 Okay, so I'm going to talk again about systemic therapy, focus is stage four metastatic disease and looking at immunotherapy drugs that we have available, both established agents and then what's coming down the pipeline. So just as a brief overview, there's a variety of lines of evidence that have suggested that kidney cancer may be uniquely sensitive and responsive to immune-based therapies. There's a mouse model called the RENCA model that's been used by investigators to try and show that that model system is a disease that can be manipulated by vaccines and by immune-based therapies. In human data, human and renal cell cancer, there's a variety of lines of evidence that point towards the immune system doing something helpful. There's a lovely literature of spontaneous regressions of kidney cancers, melanomas, lymphomas, or the diseases where you really see this phenomenon. That implies that for a rare patient, something happens, something changes, and metastatic tumor can begin to shrink and go away without active therapy applied. The assumption is that's an immunologic mechanism that's been activated in some fashion. If you look at tumors, the subset of tumors have immune cells that are infiltrating into the tumor itself. In laboratory studies for kidney cancer, for melanomas, people have worked very hard to try and show that if you take those cells out of the tumor, you can propagate them in the laboratory and show they have the capacity to recognize tumor cells. The biology of the immune system is that telanthocytes are all unique entities. When they see a target, they copy themselves. They expand. Expansions of redundant T cells that see the same target, so-called oligoclonal expansions within tumors, implies that the immune system is actually turned on. It's active and it's doing something. Then part three is that we can take different compounds that stimulate the immune system and apply them therapeutically. For some patients, it works quite well. Again, going back to a timeline slide we looked at before. The onset of the modern immune therapies for kidney cancer that worked well enough to become standard therapies goes back, as we said, to the mid-'80s, early-'90s. Interferonalpha and then interleukin-2 became standard therapies applied to kidney cancer for quite a long time until the targeted agents that we just spent some time looking at became commercially available starting in 2005 and rapidly thereafter several other drugs were approved. One thing I want to look at is going back to interleukin-2, a drug that's still used on a regular basis, and then we'll jump forward to a new generation of drugs called immune checkpoint agents that are likely to become available fairly soon for kidney cancer. They're already commercially available for melanomas and for some lung cancers. Hidosinterleukin-2, it's not a drug most local oncologists try and use. The number of patients they would treat annually would be very small and you need your staff, your nurses, your hospitalists to be familiar with what's going on. So it's a drug you're going to refer your patient to a center. We're the only center in Seattle that regularly does IL-2 therapy. There's a practitioner in Portland, Oregon, Brent and Currie does a lot of IL-2 therapy. There's IL-2 therapy that can be obtained in Spokane. So the Northwest, those are typical destinations for patients for IL-2 therapy. IL-2 is a cytokine your body makes normally. It's a growth signal for a subset of white cells called T lymphocytes. Activates those cells, makes them grow and expand and become more effective. And it was developed in a treatment approach at the highest tolerated doses that people can stand back in the late 80s, early 90s. So so-called Hidosinterleukin-2, difficult and toxic to administer. Patients are treated in the hospital setting typically in an ICU care bed. And again, you need some experience to know what's happening. So limited to referral centers. The patients that are good candidates for IL-2 because of the toxicity are going to be young patients. So physiologically young, no organ dysfunctions. We're going to ask for screening brain imaging to make sure there were no occult brain lesions. Cardiac stress tests to make sure the heart function is normal. If there's a long smoking history or lung disease, probably pulmonary function studies. Performance status is a crude yardstick in the oncology field that you're functioning well, you're doing normal activities without limitations. It's a drug that empirically has been found to work better for clear cell kidney cancer than the other subtypes. So it's only offered to clear cell type tumors. I don't have a slide on it, but historically most patients getting IL-2 therapy had had prior side reductive surgery and we commented on that at the outset. There does seem to be a therapeutic role there. And so that's the expectation that IL-2 is going to be offered in patients that have had quote surgical debulking. They're going to have the majority of their tumor removed surgically. And we're looking for patients with limited disease. There's time invested to do screening tests to set up the treatment calendar. And if you're at risk to have something very bad happen, if the cancer grows slightly larger, that's not a good situation. And then we usually like to try and give IL-2 as the first therapy for patients. There's some suggestion that perhaps exposure to other medical therapies might change the risk of IL-2 therapy. The reason we still do IL-2 while it's been around going way back to the 1980s is really shown here. This is data set from the National Cancer Institute campus. It was reported in 2006. So it's data that really is treatment before the targeted drugs became widely available. And so shown on the panel on the left is the response for patients getting IL-2 therapy. So 8% of their patients achieved a complete response on their campus, 12% partial response. And the rest of the patients would be judging on responders. And it's really for the hope that you've fallen to the complete response category. So of all the complete responders at time zero, what happens to those patients over time as you move to the right? And this axis is measured in years. So you're looking at nearly 20 years of follow-up of patients treated with IL-2. Most of the complete responses stay complete responses. And so a relapse recurrence of folks in that category is extremely uncommon. Only 10 or 20% of those patients. And so it's really the only situation with any regularity in metastatic kidney cancer where we think we may have a therapy that can cure a small percent of our patients. The partial responders, when you look at the survival curves, actually do pretty well. So the survival for the complete responses is spectacular. Very few deaths in that patient group. The partial responders, if you look at the median here, they're out almost four years of survival. That's actually a pretty decent number. And again, in an era where these patients didn't have targeted therapies to move on to. In a more contemporary grouping of IL-2 treated patients, there's been an attempt to collect patients treated with IL-2 into a national registry. So we can look at larger numbers of patients treated and maybe see associations and patterns that you can't really tease out statistically at a single institution with maybe one or 200 patients. If you can look at thousands of patients, you might learn something. So this is looking at this data that's being input into the registry called the Proclaim Registry. And looking at patients by their response, there's my arrow here. So total responders, patients entered into the registry, 8 percent. That corresponds very well to single institution series. And so the implication is that these aren't simply all the very good responding patients that investigators start to input. This seems like a pretty fair representation. Partial responders, 14 percent stable disease, 24 percent of patients. And then everyone else, more than half, not having any evidence of tumor shrinkage. So progressing disease after IL-2 therapy administered. And looking over here on the right, the median survival for these different categories, even for the patients that had progressing disease. So the therapy applied failed. Their cancer grew bigger after IL-2. Patients enrolled in an era where they probably moved on to other treatments, targeted agents. A median survival of 40 months in that patient cohort. That seems like a very big number. So just for a comparison, here's three of the phase three studies that was the data submitted to the FDA to gain approval. Sinitinib, Pizopinib, and Bevacizumab. Median survival for these drugs administered in the frontline setting between 18 and 26 months. So in comparison, 40 months seems extremely good. And so the question is, are you doing something to the tumor, even if the tumor doesn't shrink down and get smaller? And there's been precedent from other immunotherapy treatments. For example, Proven should apply to prostate cancer. But maybe immunotherapy drugs, even if they don't cause shrinkage of tumor, change the natural history, slow down the tumor growth. And so maybe survival is actually better after applying immunotherapy drug, even when conventional measurements of disease status say that you don't feel like you did what you wanted, the tumor didn't shrink. Certainly not proof of that concept, but I thought provocative data from the Proclaim Registry. So changing tracks. So IL-2, we still do. We have an active program and we're a referral center for IL-2. Moving forward to newer drugs that are immunotherapy drugs and what's coming and likely to be available fairly soon. So this little cartoon is a little cellular immunology for you. To try and describe what we think is happening with the new wave of what are called immune checkpoint drugs that are becoming available. And available not just for kidney cancer, but there seems to be a commonality to these drugs and to the biology. And they seem to have activity across a wide range of cancers. So these are drugs that are going to be widely used in oncology in the coming years. What's in the center of this figure here? So the T-cell we think is the engine that is giving you an anti-cancer effect. Some people, the immune system is able to recognize their tumor, turn on and respond to the tumor, but not in a way that's effective enough to eliminate the tumor. And so the hope of IL-2, of interferon and the new generation of drugs is could you not stimulate the immune system and gain an anti-cancer effect with your immune cells? So a T-cell we think has the capacity to see a discrete target and that target might be a target on a tumor cell, which would be a good thing. When a T-cell turns on, it activates, it gains functional activity. It can make cytokine molecules that are inflammatory. It gains the capacity to actually kill a target cell that has the right target. It also turns on a differentiation program that lets the T-cell turn off and lets the immune system be regulated and controlled. So it doesn't just activate and spiral out of control and make us sick. And so in the last several years, receptors that turn on on T-cells that actually turn off the function of the T-cell have been identified. And so it's those negative regulatory receptors that are the targets for antibodies. So you're blocking the off switch on T-cells. You're letting them stay on, stay activated. And if they're responding to cancer, maybe they're going to have a more potent effect. And so there's a drug that blocks a protein called CTLA4, was approved for melanoma back in 2011, a drug called ipilimumab. And then what's gaining more attention recently are drugs that block a protein called PD1. PD1 is the receptor protein that's turned on on T-cells. And it's binding partner called PDL1 actually can be turned on on tumor cells. So right at the interface of your T-cell that you want to do its job, kill off tumor cells, is an immune defense protein that gets turned on within the tumor, PDL1. So you can try and interfere with that interaction on either side of the interaction. You can make an antibody that binds to the PD1 protein and stops it from seeing the PDL1, or you can make an antibody that binds the PDL1 and blocks it from seeing PD1. Both agents in both approaches are in clinical studies. So what is the biology of this pathway to how does it impact kidney cancer? This is an observation that goes back before there were drugs available to manipulate this pathway. In 2006, a report from Mayo Clinic that looked backwards at 300 kidney cancer tumors on their campus that have been removed surgically. And it stained, it looked for expression of what we now call PDL1. Back in 2006, it was called B7H1. Was that protein being expressed by kidney tumors? And it was in about a quarter of tumors and it was absent in the rest of tumors. And these are survival figures. So surviving means you're still alive, you're not being counted as something that's pulling you down towards the bottom axis. So the PDL1 expressing tumors had much worse cancer specific survival than the tumors that didn't make that protein. So supporting the idea if the tumor can defend itself from the immune system, that's a bad deal. And the tumor is more aggressive, it grows faster, and it's more morbid. This is a picture that sort of gives you the feel of what we think is happening inside of tumors. This is actually melanoma tumor, but the biology is thought to be common to many different types of cancer. What turns on PDL1 expression inside of a tumor we think is the immune system and T cells themselves. Seems I thought sort of counterintuitive at first. But so this is a field of melanoma tumor and within part of the tumor, there are a lot of immune cells or a lot of T cells and they're staying purple over here and they just drew a geographic area just to draw your attention. So all those purple spots are T cells inside of the melanoma tumor. And then they took another cut of the same tumor and they marked it for PDL1 protein. So this is on the immune cells and the tumor cells. And so the dark brown staining where there's the most PDL1 exactly overlaps where there's immune cells. And so leading to the hypothesis that it's the immune system activation and recognition of the tumor that is the driver to turn on this defense pathway on the tumor cells itself. So what's been termed adaptive resistance? T cells that have the capacity to see the tumor, they begin to infiltrate into the tumor. But what they do, their job, their inflammatory molecules that they make actually turns on the expression of PDL1 and helps to protect the tumor from this immune activity. And the tumor goes about its business keeps growing and is resistant to the immune response. So there are drugs as we said in developments that block the PDL1 axis. And the lead compound, a drug called Nivolumab or Optivo, is actually now commercially available. It's approved for treating melanomas and for treating some lung cancers. It has been studied in kidney cancer. So I just want to show you some of the data and some of the key points. The most advanced study that's been presented publicly so far, it was a phase two. So an intermediate size study that looked at a couple of different doses of the Nivolumab drug. I think about 50 patients per group. The response rates, and these were patients that had to have failed standard treatments to be eligible for the study, was 20 to 22% didn't seem to matter, the dose of the antibody all that much. You say, well, is that a good number? Is that a bad number? Comparison in the field. So secondary therapy of standard drugs. Everlimus or Exitinib that are commonly used in patients that stop responding to Su-10 or Votrin. Response rates of 1 to 9%. So in comparison, 20 looks pretty good. Progression-free survival was not that different, but the overall survival of patients in the study also looked quite provocative. So for the higher doses, 25 months response, survival for patients enrolled in the study, compared to standard drugs, again, it looked quite favorable. So certainly compelling enough that this drug has moved forward to a, I guess that slides further down, to a definitive phase three study that's been completed. The results aren't yet known, but the assumption is that will be criteria to ask for FDA approval coming down the line. This is what people commonly refer to as a spider plot. And I think it just gives a nice pictorial feel of what's happening to patients that receive these kinds of drugs. This is the quantitation here is tumor volume assessed by CT scans. So at time zero, everyone is their tumor size is adjusted to zero. And then every eight weeks, patients get scanned on the study. And if the tumor grew larger, you have a positive value. If the tumor shrunk and gets smaller, you have a negative value. So the patients that respond to this therapy, you can see very quickly within the first one or two scans, significant shrinkage in their overall amount of tumor in their body. In the very good responders, this goes on and on and on. We're out to about two years of follow up on this graph here. But for most patients, the line becomes flat and the amount of tumor is not zero. There's still tumor present. So tumor shrinkage and stability seems to be the most common favorable response. The rate of complete response seems quite low. Unfortunately, a lot of patients don't have a good effect. The tumor grows larger. And very quickly as your tumor grows, you stop the study. So that's why these lines don't go on and on. Those patients were judged to not be responding and ended the study. So this class of drugs have been very exciting. The last couple of years at the big ASCO cancer meeting have been really, I think, the top story in the oncology field. So when you apply these drugs, you see spontaneously shrinkage of tumor in many patients and durable lasting at least as long as one to two years, as long as patients have been followed on some of the early studies. There doesn't seem to be a huge difference between blocking either PD1 or PDL1. Both approaches seem to work fairly well. The side effects of these drugs, I didn't put up a lot of slides, but autoimmune phenomenon. You turn on the immune system in a more vigorous way than is normal. The side scatter is that you get an inflammation of normal organs. So skin symptoms, diarrhea, inflammation in the liver, thyroid, inflammation that stops the thyroid from working, those are the common side effects. And there is a commonality between the ipilimumab drug that was approved for melanoma and the PD1 drugs, very similar pattern of side effects for the two drugs. There's a question, the PDL1 expression on the tumor, should that be looked at? Should we be testing everybody for their tumor expression of PDL1? Is that going to guide us to the optimal use of these drugs? And I think I have a slide that comments on that a little bit down the road here. So this is a figure just showing you the schematic. I should have put these two slides back. How the study was designed for phase three comparison study of the nevolumab drug versus everlimus. So patients had to have clear cell tumors. It's common in the field. If you don't have a clear cell tumor, there's not a lot of research that speaks directly to that family of tumors. You had to have had a prior standard therapy, a VEGF pathway therapy that was no longer working. You couldn't have had more than three total treatments for your cancer and you couldn't have had something in the same drug family as everlimus. You couldn't have failed that class of drug. So comparison head to head, 50-50 split, the nevolumab drug versus everlimus. That study completed an enrollment over a year ago. We still haven't heard results when that's released publicly. Probably will be in advance of an FDA announcement, hopefully showing if the nevolumab is clearly better than everlimus. It's approved for use in patients. The approval and the prescribing language usually is very closely wedded to how the pivotal study was conducted. So the expectation is that FDA approval will be for kidney cancer patients that have failed standard therapy. So it'll become available as a secondary therapy for patients, not as their primary treatment. Best guess is FDA approval maybe as early as late 2015 or if not, hopefully sometime in the first part of 2016. In advance of the drug becoming available commercially, we're hoping to have access to what the company is calling a phase four clinical trial, which would be a study that would grant patients use of the drug, no randomization, no blinding, just use at the standard doses, but formerly the umbrella of a research study. And because it's considered investigational, the drug would be provided no cost. And that would be a stepping stone to the commercial availability. So we're hoping we may have that later in 2015. That would run up until whenever there's an announcement that the drug is available. So the drug gets approved for use as secondary therapy. What about bringing that class of drugs into the first line? So first therapy for kidney cancer patients. And that's being looked at, but not with nivolumab in isolation. It's being looked at in combination therapy. So both these drugs are owned by the same company. So this combination of ipilimumab and nivolumab has been explored in melanoma patients and is argued to look promising and looks better than either of the drugs given individually to melanoma. So that concept of the combination is being moved forward to other diseases, to lung cancer, and it's being actively exploring kidney cancer. So there was a pilot study, a dose-finding study, and the results have been talked about, a two-arm study where the doses of the two different antibodies were adjusted a little bit. So the numbers are the milligram per kilogram dose. And so the standard dose of the ipilimumab drug is three milligrams per kilogram when it's given by itself. So it's given a standard dose, a reduced dose, and then the flip of the other drug, the standard dose of nivolumab is three milligrams per kilogram and it was given at three or at one. So holding one dose steady and dropping the dose of the other drug and then reversing what you're doing to the two drugs and comparing to see if it makes the big difference, the dosing of the two drugs and what happens to patients. So this is a little summary and so this data was what guided the company to pick the winner, if you will, to carry forward to a much bigger study. So fairly small number of patients, but looking first at the response, so tumor shrinkage, fairly comparable between the two different arms, the two different doses, stable disease, a little bit different, slightly better favoring the higher dose of ipilimumab, but progression free survival and stable disease. So at 24 weeks, six months, your count heads, what percent of patients have not had their disease grow larger and progress, 64, 65% virtually identical. So I think by several of the metrics you'd say there really doesn't seem to be an important difference between the two different doses. If you come back and look at side effects, so adverse events get quantified as part of a research study at the five point scale, the higher the number the worse. Grade five toxicity is death, so that's not a good deal. You don't want any grade fives. Grade three, four is a bad side effect. We've made you sick, probably bad enough to delay the therapy or even provide some kind of remedy for the side effect. Grade one and two are mild things that happen that really aren't a big deal that don't interfere with your lifestyle, probably don't disrupt the treatment that you're receiving. So most people look at grade three and four as being concerning problems with treatments. So twice the rate of high grade side effects with the ipilimumab three milligram dose combo, discontinuation, what percent of patients stopped the therapy was too toxic. They couldn't tolerate it, 26% versus 10%. So really for the toxicity signal, the company went with the lower dose of ipilimumab, higher dose of demolababab as the combination. And that is carrying forward to a study. Again, I think I have a schematic, a phase three comparison study. That would be a definitive study that if it's clearly positive favoring the combination immunotherapy would get into the marketplace as approved for first line therapy for kidney cancer. So coming back to the idea of side effects, and this kind of has the same feel of IL-2 therapy, high toxicity drugs are a little bit discordant with our patients. If you go way back to my first few slides, kidney cancer effects is an older population, common is the other medical complications. If you have a treatment that's pretty obnoxious and makes people ill, that doesn't jive so well with an elderly population. So that's going to be treatments usually applied to a younger age range. That's the problem with IL-2. We're really picking out the uncommonly young and healthy patients and a lot of patients simply aren't eligible by their calendar age. I just want to show you the top line here. This is a table that pulls together the side effects profile for several of the drugs or the two different drugs we're talking about. And for two different patient populations, there's more data with melanoma than there is with kidney cancer for these compounds. And so the first half here are melanoma studies and the second half are kidney cancer. And so the high-grade side effect in total for different compounds. So ipilimumab, when we studied for melanoma, 23%, nivolumab, and a competitor, pembrolizumab. They're both PD1 antibodies. When they're used in isolation, this grade 3-4 side effect profile is not so bad. Five to 12% of patients getting fairly ill with these compounds. When you combine these and you do the combination for melanoma, it's pretty crazy. Two-thirds of patients get quite ill with the combination. The doses for melanoma are slightly different. The doses used for melanoma are the doses that were the worst side effects for kidney cancer, kidney they've gone with a slightly different dose combination. But this is not trivial. We're actively using combination therapy for melanoma patients and it's pretty unpleasant for many patients. When you look at the same drug nivolumab and the phase 2 experience for kidney cancer, the side effect profile is fairly comparable to what you see in melanoma. And then when you mix the two drugs in a slightly different dosing ratio, that side effect risk goes up, but hopefully not as bad as it is for melanoma. So I think it remains to be seen how unpleasant therapy is. And if that's a big part of administering treatment, even if it's better if you will for patients than other drugs like Sunitinib, is it going to be better for everyone or side effects going to be a real problem? So this combination nivolumab and ipilimumab is coming forward in a comparison study. The comparator is Sutent or Sunitinib. It's an active study that's ongoing. We have it running at our center and it's a nationwide, actually an international study, I believe. And then coming right behind it is a similar approach, different drugs owned by a different company. This NPDL3280A is a PDL1 antibody owned by Genitech and that's going to be studied in combination with Bevacizumab. That's a different drug class. It's not an immunotherapy. It's an anti-vegetary antibody. So you're mixing an immunotherapy with a so-called targeted or anti-vascular agent and that's going to be studied again head to head versus Sutent as the comparator. So two studies that'll be running more or less in parallel that will look to get either PDL1 or PDL1 antibodies into kidney cancer therapy as primary therapy for patients. Just a little figure here and I think it's interesting to think about it's a little bit off target but these drugs are blockbuster drugs by any metric you care to use in the oncology world and so the discussion and the hype of their activity but the anxiety of their cost is really a hot topic. This is somebody trying to estimate what they see to be the likely financial return for the companies that own these drugs in the next few years as they enter the marketplace for a variety of different diagnoses and this is estimating not just the United States but also Western Europe and Japan. The purple here at the bottom is the ipilimumab drug which is approved for treating melanoma. So it's already in the marketplace and they're saying that total revenue generated by this drug is about a billion dollars. So a thousand millions, a billion and then predicting that nivolumab and pembrolizumab the two lead compounds that are PD1 antibodies are going to be jackpots for the companies that own these drugs and predicting you know three to four billion dollars total revenue for these drugs. So that's it's really it's a massive amount of money and these numbers may actually be an underestimate because the range of disease that these drugs are going to work for keeps expanding every time there's a national meeting there's new diseases where these drugs clearly work and so their scope of use is really going to be massive. Just a comment on the idea about using a biomarker for these drugs it's been looked at through all of the clinical studies but it's never been held as a requirement to participate in the studies. So all the studies have allowed patients to participate regardless of whether the tumor makes the PD1 protein. It's pretty clear when you look backwards on studies that if your tumor makes PD1 you have a higher chance of responding to these drugs but not having PD1 isn't completely negative for activity. Some research labs have looked at a variety of inflammatory and immune markers and PD1 does seem to hold up pretty well as a predictor for response but because you see activity in tumors that don't have this marker because only a minority of patients tumors have the marker you actually see more total responses in the two-thirds of patients that don't make the PD1 protein and when you start combining these drugs with other agents you really lose the association with PD1. So this just shows you a comparison. When nivolumab is given by itself so anti-PD1 antibody alone and you look at tumor staining for PD1 or no PD1 response rate is what two and a half fold better in the PD1 positive tumors but when you mix the nivolumab with ipilimumab the numbers here are quite small but you can see most the tumors were PD1 negative but the response rate was very good 56%. So you're completely skewed away from this marker as being your guide to response when you combine the therapies and because the combination treatments are moving forward as initial primary therapy for tumors I don't think it's going to be commonplace that we'll be using the PD1 marker for patients receiving these therapies. And the last comments you know the discussion about complete response comes up in our clinic most often when we're seeing patients and we're counseling about IL-2. You can't give IL-2 indefinitely. It patients become sensitized to the drug side effects so it's a finite period of therapy and either win the game or you don't. And as I showed complete responses in upwards of five to eight percent of patients and so we definitely see it we have many patients in our clinical practice that are living complete response post IL-2 you don't give ongoing continuous therapy it's an un-maintained ongoing response when it happens. What about these other drugs? The early going with the nevolumab drug rare complete response listed in the early studies about a one or two percent complete response rate even in a combination study very small numbers of patients but again a two percent complete response rate maybe that'll change as you watch those patients over a longer period of time maybe it'll take a while to see shrinkage to the point of complete loss of tumor but in the early going it's not obvious these drugs are stepping in to replace IL-2 therapy because they can achieve a six or eight or 10 percent complete response rate. And just to include targeted agents it does happen on occasion that somebody truly loses all signs of their cancer it's uncommon but when you look at large collections of patients getting targeted agents about a one or two percent rate of complete response and just to throw out there if you if you think that's an important end point and you want to try and extend it augment that why wouldn't you try and start with the drug that gains you five to eight percent complete response and then add something to it and hope that things get better we're hoping to do just that we are moving forward with a pilot study on our campus that would be IL-2 and then you add in the PD-1 antibody on top of IL-2 so we hope that we start with a chance of seeing a complete response and that might get higher yet with a combination. So last slide just to kind of summarize graphically what's happening what's likely to change in the field the next months to years again we are a referral site for high-dose IL-2 so green means go it's actively available and we have regular IL-2 business this study is ongoing nivolumab plus ipilimumab versus sutent third line randomized study is open and running it'll be a couple years before that data is collected and mature to know if that's going to change standard practice but it's the study is ongoing right now and then the comparison study we're also going to have available on our campus PD-L1 plus bevacizumab so again looking to get the immune checkpoint drugs into the frontline treatment for patients that have already had prior therapy the nivolumab drug is probably going to get FDA approved at some point next year or so and we hope to have early access with the phase four mechanism and then a study that we hope to open that we think is provocative combining IL-2 with the checkpoint drug so that's immunotherapy in a nutshell there are a lot of other features of it and trying to limit it to a 20-something minute talk is challenging but hopefully we'll have some good questions