 Okay, I think we're mostly back, we're still on time. Good, so I'm delighted to move things forward and talk to you about new and emerging systemic treatment options for minestatic kidney cancer. Trying to hit a few highlights for really more of an overview of the medical oncology field. So going back to the figure I showed you at the outset, kind of an overview of what's available, what we have for kidney cancer in a comprehensive way over time. And as I pointed out previously, changes in the overall concept of approach to treating kidney cancer from a time where there really was no effective therapy and just supportive care for patients to a long interval of immunotherapy, which was a fairly novel for for metastatic cancer. With cytokine therapy, those guys still hang around, both interferon and interleukin too, still have a role for some patients. But the dominant drug in the last 10 years has been agents from what are called targeted therapies. And until just recently, as I made reference to, a brand new and trinted new drug class immune checkpoint blocking antibodies. And so we'll touch on some of the changes, three new drug approvals in the last eight months for kidney cancer. So just to remind you that the diagnosis of renal cell carcinoma is a broad category that includes multiple different subtypes. And the identification is based on your pathologist looking at the tissue under the microscope and reading out the histologic pattern of the tumor growth and declaring what subtype the tumor is. Most of the clinical research and data we'll look at is for better or worse, limited to clear cell patients. So it homogenizes the range of tumors to some degree, but many of you here probably don't have clear cell. And so unfortunately that the talk today really won't touch on some of the nuances for the less common subtypes of kidney cancer. So I put together a table that shows you sort of by drug category, 12 FDA approved therapies that we have available to us. So breaking down the whole family of drugs into either immunotherapy compounds or targeted agents. So the immunotherapy, the old-time cytokines interleukin-2 and interferon-alpha. And then the brand new entrant that is a new drug class, what are called checkpoint blocking antibodies, nevolobab or abdevo. That was FDA approved November 2015. Our targeted therapies, many of the agents attack or block a signal from a hormone, a growth signal called VEGF, vascular endothelial growth factor. That's made by the tumors and acts on the vasculature around the tumor to drive blood flow, oxygen, nutrient supply to the evolving tumor. So blocking that biology either with an antibody, Bevacizumab or Vastin that binds the VEGF hormone itself. Or what are called tyrosine kinase inhibitors, uniformly oral medications that block the signal at the end organ, the vasculature. That's the VEGF binding to its receptor crates. And so two brand new entrants within this field of drugs, two new TKI's approved in this calendar year in 2016. And we'll comment on that a little bit. And then another target within the tumor proper, a signaling hub called the mTOR protein and drugs that block that signal cascade. Temsir limus, Everlimus. So where do we start? Newly diagnosed kidney cancer, you come into the clinic, we're going to talk to you about medical therapy. So a couple of pertinent features. Right now, 2016, we do not have predictive markers we can use that really guide us in a meaningful way to choice of treatment. We'd love to have some molecular profiling that we could look at and we'd give you a personalized roadmap and say these are the best drugs for your cancer. These don't work at all and here's where we're going. And the next patient may be 180 degrees opposite. Lovely idea, personalized medicine. It's a lot of play in the field, but we're really not at that point at this point in time. And the other point is pragmatic. Not all of our drugs have an FDA approval to be used as initial therapy for kidney cancer. So you can't simply prescribe across the board any of the drugs that you choose. If you apply the amount of context, your prescription will be declined as an off-label prescription by most insurance providers. So it boils down to a simplified number of choices. And once again, thinking for the most common presentation, menostatic clear cell. What are we thinking about as standard agents? We're thinking about the option of high-dose interleukin-2, which still has a role in our clinic. For most patients, we're thinking about targeted therapies. And the three agents or combinations that right now are considered the best available therapy as initial treatment are the oral medicines, Sunitinib or Sutent, Pizopinib or Votrient. And then the combination of Bevacizumab with Interferon is considered an equivalent choice. I can tell you I almost never use that combination in patients coming to me from other oncologists in the community. Nobody uses Bevacizumab, Interferon very much. Really, for practical reasons, Bevacizumab's an IV infusion every two weeks. So you have a fixed clinic schedule. Interferon is pretty obnoxious if anybody's had that drug. It's not a friendly drug. So you don't come out ahead with that combination. It's more cumbersome. The oral medicines, Sutent and Votrient, we feel are very patient-friendly. You're taking medicine at home. Patients that want to travel be out of town. It's very flexible. It's a fairly convenient way to go. So a choice between those agents is almost always the first choice for targeted therapy. And not to forget our clinical trials program. All of our treatments are fundamentally imperfect. So we're always looking for what's coming, what's new, what may be better than what we have. And we think participating in a research trial would make sense for where you stand disease-wise is a good choice. So many of you here have been in our clinic and we've had a conversation about three different options for kidney cancer. And that's the different categories we're thinking about. So just a couple comments on IL-2. It is a unique therapy. We're the only center in Seattle to coma that routinely does IL-2 therapy. So we do get some patients coming to us specifically interested in IL-2. It's a toxic therapy. It's cumbersome to deliver. You have to be in the hospital. In fact, you're admitted to the ICU care suite in the hospital. And some of the nuances for IL-2, we only offer it to patients with clear cell histology. It seems to work less well for the other family of kidney tumors. You have to be physiologically young. So you can't have bad medical problems, no organ dysfunctions, good kidney, good heart function. There's a common sensical scale called a performance status in the oncology field. Basically, how sick are you from your cancer? Is it totally unknown to you? You function at a normal level and it's just a scan that has spots on it? Or is the cancer making you ill in some fashion? So performance status needs to be a person that's functioning at a normal level despite their cancer. We like the idea of treating patients that have very limited disease in their body. And so we're expecting patients that are candidates for IL-2, have seen Dr. Gore or one of his colleagues. They've had so-called cytoreductive diffractomy. We've taken out the primary tumor and ideally the dominant tumor mass in their body. And they're left with small volume tumor findings that are not causing symptoms. They're not poised to cause symptoms or some catastrophe if they grow larger. It does chew up some time to get organized for IL-2. You can't have a cancer that if it grows slightly larger, something awful is going to happen. And there's data that says prior kidney cancer therapies may pose a risk for IL-2 treatment. It may increase the side effect profile. And so we prefer to offer IL-2 as your initial therapy and not leave it for a rainy day after you've had multiple prior treatments. If we're going to do IL-2, we're going to ask you for a couple of screening tests, a brain imaging study, a cardiac stress test to be things that we wouldn't typically do in the clinic for other therapies. Depending on the medical history, maybe a formal lung study as well of pulmonary function studies. Why do we still think about IL-2? It's cumbersome. We put you in the hospital. We've got simple oral medications you can take at home and go about your business. And so these graphs really give you a picture of what we're hoping to accomplish with IL-2 therapy. So starting on the left side here, the response profile, this is data from the NCI campus, the first medical campus that used IL-2 in the country, 20-year experience in their hands. So 86 to 2006, nearly 260 patients that they're reporting on. So what happens to patients? A small group of patients had a complete response of their kidney cancer. All findings on their scans went away, 8% of patients in their hands. Another group of patients, the cancer shrunk, but it didn't fully disappear. So partial effects in 12%. So 20% of patients having marked effects in terms of their follow-on scans. Unfortunately, that means 80% of patients went to the trouble of receiving IL-2 and really didn't benefit in a strong way. But it's the complete responders that we're fascinated with in the kidney cancer field. If you have a complete response and you follow these patients over time, and given the very long time IL-2 has been available to us, 20 years of follow-up. The solid majority, 70% of patients with a complete response, maintain that response. The cancer never comes back. And if you look at the overall survival stratified by the response, if you're a complete response, partial or no response, almost all the patients living with 20 years of follow-up. So it's the one scenario in the clinic where we actually talk about maybe truly curing the cancer, where patients can go on and on with a complete effect, but unfortunately only a small fraction of the patients that received that style of therapy. Partial response in a time where there really weren't other therapies to offer patients seemed to have an effect. Patients did live longer. They shrunk the disease, reset the clock. They did better than patients that had no effect by IL-2. So I put together a table that I hope convinces you that we're making some progress in the field of kidney cancer and we look over a very broad interval of time. And so focusing really on the overall survival data with different groups of patients and the doesn't project very well, but the coloring of the different lines corresponds to the timeline I showed you and the different areas of therapy for kidney cancer. So the first line harkens back to studies done with interferon where the comparison with the drugs available in the early 80s or even older drugs, conventional chemotherapy agents, hormonal therapy that was sometimes applied, that was really extremely ineffective, response rates of tumor shrinkage less than 10%, and immediate overall survival of cohorts of patients formally recorded in research studies of six to nine months to the midpoints of the survival, extremely bad for the historical experience of kidney cancer. The cytokine drugs moved the bar. They were good enough to gain FDA approval and become standard treatments, although were highly imperfect. Rates of response of 12 to 20% for interferon and interleukin-2. And in large studies done, phase three studies, median survival in the teens were beyond a year, recognizing that the best response was limited to a very small fraction of patients. So when you look at the midpoint of all patients treated, you're missing the patients deriving the most benefit, but these drugs did seem to be better than what had been available previously. Jump forward to the targeted agents we now commonly use. In the research studies that gained their FDA approval, comparing these drugs to interferon alpha, these drugs came out ahead. So either SUTENT or VOTRIENT response rates now of 30% of patients and median survival of months counted out in the 20s, 22 months, 26 months. The Bevacizumab interferon combination, similar numbers for response and overall survival is not terribly different. So we think we've moved the bar once again with our targeted therapies, but the current state of the art isn't stopping after the first therapy is applied to most patients. We believe the natural history of these drugs has eventual tumor resistance. The tumor grows back and we move on to an alternate therapy. So how can we gain a picture of using multiple sequential agents? That's a really hard perspective and number to come up with to give you something that tells you what's truly happening. But one study that used two drugs in sequence as part of a study, called the record three trial, patients received synitinim or everlimus in sequence and all training sequences were both studied, had to had 50-50 randomization. The synitinim first everlimus second proved to be best, but the point of this is to show you that data was collected over two drugs given in sequence. And so the response rate of first line synitinim, not so different than the phase three study, makes the point that there's some heterogeneity in an absolute number if you look at multiple studies, so you can't be too honed in on the absolute number. But again, looking at overall survival of patients that received two drugs in sequence, so the duration that they're able to use the drugs, progression free survival, that's my mouse, 25 months versus 10 to 12 months for a single agent, and then 32 months median survival, so the midpoint of the population getting two drugs in a row. And we think that effect is manifesting itself as patients move on to third and fourth drugs as currently practiced for many patients, that the average survival is getting better and better. It's kind of hard to capture by individual research studies, but we do think we're making progress that we're moving the bar. This number of 32 months certainly looks a whole lot better than a six to nine month nine month median survival from the late 80s. Time from start of therapy. I wanted to show you a figure that's called the waterfall plot. The way data is commonly reflected in research studies, because I think that response rate number is a little bit misleading, you think. 30%, yeah, that's not such a big number. This drug's not so great. But I think this gives you a better reflection of what we actually experienced in the clinic and what we think about these drugs. So this is a figure from a study with Pizzopinib or Votrient, a drug many of you here probably have actually taken. And there's guidelines about how you interpret radiology studies as you participate in the study, you collect imaging data, and you put a label on what's happening to patients. They're having progression, they're having stable tumor findings, they're having a response, and what that means, a partial or complete response. So before you start on a treatment, you obtain a scan, it shows you a spectrum of tumor findings, and as you move forward in time, you receive a drug, you repeat the same scan, and you compare the scan findings. So the tumor that you had before you started, you look at it again, and you actually measure the size of lesions, lesions get bigger or get smaller, you normalize those values to where you started. And so if your tumor grew bigger, you have tumor findings that fall above the zero line, your tumor grew, if your tumor got smaller, you fall below the zero line. So this represents shrinkage of tumor compared to where you started before therapy was applied. So the point of this plot, this is the best response seen at any point in time after starting Pizzopinib therapy on a clinical trial, is that 70 to 80% of patients have their starting tumors shrink down incrementally after they start therapy. Even though, so in this study, the response rate you'd read in the study abstracts is 35% response rate, that's true, and how do they come up with that number? Well, the guidelines for applying a response category say that to label somebody as a responder, you have to have at least 30% shrinkage, the dotted line, of your tumor compared to baseline. So a lot of patients, their tumor gets a little bit smaller, doesn't meet the 30% criteria, and that's labeled as not a response. They're stable disease. If your tumor shrinks down, that's based on the tumors that you had before you started therapy. If you collect a brand new tumor, the guidelines are intolerance to any new tumor findings in your label as disease progression, even if your starting tumors got smaller. So the blue lines here are patients that their baseline tumor's got a lot smaller, but they had a new tumor finding in their label as progressing disease. So you look at that and you realize we're looking at a subset of patients that have pretty significant tumor shrinkage in labeling them as disease response, the 35%, but what we're thinking about when we see them in the clinic, we're saying, well, our drug's imperfect. It's not going to put you into a cure where we're going to stop the therapy. We really are just trying to control the disease, stop it from growing, stop the cancer from spreading, making it sick and causing problems. So everybody that's having a nice effect where the disease really isn't growing in a meaningful way, we're going to roll forward, say the drug's working just fine, that's what we wanted, that's what we expected. And so the percent of patients that we think we're benefiting is the solid majority, 70, 80% of patients with our targeted therapies. And so I think this graphical picture hopefully gives you a better flavor of what happens to individual tumors when you apply these drugs. When you look at research studies and you start seeing 20%, 30%, 35% response rate, that feels like a smaller number than the group of patients that we think are benefiting in how we think about these drugs. So unfortunately, even our best drugs, the natural history for most patients is the tumors become resistant, they start to grow back. And then what do you do next? So right now, state-of-the-art, most patients are going to get offered either Sioux Tent or Votrin. There's nuances to the two drugs. We can talk about that at the end. Our IL-2 patients, if it doesn't work, and unfortunately that's the solid majority of IL-2 patients, we're going to offer them the best available targeted therapy. They're also going to move on to Sioux Tent and Votrin. So just about everybody in the clinic is going to wind up here. At some point in time, we're going to say, oh, it's not doing the job any longer. We need to move on and try second therapy. So what is state-of-the-art for the second therapy you're going to apply to kidney cancer? And that's where things have really changed dramatically in the last eight months. So until November of 2015, there were two drugs that had done large-scale advanced testing in this context, failure of primary therapy. And so we were almost always choosing between Everlimus and Exitinibus, our two best drugs. There was no head-to-head data, so one or the other, there really wasn't a compelling reason to say one was the best. But we now have three brand new options to treat patients in this setting. So the drug Nevolamam or Octevo, an immunotherapy compound, the first entrant for kidney cancer from what are called immune checkpoint blocking drugs, Cabosantinib, an oral tyrosine kinase inhibitor, so related to sutent and votrient, and a third option, Vatinib, another tyrosine kinase inhibitor, another oral agent that was studied in combination with Everlimus, so a two-drug cocktail. And each of these studies compared itself to Everlimus, a perfectly acceptable standard agent that was used in secondary therapy. And each of these three large studies said the new drug was better than Everlimus. So what that means for Everlimus is bad news. Nobody is going to look at Everlimus as being a smart choice as single agent, second therapy for kidney cancer. So now we've got three brand new choices, plus we still have Exitinib as being a little bit older drug that's also available to us. Once again, just to point out, again, our therapies are imperfect. Clinical trials are a very sensible choice. That's always in the background when we're talking about what we're going to do next. So kind of a busy table, but I wanted to put out there this truly the discussion that was had at the big clinical oncology meeting ASCO 2016. There wasn't brand new data for kidney cancer. It was rehashing this flurry of activity and three brand new drugs for kidney cancer. And what does it mean? What are we actually going to do with our patients? Which drugs are we going to select? So let's just walk through this and look at a couple of issues. We're looking at four different drugs that are all sensible options. Exitinib and the three new players for previously treated. So the data reflects patients that had a prior tyrosine kind of inhibitor, almost always, Su-10 or Votrint that's failing and they're moving on to a second therapy. The three new guys all compared to Everlimus, the Exitinib data was collected in comparison to Seraphim. And let's look at my highlighting is not really working. The first three lines here are metrics of the anti-tumor properties. So overall response rate and we just spent a minute educating ourselves about, you know, what does that really mean? But we have to have everyone measure in the same fashion so we can compare between trials. And so we know a little bit now about what we're seeing when we're seeing this response, the extent of shrinkage in patients. So overall response rate across the board, the new guys, high teens, 20s, 35% with the combination. Those numbers sound pretty good compared to 9% for the Exitinib drug. But more importantly, I think when you look at survival, at the end of the day, imperfect drugs were really just wanting to stop cancer growth, control it, have you function well, perform at a very good level. So perhaps less important than whether the tumor shrinks or doesn't shrink, are we stopping the cancer growth and you're living the life you want to live. So the survival, I would say, is probably the most important statistic. And so the Exitinib median survival in TKI failures of 15 months with state-of-the-art until last November, and all three of the new guys look to be meaningfully better. So 20 to 25 months of median survival with any of the new agents. So I would have to say, I think right now our practice would be to pick one of the new choices and skip over the older choices that we had. The flip side is, well, we apply a new drug. What are you taking on in terms of nuisance and toxicity? Are we going to make it profoundly ill and it's not going to go well. So the bottom lines here all look at metrics of side effects and problems with the drug. So what fraction of patients had to have the dose of the drug cut back for the two new oral agent options pretty substantial, more than half a patient didn't tolerate the maximum dose and cut the dose back. Nevolumab as it was developed, there was no option for changing dose. It's a fixed dose. And so that's not meaningful for Nevolumab. And then side effects profile. So there's codification research studies for side effects. They all get a list listed out, rostered out. So what fraction of patients have side effects and then there's grading for how extreme they are. One, two, three, four. One and twos are things that are mild that really don't interfere with your daily function. Grade three and grade four make you sick, cause problems. You need a remedy. You have to stop therapy that you're taking. So we're most interested in the grade three and grade four side effect profile. So the Nevolumab numbers for stopping the medication outright or having bad problems, I would say look better than their comparison here. These guys that can really give patients bad side effects. Now the oral agents are fairly flexible. You can stop them for a period of time and let the side effects fade out. You might try again at a lower dose. So there's a lot of work that goes into trying to optimize things. But I would say the field is really quite pleased with Nevolumab. That's being a drug that generally goes pretty smoothly for patients and very often traffics with very few side effects. So we definitely, I think at our institution and as a field, are really taken with immunotherapy. For kidney cancer, for melanoma doctors, it's preaching to the choir. We've been using immunotherapy for 20 plus years and so are kind of outliers in the broader field of oncology. But a point about the immunotherapy drugs, I think this figure really illustrates very well. This is neither kidney cancer or Nevolumab. What this is is a figure of melanoma patients treated with a drug called Urvoi or Ipilimumab. That was the first drug in this class of what are called immune checkpoint blocking antibodies. It's been in clinical development the longest and so we have the longest perspective on what this drug can accomplish. So this is looking at survival of melanoma patients with a timeline that extends to 10 years from the start of therapy. And so what this shows you is that unfortunately for many patients the drug does virtually nothing. Their disease grows, progresses, they die of their disease. But by about three years you hit a plateau where this flattens out. So patients with long-term survival of their disease receiving an immunotherapy compound. And I can tell you that the incidence of a complete response with this drug is really quite uncommon, less than 5%. And what's happening here, the fascinating biology are patients that still retain tumor findings on their scans but they stay dormant, they stay stable and time goes on and on. So disease control in a subset of patients that seems extremely long-lived, very durable, but imperfect. It's not a complete effect. And so the idea that for some patients with immunotherapy the so-called tail of the survival curve may flatten out and be very long. If you can't achieve a complete cure, maybe the next best thing is more or less permanent control of the disease and you go on and on without the disease changing. So now this is nivolumab and this is kidney cancer and this was data shown this summer at ASCO. The longest survival follow-up observation in patients receiving nivolumab, this is the very first study of nivolumab in a variety of patients including kidney cancer and then a dedicated kidney cancer study at Phase 2 study looking at the same metric overall survival of patients that have enrolled in these studies and got nivolumab and the shape of the survival curve hearkening to the hypolymumab data, although it's less follow-up but lines drawn here at four and five years of follow-up total patient numbers are not terribly large but giving you the feeling that there's a flattening of the survival curve there isn't a steady degradation where eventually you're going to cross the zero line and all patients have died from their disease. So maybe once again we can achieve very long-lived disease control that goes on and on for many years even if it's imperfect and patients still retain findings of their disease on their scans. So let me show you a figure. Is that, that last graph, does that represent people in stage one, two, three and four total or is it... For their cancer? Yeah, what they presented. So these are all patients that have metastatic kidney cancer. To get on to both phase one and phase two clinical trials you already had prior therapy, at least one prior treatment that failed to be eligible to receive what was an investigational compound at the time these studies began. So these are all metastatic kidney cancer patients and once again all clear cell metastatic kidney cancer patients that all received nivolumab as part of these studies. The data is a little bit unclean but that's some patients in this survival data set left the studies, maybe went on to receive other types of therapy and so it's not patients that are ongoing necessarily actively receiving nivolumab but it is the true survival of what happened to these patients that participated in the trials and did get drug as part of the studies. This is not a survival figure but this is a metric of tumor findings in two patients treated here at our campus at the start of the large phase three study of nivolumab that was the data that was criteria for FDA approval. So showing you here in real patients what the biology that we're speaking about so each spot on this graph is reflection of the CT scan findings of these patients time zero is the start of participation in the clinical trial both these patients getting the nivolumab drug and so again comparing their scan findings from overall tumor size to their pre-treatment baseline imaging so both patients every time they get scanned the first couple of scans their tumors get smaller and get smaller but finally sort of hit a plateau here this isn't 100% shrinkage of their tumor they still have abnormalities in their scans that we're calling tumor they've become very stable they haven't changed both patients are well over two years of ongoing nivolumab therapy and so is this now the biology the pattern of existence that we see with the nivolumab drug and melanoma that extends out to 10 years how long is this going to go on is it going to go on 2 years, 5 years, 8 years, 10 years is this you know functionally a complete effect and ongoing durable control of tumor we don't know we need longer follow-up but it's provocative findings that make us think that maybe there's something that's unique about our immunotherapy compounds that may not be common to the targeted agents so it sues us to think about prioritizing the immunotherapy drugs ahead of targeted agents and so last point given what we consider to be a very good patient tolerance with the new immunotherapy drugs they're getting great attention in the field and this is just a little schematic showing you that they're going to become the building block to test combinations of checkpoint blocking drugs with a whole slew of other agents hoping to get a more potent and more durable anti-cancer effect nivolumab is an antibody that blocks a protein called PD1 there are competing antibodies owned by other companies that share that identical biology there are also similar antibodies that block a very similar protein the binding partner for PD1 is called PDL1 so a lock in key phenomenon you can block either side of that interaction and we think you get the same biological effect there are many of these agents in development by different drug companies coming forward and looking to combine with other agents to trump nivolumab and do better with a combination approach and these all reflect research study opportunities that are actively in our clinic now or that we believe are coming to our clinic in the next several months so combining these drugs with interleukin2 combining these drugs with other similar agents antibody molecules that have been generated to be very selective to manipulate other targets in the immune system so each one of these names and numbers here is a protein that's on T lymphocytes the same target for nivolumab and for the urovoid drug so can you find other ways to manipulate the same immune compartment and get a more potent effect so combinations of all these guys with PD1 or PDL1 antibodies a brand new drug class what's called what's a metabolic therapy that blocks glutaminase which degrades glutamine by the tumor the tumor is doing this that's thought to be a bad thing for your T lymphocytes they need glutamine as an energy source so manipulating the so called micro environment around the tumor to augment immune responses that may be occurring in that space combining one drug that works with the second drug that works old school oncology therapy A is good and B is good A plus B might be better so mixing our checkpoint blocking drugs that work in their own right with our target therapy drugs that work in their own right and see if those combinations are a smarter way to go combining these drugs with something called epigenetic modulation for today's purposes won't worry too much about what that means but a way to manipulate tumors that are thought to change gene expression profiles perhaps make the tumor look more inflamed be more exciting to the immune system and give you a better effect so looking what's coming down the road soon what's maybe changing though we practice kidney cancer therapy in the next couple of years so looking to take the immune checkpoint drugs that are approved now for patients that have failed a prior therapy and saying well they look very promising shouldn't we pull them up and use them as the initial therapy for our patients so trying to prove that that's the right way to go in a formal research study that gives you data that makes the case so three different studies with compounds owned by different companies that are similar in concept combining the volumab the drug that's truly FDA approved for kidney cancer with the Uruguay drug or ipilimumab in a two drug combination that's a study that's comparing those two drugs to sutent head-to-head for untreated patients that studies are already completed it's patient enrollment so now we're just going to wait and see if it's presented and what the results are probably a couple years away from a result on that a drug that's a PD-L1 targeting antibody and combining that with bevacizumab that we know is a standard drug for kidney cancer so targeted therapy plus an immunotherapy again comparing to sutent and then a similar approach another PD-L1 antibody owned by a different company combining with the TKI as a combination approach again compared to sutent so as everlimus was beat up with all the new drugs coming available sutent will be the common comparator so we'll have three competing studies that are similar in kind and see if one or more of these approaches gains the upper hand and becomes the standard approach to treating patients a couple years down the road so a couple points I hope came through when you look very broadly over time I would say that the pace of drug development and new drug approval for kidney cancer is accelerating if you look in recent years versus the distant past we think our new drugs are better than what we've had before we're making incremental progress in disease control the most recent flurry of new approvals are all for patients that had failed prior therapy we're very interested in the new immunotherapy that are blocking drugs in their own right and they are going to be the building block for multiple research studies of a variety of combinations looking to improve on their activity there's studies that are looking to change the way we come after patients and apply therapy in the first line setting and so that's all very promising and optimistic but it remains a true statement that true cures of cancer and the ability to stop therapy because the cancer is gone remains a very elusive goal not only for kidney cancer but advanced cancers across the board so that's a very high bar we'd love to see patients start developing complete responses and come off therapy but so far that really isn't part of the equation for advanced kidney cancer so I appreciate the chance to speak today that was kind of a very cursory overview I think we have a little bit of time if anybody has a couple of questions in one of the graphs that you had there you had a papillary type 1 and 2 what's the difference between papillary 1 and 2 and is one more aggressive than the other? so that's a distinction made histologically by the pathologist in terms of the growth pattern of the tumor there's no formal metabolic or molecular profiling that gives you an absolute distinction between those two there are gene differences that are somewhat unique to the two different subtypes generally for therapy there's not a distinction made between those two subtypes so papillary gets bundled together in terms of thinking about what we're going to do therapy-wise and I have one more question you were talking about combination therapies, the OPTIVO plus etillumab? yeah etillumab that's in a research study at present, right? so that was the research study that's completed its enrollment but it's not an active opportunity for patients but now we have to wait to see what the outcome shows okay, thank you so maybe one more and then we should move forward with the next speaker yeah I wondered you were talking particularly about clear cell and I wondered if there was anything that you knew that worked against papillary and then also the secondary thing was it talked about the studies where they compared it to or however you say that but you also had in LIDA or whatever list is there did they compare against that at all? so for papillary kidney cancer overall when you look at the success of targeted therapies if you bundle all the non-clear cell patients together the outcome success is inferior so having a non-clear cell diagnosis is a bad deal the drugs that we have available seem to work less well there are no drugs that were developed specifically for papillary or chromophobe patients in mind so we take what we know about results with clear cell and we apply it to the other subsets but don't really know for sure what's best there is a data set of head-to-head comparison of SU-10 versus the Everlimas drug, a finitor and SU-10 was superior so based on that available data I typically recommend a patient starting with SU-10 for papillary kidney cancer unless we have a research study opportunity and again success is incomplete so if something that looks promising that's brand new we're happy to try and make that available as a choice for non-clear cell patients