer term that kind of intermittent approach is I think healthier. I recently started an exercise program. I don't know if this was a gift or a punishment but my wife got me a rowing machine. I don't know if you know this is these old school kind of torture machines. There's nothing to plug in. It's a chain, it's a fan, you pull this thing, you slide on the seat, it's rough. And I was doing this, I used to row in high school. So that was I think why she got it for me. That or the house of cards show, I can't decide. But she got me this rowing machine and I was working out and I was doing about 20 minutes for about 5,000 meters and it was killing me. And then somebody at my swim team told me that there's this intermittent approach where you work really hard for 20 seconds and you go easy for 10 seconds. So you do that for four minutes and then you know what I'm talking about. Yeah, okay, so I tried this and it was faster. I and I finished and I was still tired but I finished faster and I was still able to pick up my rate and go faster for those 20 seconds by just taking that 10 second break and it wasn't enough to totally get back to restful but it was enough to give me a break. I think to some extent, you know, that sort of suit 10 approach is kind of like that. The other approach is a constant one and that for some patients that works too because their body just acclimates to what it is. I'll give you a clue on these drugs. For both these drugs, the hardest thing is the first cycle. And I don't think people necessarily realize this, particularly people in the community, but the first time you take these drugs is the worst. You know, usually we think like with chemotherapies and stuff there's a buildup effect and with each cycle, with each month that goes by it gets harder and harder. That's not true with these drugs. The first time you take it, that first month is the hardest. We look at our patient reported symptom profiles, they all fatigue, all that is the worst with the first month and then it gets better. So it's so important that people know that, that we're really active in managing around that first month but we don't put people, you know, hit them too hard with those drugs. I think more important than which drug you choose is how you administer it, how you manage the patient. You're gonna hear about side effects and symptoms and management, but to me that is by far and away the biggest differentiator and outcome is how you manage a patient on one of these drugs rather than which one you choose. They've done head to head studies and they look pretty equivalent and you know, I'm not gonna argue one is better than the other. I don't think we can make that argument but I do think that how you treat patients through these therapies, how you maximize that benefit is critical and there's not an art or a science, it's just plain old common sense on listening to patients' symptoms and just knowing, experience what the thresholds are for when you need to change or take a break or lower the dose and do things or even change that regimen from four weeks on, two weeks off to two weeks on, one week off or things like that. So those are all the things that I think of when I'm choosing these therapies with patients. Do I need to treat patient at all? If I am, what's our goal? Is it cure? Is it help them live as long as possible, disease control? Are there symptoms we need to manage out front? Is there a kidney we need to take out first? If we're gonna start therapy, is it a clinical trial because I think that they need that in a combination we should do or is it a standard of care and if it's a standard of care, which of these drugs do I feel comfortable with? So that's kind of my up front talk right now. There's one other therapy we use in rare circumstances and that's Temsary Limus. That's an IVM tour inhibitor for particularly patients with poor functional status. It's an IV drug you get once a week so we really get to control how much patients can manage. We get to see them and manage them closely every week, which I like. It's really for the particularly sick patient that I don't think is gonna tolerate some of the other therapies. Fortunately, at places like Duke and Isisbeck UNC, we don't see a lot of those folks. Those folks can't make it all the way in and so a lot of our patients don't have to resort to something like that. It's nice to know we have a therapy even for those patients but a lot of that are patients that are pretty sick. They need therapy right away and I counsel a lot of doctors out in the community about that and we'd still use it there and it's a good drug but unfortunately that's a patient population. We're still, it's still not enough but that's the last piece of this sort of upfront regimen. So I don't know if that's 20 minutes, I probably went over Kim but we'll save questions. Thank you all very much for coming in your attention today. Look forward to this discussion later. Thank you.