 Thanks Chris, and I'd like to thank the organizers for inviting me and you all for being here to hear my talk It's a real honor to be here, and I just want to emphasize like Chris said we're now moving back to the metastatic space We're talking about frontline therapy some of the other speakers and subsequent talks. We'll talk about second-line therapy I'm emphasizing clear cell RCC some of the later speakers will talk about non clear cell RCC And I'm emphasizing what is now FDA approved and available here on September 22nd 2018 So there's as we all know there are a lot of exciting therapies and trials and subsequent speakers will focus on those These are my disclosures And I want to ground our talk by just starting to show you the NCCN guidelines And the NCCN guidelines have really evolved over the past several years as I've been involved with them To this is the most recent version actually that's hot off the press in the last couple of weeks to to emphasize more Prognostic risk factors and this is something that dr. Singer and other Speakers have focused a little bit on But if you start at the top here on the green arrow You can see that again. We're talking about the relapsed or metastatic first-line clear cell patient That the patient with favorable risk They list two options Pazopinib and Sunitinib they list those both as category one And I want to emphasize again that the NCCN guidelines have started putting things like category one Preferred I'm listing below there what what constitutes category one essentially you can think of category one as a phase three trial Or or even multiple phase three trials category two Starts to be things like phase two trials or instances where there's you know inconsistent data And then the distinction between a and b is really if there's less Less consistent data for example as dr. Haas talked about in the adjuvant space where you have one positive trial and three negative trials There's you know a little bit of a discrepancy So now if you move from the preferred regimens column to the right you see there are also other recommended regimens Ipilimumab nevolumab could be reasonable for that favorable risk patient Cabo-Xantinib listed as category 2b and then there are also other options as well to the right of that such as active surveillance If you go down one notch to the poor intermediate risk group They list essentially two options that are preferred regimens either Ipilimumab nevolumab as category one or Cabo-Xantinib As category 2a then there are also other other options as well. So Now you might just think your oncologist could look at this grid and just pick off the grid And if it were that easy I could just drop the mic and walk off the stage But as we all know you know for the individual patient sitting in front of us as clinicians Everyone is different. Everyone has different preferences and so on different comorbidities And so I want to present to you a little bit more of a nuanced view So I'm going to answer this question. What is the best front line therapy for metastatic RCC that's clear cell component in 2018 I'm going to say it depends and I have two daughters. They're four and seven so I have become an aficionado of children's books and The best kind of metaphor for it depends that I've seen recently Comes from this book called duck rabbit and so you see this figure or picture at the bottom If you look at it from one angle looks like a duck from the other angle looks like a rabbit and I would submit to you It's a little bit that way when choosing the front line therapy for the patient sitting in in front of you as a clinician And that you know everybody's coming at this from a different angle Some people are going to see the duck some people are going to see the rabbit So there's really no one right answer across the board So I'm showing you though What are the things that go through my mind and these are the top kind of three things There are other factors of course that go into this tough decision, but I think about first I'm assuming that they've seen urologist like dr. Margulis Dr. Singer they we've thought about things like cytoreductrinofractomy things, you know other local therapies dr. Speese thought about metastasectomy We're past that part, but I think to myself does this patient even need systemic therapy and I'll tell you a little bit more about that I Also think about prognostic factors as outlined in those NCCN guidelines But I also think about the patient's disease burden in terms of their pace of disease in terms of their volume of disease And in terms of whether they're having symptoms from their disease. I also take into account patient goals You know as a young oncologist I thought every patient's goal would be to cure their cancer no matter what but if you if you talk to patients and the More and more I talked to patients everyone's goals are a little bit Nuanced and you don't know what they are unless you ask so it's important to do that I'll talk a little bit about that Then there are also some kind of technicalities which are contraindications It may be that a certain therapy is just not safe or or a patient is just not fit for a certain therapy So going and touching on this first question does the patient even need systemic therapy? And there's emerging evidence that not every patient who is diagnosed with metastatic clear-cell RCC needs at least immediate Systemic therapy so on the left panel is is showing you the first prospective series. This is dr. Rennie's group who showed that Patients who are prospectively enrolled and who got active surveillance did very well This curve is showing you the proportion of patients over time And how they kind of decline and you can see though that they're a sizable Proportion of patients 24 months out two years out three years out and so on Our series is shown on the right. This is from the prospective mark observational study Dr. Rennie's number of patients is about 50 We had around 170 patients who are again diagnosed with metastatic disease But in whom systemic therapy was deferred and this curve is showing you the fraction of patients on that deferred systemic therapy So meaning they had not gotten systemic therapy Over time and you can see that as the data cut off About two-thirds of the patients who initially were selected for that deferred approach Were still not receiving systemic therapy and furthermore that was about a quarter of all of the patients Which are 500 patients in the overall observational study so This is again now listed in the ncc and guidelines as useful under certain circumstances So what about prognostic factors? This has been covered by Dr. Singer and others But I just want to reiterate this just to make sure we're on the same page RCC is a heterogeneous tumor as this panel on the left shown shows It's heterogeneous from patient to patient Within patients tumors may be heterogeneous and even within specific tumors There may be heterogeneous components and of course RCC is heterogeneous at a genetic level But on the right we're really focusing on that patient to patient variability And this is this this curve on the right these curves on the right are showing the IMDC or Sometimes known as the hang prognostic model and as you can see According to whether the patient has a favorable intermediate and poor risk There are different proportions of patients alive at 24 months and there are basically six Factors that we take into account two clinical factors for lab factors The two clinical factors are the time from when the patient was diagnosed With RCC whether it's metastatic or not to when the patient needs systemic therapy for metastatic disease According to whether that's less than or greater than one year the patients Karnofsky for format status, which dr Singer covered whether that's less than 80 or 80 or greater And then the laboratory factors being a high corrected calcium a low hemoglobin a high Nutri-fil count or a high platelet count all of those being risk factors Essentially you add them up and you can you can dichotomize patients and and the most important Categorizations are really is the patient favorable risk or is the patient intermediate or poor risk? So moving on to disease burden. This is this is something that you know, I've combed the literature It's not that well described They did attempt to describe disease burden in that Rini series by looking at the sum of Lesions so the longest you know diameter of all of the lesions and so kind of categorizing patients on on that basis But I think in reality Oncologists this is more of a gestalt you kind of put your finger up in the air And you you look at you know scans to see how fast the patient's disease is progressing You look at things like you know, is there you know, is there one lesion or a couple of lesions? Is it only in one organ? Is it in multiple organ sites? And you kind of take all of this into account? I think another important thing to take into account is is the patient symptomatic from RCC and this cartoon here shows You know different symptoms that a patient might experience from RCC So the next and I think one of the most important things is talking about the patient's goals So these are some possible goals so thinking about cure which would you know? We would describe as a complete response that's durable thinking about living longer that would be improved survival Thinking about living better that would be having a good quality of life for an improvement in the quality of life So I just put one of the questions that I asked patients so and I think this can kind of flesh a lot of things out What are you willing to risk now to achieve one or a combination of these goals in the future? And you know, I think I always come in with a certain bias based on what I've read in the patient's chart And I'm always surprised what what individual patients say so I think it's very important to actually ask the question The third I mentioned it is just contraindications and I'm giving you a few examples here You know, is there a contraindication to immuno oncology theories therapy specifically immune checkpoint inhibitors? So examples would be that does the patient have an autoimmune disease and what is that autoimmune disease? Not all autoimmune diseases are created equal Conversely, is there a contraindication at TKI therapy like Sunet nib Pazopinib or Kebazantinib? Maybe the patient has a decreased heart function Maybe the patient has uncontrolled high blood pressure Possibly there, you know, the patient is at risk for bleeding Maybe the patient is on one of the new blood thinners for atrial fibrillation Is the patient at risk for poor wound healing? Maybe they've undergone a cytoreductin nephrectomy recently or a metasysectomy and then thinking about How serious are these contraindications there are certain things that definitely were you but they might not be a Deal breaker those would be relative contraindications There are things that are absolute contraindications that you know, we definitely cannot go forward because it's just not safe So before I get into the specific trials, and I'm going to cover two I just want to review how the different therapies work and other speakers have have discussed this But I just want to give you a little bit of my take here So on the left this is showing you how the the VEGF receptor TKI's work and again I'm going to focus on Sunitinib, Pazopinib and Cabo-Zantinib, but it's showing you if I can get my pointer to work It's showing you right here on the left as has been mentioned earlier in this meeting that one of the seminal kind of problems with clear cell RCC is an inactivated or mutated Von Hippel-Lindau tumor suppressor and that leads to all these downstream effects that result in increased angiogenesis These targeted therapies or TKI's as we call them block those receptor kinases and essentially block the consequences of that Another way to think about this is the gas versus brake pedal analogy, which I really like so thinking about the I can get my pointer to work here Thinking about what's going on in clear cell RCC is a little bit like this bottom right panel where the brakes are out because the tumor Suppressor is inactivated and essentially we're blocking the consequences of that with these targeted therapies I Also, I'm going to talk about epilumimab and nevolumab which are two Immuno-oncology agents you may know epilumimab by the trade name Yervoi or nevolumab as Dr. Haas said by the trade name Optivo, but I'm going to refer to them in this talk as ipinevo in combination So what what this slide is showing you here on the left is how your immune system? Recognizes and fights cancer and this this kind of a wheel is called the cancer immunity cycle And so what it's showing you is that your immune system? Reaction of cancer is really taking place both over space and time so as you start here with number one As cancer cells die or are killed they're releasing cancer cancer antigens that is into the bloodstream That's causing those cancer cancer antigens to be presented to the immune system and for T cells to be activated One analogy you can think about this is is that the this occurs in the lymph node Which is like the police station where the the police which are the T cells live Those T cells then have to traffic through the vasculature to the tumor You can think about the the the policeman is getting into their cars and driving to the scene of the crime And then the policeman then arresting or or or killing the tumor So specifically then what ipilimumab on the left of the right most panel here does and what nevolumab does is that? Ipilimumab creates more cars coming from the police station So more police get to the scene of the crime and then the volumab actually Activates the policemen at the scene of the crime so maybe the maybe the police are kind of letting a lot of crimes happen under their nose But they suddenly wake up and and see what's going on so This is an analogy I like So to show you the just to show you the historical context here Sunit nib which is a veggie for scepter TKI again It was really the standard of care for first-line clear-cell RCC for over a decade So you see here since about 2006 a trial called compares showed that Pazopinib another veggie for scepter TKI was not inferior to Sunit nib and may possibly have better Quality of life and other toxicity profile compared with it. So both of these then became the standard of care now around about in 2017 There started to be a change in this paradigm when first Cabo Zantinib was approved And then that Ipilimumab and Nevolumab were approved And so I'm going to show you the two trials that led to the approval And I want to point out some key features that I think can help us make a decision for for an individual patient So first I will talk about the check checkmate 214 study design This was the trial of Ipilimumab and Nevolumab compared to Sunit nib again. This was first-line Metastatic clear-cell RCC Patients were treated until they had progression or unacceptable toxicity and of course scans were done to monitor their disease They were also followed for survival This study had three co-primary endpoints, and I'm going to show you the first one here This is the overall response rate in the intermediate and poor risk group only now Just as a side note they did enroll favorable risk patients They kept that at about 25% of the study and I've put in boxes here What I think are kind of the key aspects of this overall response rate So first of all the overall response rate with the ipinevo immunotherapy combo is higher than with Sunit nib That was highly statistically Significant and importantly we saw something that we had rarely seen in RCC Which was that a reasonable proportion of patients 9% had complete responses compared to only 1% with Sunit nib In terms of the duration of response if you look up here in the right Upper quadrant here the the duration of response So so that's a measure again of how durable the response is that was not reached But the lower end of the 95% confidence interval was 21.8 months Whereas with Sunit nib the duration of response was about a year and a half So patients in both groups did have ongoing response And so it'll be interesting to see what this shows in the future in terms of how how long the duration of responses are And specifically in that that complete response group some of that data will be actually presented at ESMO I think the last thing I would want to leave you with is to think about the time to response And this is shown pretty small here up in the upper left Corner, but that's important when the patient sitting in front of me is Experiencing symptoms or has a really high burden of disease or fast pace of disease We want to think about how quick you know is this therapy going to work now This is colored by how frequently the scans were done But at least in this trial it was about 2.8 months So what about the other primary endpoints? This is the second one progression free survival This was longer with the immunotherapy combination versus Sunit nib the previous standard of care So 11.6 versus 8.4 months Also the overall survival was better With the Epinebo combo compared with Sunit nib this was highly statistically significant So I would be remiss if I didn't show you a little bit about adverse events because I think these do play into our Decision making at least a little bit what's difficult though is you know for the patient sitting in front of me They may have many of these or none of these but just to show you this is a busy slide So just to point out a few key things In terms of the grade 3 to 5 adverse events with the epinebo combo and again as dr. Haas mentioned these are the these are the serious events that are requiring intensive treatment Hospitalization etc. The epinebo had fewer of those 46 percent versus 63 percent If we look at the the classic kind of Sunit nib and TKI side effects Such as fatigue those tended to be less with the epinebo combo things like Diarrhea tended to be less and then some of the other TKI side effects, which I'll cover in subsequent slides Now importantly in terms of what we think of our Immune mediated adverse events so the immune system being revved up and attacking the the patient's normal tissue If you look at any grade Adverse events these range from you know one to about 19 percent and Reassuringly the grade three to four adverse events were were not that high at about six percent You know so you can think of one in 20 patients or a little more having Having a one of these serious adverse events now that said 60% of the patients on the trial though on the epinebo arm did require steroids for an adverse events And I'm for an adverse event that is and I'm not showing you this here But there was a there was a small number of treatment related deaths in the epilimum ab Nevolumab arm about seven deaths compared to four deaths with the Sunit nib arm so small numbers but Important to note that that you know that is a risk So what about quality of life? I mentioned quality of life And I think this is this is really interesting to me because I think this is really a way of Summarizing how the adverse of that events may affect a given patient so kind of integrating that fatigue diarrhea Whatever else they're experiencing and I think you know So not only did ipilimum ab and evolumab beat Sunit nib in terms of some of these important cancer control endpoints It also had a better quality of life So what this is showing you over the over the weeks that the patient with patients were on trial up to about two years The ipinebo immunotherapy combo is on the top here And and kind of increasing over time whereas the Sunit nib quality of life Declined initially and then and then improved somewhat but still remain separated from the immunotherapy combo So what about the favorable risk patients all of the the data that I was showing you except for the quality of life But the tumor control endpoints were really in that group of intermediate and porous patients Which was the primary analysis cohort well the favorable risk patients actually had a little bit different outcome And this was somewhat surprising. I think to people So in terms of the overall survival The overall survival was actually better for Sunit nib So the way to think about this hazard ratio is that the overall survival may have been about 45 percent or 50 percent worse For the ipinebo group now this I would caution you as I note is based on a small number of events And when you base these analyses on a small number of events, they're kind of unstable and may change over time So there were 250 patients, but only 37 deaths But you know interesting I think If you looked at the proportions of patients who are alive at 12 and 18 months It also favored Sunit nib the overall response rate favored Sunit nib and the progression free survival Favored Sunit nib now one outlier though was the complete response rate It's the complete response rate was higher with ipinebo So I think a way to think about this is that you know You may be less likely to respond with ipinebo, but if you do get a response You may be more likely to have a complete response if if that is the patient's goal You might take that into into consideration in your decision-making The other thing to think about with these favorable risk patients is that Favorable risk patients may have 12 weeks 24 weeks to see what happens with ipinebo If they have a small burden of disease or a slowly progressing burden of disease And things get a little bit worse over 12 or 24 months. It may not be the end of the world So it may be worth taking that risk So with the checkmate 214 study that I've described. I want to kind of compare and contrast that with the Cabo Sun study This is the second study. I'm going to talk about this was a randomized phase 2 trial of Cabo Zantnib versus Sunit nib. This was a cooperative group trial again looking at Clear cell component patients who'd had no prior systemic therapy and focusing Exclusively on that intermediate and porous group. This is only a hundred and fifty patients as opposed to the more than thousand on the last trial Patients were randomized one-to-one and followed with with scans et cetera so Cabo Zantnib did beat Sunit nib in terms of progression free survival. This is shown here. This is the investigator assessed version It was also confirmed with independent radiographic review There were more objective responses with Cabo Zantnib than with Sunit nib. The response rates were about 46 versus 18 percent But I'm highlighting here that there were still only about 1% of patients that had that those confirmed CRs on the bottom is showing you the the response waterfall plots, but I think One thing that's important to think about is the time to response and I've highlighted that here again caveat that this is really Colored by how frequently you do the scans. We're not doing the scans every day So we can't pinpoint with accuracy when the patient's responses occur But at least in the meteor trial Which was a second line trial responses with Cabo Zantnib occurred fairly early in this This does correlate with my my clinical response I'm showing my clinical experience and when I talk to other clinicians it does as well So if we need a response fast, I tend to lean more towards Cabo Zantnib depending on the other factors Overall survival again, the study was small not powered for this but there was at least a trend numerically towards improved survival with Cabo Zantnib with a With the number of deaths you see there What about adverse events and quality of life well This is showing you in the left panel that adverse events with Cabo Zantnib versus Sunitnib and these have the kind of classic VEGF receptor TKI profile of things like fatigue high blood pressure Diarrhea increases in some liver function tests loss of appetite hand-foot syndrome and Loss of taste there were some Variations, but they're they're fairly comparable. I think you can you can nitpick it a little bit, but keeping in mind It's a small trial There was an analysis presented at ASCO that showed what's called a Q twist analysis And this is a way of looking at quality adjusted time without symptoms or toxicity essentially it integrates both length and quality of life and it did show that that there may be You know better Better control of disease symptoms over time with Cabo Zantnib. There were some limitations to this though So to conclude I just want to go back to this This analogy here of the duck versus the rabbit and so I think you know for every patient That's sitting in front of me. It's going to be a little bit of a different A little bit of a different answer that is but I have listed some of the factors that go through my mind And I put a little checkbox by the one that you know Maybe may tend to be the more of the right answer. So for that favorable risk patient I might think more strongly about Sunitinib or Pesopinib. I don't think Cabo Cabo Zantnib is wrong If you Nevo could be considered in select patients for those those patients who have a high burden of disease fast-pace of disease or a Symptomatic I'm really thinking more about Cabo Zantnib Doesn't mean it's going to be the right answer and everybody with patients who have a goal of cure or what we would think of as a Complete response that's durable With a good quality of life. I'm thinking more about the Ipillum amabini volumab immunotherapy combo Goal to live longer, you know, it depends but you know a lot of these a lot of these agents have shown that it depends again On the patient's risk probably if the patient isn't an epineevo candidate I think I'm thinking more about one of the one of the TKI's Cabo Zantnib or Sunitinib Pesopinib and that the patient Isn't a TKI candidate. It's easy. You know, I think epineevo is is probably the right answer So with that I will close. Thanks so much for your attention and I'm happy to answer any questions