 شكرا لك دكتورود للتساعدة شكرا all for coming It's great to see familiar faces, friends among you here And to come to MD Anderson on a beautiful spring Weekend of Easter, this shows your motivation And your advocacy for this field So this is my disclosure slide So this is a timeline of the several of the therapies we have now For Riyan Sakkar Sinoma We have 11 therapies approved by the FDA And are available in the clinic Starting with high dose interleuk in 2 In 1992 And over the past decade or so We've had 10 therapies come from December 2005 With the first target agent Sourafnib And then a month later Sunitnib Which you heard about from Dr. Yonash And then Tamsir Alamisi Which you heard about him Also the mTOR inhibitor in 2007 And while several of these agents Can be used in the first line Or second line or beyond Really what I show here in this Is the 5 drugs that are used in the second line And beyond Meaning third line, fourth line, etc Everolimus, the mTOR inhibitor The brand is called Affinitor And Aksitinib Which was approved in 2012 And that's called Enlighta And that's another VEGF TKI A drug that starts the blood vessels It starts the tumor by blocking the blood vessels And then 3 therapies came In the past 18 months or so And that's the immune checkpoint inhibitor Nevolumab or Aptivo in November 2015 And then in 2016 In April, Cabosantinib, Cabometix And then this doublet Is a pair here of Linvatinib Another tyrosine kinase inhibitor A drug that targets the blood vessels Plus other things And then again we see here Everolimus being paired in combination So since 2015 The RCC landscape for second line And beyond has rapidly changed And here we have these therapies And I'll be going through Each one of these trials That led to the approval of these therapies Nevolumab I'll start with Nevolumab first And the study that brought it Is checkmate 025 Then I'll show data from the Meteor trial that brought in Cabosantinib And then a study called 205 that brought in Linvatinib plus Everolimus So it's important to note That all those 3 trials Were conducted in patients With the most common type Of kidney cancer The clear cell Our conventional type Riansoccasinoma And it's also important to note That the majority of patients Treated on these trials Had good or intermediate Trisk disease And I would like to thank Dr. Yonash for the grocery He provided So I don't have to go through this Again the definitions Of what good, intermediate And poor risk means And coupling mild curves Progressive free survival And overall survival etc So first starting with Nevolumab This is the design Of the checkmate 025 Study So patients with clear cell Again the most common type Of Riansoccasinoma Were recruited to the study After they had already Up to 3 prior therapies Before they go on to this Trial And those patients Had to have 1 or 2 VEGFR TKI Meaning drugs That are approved In the first line Something such as Sinitinib or Prisopinib That you heard from Dr. Yonash They could have received Also interleukin 2 So they could have received Up to 3 prior therapies Including interleukin 2 They could have received 1 or 2 of these Front line therapies The oral agents That are the approved Sinitinib or Prisopinib And then once they They are screened And they are found To be eligible They qualify For enrollment on the trial They get randomized Meaning half the patients It's like passing a coin Half the patients Get A standard of care For second line At that time Of the time Of the enrollment On the trial And the other half Of the patients The other group Will receive this Immune checkpoint inhibitor Nevolumab At the dose shown there The primary endpoint Meaning the first Goal And the goal of that trial And the primary endpoint Is overall survival So the interest Is to show Whether patients Who are fairly Grouped Or randomized To receive This drug Or that drug With one of the Two therapies The two arms Of the trial Show a survival Advantage Over the other one So here obviously Here the interest was To see if Nevolumab Treated patients With the Immune checkpoint inhibitor That is Will have a better Survival Than Patients who Received a standard Of care agent The mTorin inhibitor Everolimus And here You heard about In my curves Where it means So this is for The overall survival So that's the primary endpoint So that means That from the Day they receive The first dose Whether the oral agent Represented in yellow here Or the IV Immune checkpoint inhibitor Nevolumab Or abdivo Here in red So the clock Starts ticking From the first dose That you see And patients are followed And You know Those who are survived Are censored Meaning They do not have The event They didn't die From the cancer And so And when The substations You know Plot these curves And that's What's called The Kaplan-Meier curves And if you can Run a Like here The arrow Or if you have A laser You can Pointer You can use If you can Run that Between the lines Then it looks like There is really The curves And there is One The top line Patients Represented by The top curve Have a better survival And indeed Patients who were Treated with Nevolumab Had a better survival Than patients Who were Treated with Everolimus And the median And you know Median means You know I think In layman term The closest You can say It's average Basically The median Was 26 Months So how you translate That into Hazard ratio The hazard ratio Was 0.73 Which means That there was a reduction Of 27% Mortality 27% Reduction of mortality In patients Who received Nevolumab And that was Statistically significant So this did not Happen Due to You know Just random It is because Of the therapy It didn't just A Happaz A random Occurrence Now As is The case With many of these Immune therapies That we have In the clinic Including vaccines For example A vaccine That's FDA For prostate cancer patients Including To look into And including These immune checkpoint Inhibitors While Survival Has been shown To be superior To these Immune therapies In this case here The Nevolumab We simply Don't really Understand Exactly why We think We understand why But the Survival Is better But When you look At scans And you look At time From Those one First those of therapy Or In the infusion Until There is progression Or death There is really No Such a significant Difference Between the two arms So somehow The immune therapy Is helping These patients Live longer Even if The Kaplan Markers For progression-free Survival Is not significantly Different Between the two arms And then There was a question Can we predict Which patients Are benefited Are surviving better Have a better chance Than Of being treated With this agent Because Every treatment Is a gift To our patients May have Some side effects So you won't Try to Give a treatment To the patients That are most Likely To benefit From therapy So this is One of those things That has Been looked at This actually Is a good Biomarker For lung cancer Who are Patients with Lung cancer Who are treated With a similar Immune Checkpoint Inhibitor Called 50% So meaning That those cells Have 50% Or more PDL1 Expression And the tumor cells Then that predicts For benefit With this agent However In Riasocasinoma At least In this trial This did not Been out Meaning We could not Really predict Whether patients Whose tumors Had an expression Here It's 1% Above Or less It didn't matter It's Regardless Of this PDL1 Expression On the On the tumor cells Responded To And benefited From Nebulumab Looking now On the Response rate About a Quarter of the Patients Responded To Nebulumab Less than 5% Responded To everolumines And here Are Here is The time It took from The Response For Both Agents Summary Of the Safety What we Refer to As Adverse Events Or side effects Of the therapy Nebulumab Treated Patients Had fewer Any grade Adverse Events Compared To Everolumines Which Everolumines Is By the way Adverse Events And Grade 3 4 Is You know Refer to The Severity Of The Adverse Events Compared To 37 So About Twice More Patients Had Severe Adverse Events That Led Patients From Protocol You have 8 Here 8% Versus 13% So More Patients Had to Come Off Protocol Of this Checkman 025 Who Are Treated With Everolumines So now With This Second Agent And Some Of In a Destruct That We're talking about Cabosantinib Or Cabometics How it works So As a result And again Here The focus Is Clear cell The most common Type Of As a result Of VHL Inactivation What happens As a result Of Mutation And The Avoid things That We call The Ligands For these Receptors So this Direct Cabosantinib Blocks These Three Pathways These Three Significant Pathways And We Know That VAGF Helps Tumors Draw Blood And Gasex Help The Tumor Progress Through Growth Invasion Metastasis And Helps Also Resistance Through VAGFR Inhibition So This is What This Direct Does And This Is The study That Led To Its Approval So This Is And Then They Were Randomized To Receive Either This Agent Which Was At That Time Investigational Versus Evernimus Again You See Evernimus Being The Comparator Or The The The Arm That Is Basically Standard Of Care There Was No Cross Over Because Not Only when it comes to progression free survival, the patient treated with Khab 2010 had a better progression free survival than patient treated with Abarolimus, it was 7.4 months versus 3.9 months, when you look at response rate, 17% versus 3%. When you look at now the overall survival, same thing, patient treated with Khab 2010 had a better survival than patient treated with Abarolimus, and here is the median for survival for both, 21 months versus 16 months. وكان ذلك مختلفة التي كانت تقلق بها وقادرها إلى المدينة من هذا المجال. عندما تظن now about exposure and those reductions هذا ليس مجدداً لتأكد من المشاهدين لكن المشاهدين حصلوا على تحديد تحديد وقط 9% came off because of adverse events and 10% for the evrolimus ولكن there was a higher rate of dose reduction in patient treated with Cabosentinib 60% versus 25%. And the average dose that patients received of Cabosentinib was 44 milligram from the starting dose of 60 milligram. And most patients on every MS received as close to the standard dose as can be. Now, this is the third trial that led to the approval of this combination. And here is this is the important thing to bring to your attention here is this is a phase 2 trial. It's not a phase 3, so it's not as large as the phase 3 trial. And it doesn't have a hypothesis testing. So basically the level of evidence that's inferred from this is not considered as robust as phase 3. However, the results were really impressive. So again, this is a second line study. Patients received one prior therapy, not more than one prior VEGF RTKR such as in internet or PASOPRI. And they were randomized to receive one of those three therapies. This combination or this agent by itself in VATINIB or every MS. Again, you see every MS being the comparator. And then patients were followed by scans. And they were stratified before they were randomized by the level of hemoglobin and the calcium. And here, when you look at the progression-free survival, again, coupling markers, you see the patients who were treated with a combination had a better progression-free survival. The median was around 14 months compared to half that for patients who received, you know, the VATINIB single agent. That's the curve here represents the VATINIB single agent. And you see here, patients received every MS had a lower, a shorter median progression-free survival of 5.5 months. And when you look at the same data, coupling markers curves for progression-free survival, but now not the physicians themselves doing the assessment of the scans, but an independent neutral objective blind radiologist to really see if this will be confirmed. You see basically the same separation. Around 12 months, median progression-free survival for the combination versus 9 months with the single agent in VATINIB versus 5.6 months. So this is another way of looking at this. And when the FDA saw the data, they were impressed even though this was a smaller study, phase 2, not phase 3, yet they decided to approve this therapy. And when you look at the survival, again, survival here was numerically better for the combination than for these other agents. So again, this is a summary of the efficacy, higher longer progression-free survival, higher response rate by the assessment of the physicians who treated those patients. This was 43%. And this is the median survival. When you look at, again, how long and if you had duration, dose reduction, this is a combination that's not easy to take. 71% of the patients had to reduce the dose. 62 had to reduce the dose for this agent by itself. The combination almost three quarters of the patient. And around a quarter of the patients had to come off study because of toxicity, because of the side effects. So this is a therapy that's toxic, although it is effective. And again, it is challenging to take two different drugs in combination at the same time. So here is, so you saw that three trials showed an experimental agent or an investigation of therapy being better, producing better results than Evrolimus, the standard of care, the comparator. And here are the studies side by side. And I put Acetanib because that's the trial, the drug that was approved in 2012. And none of these three trials compared their agent with Acetanib. So Acetanib is still there as an option to meet for our patients with Clear Sarion Sacrassinoma. So now, this is for you and this is for us physicians at academic centers, as well as in the community. And this is important also for government officials or insurance people to look at what are the considerations that we take into account that we factor when we select a second line therapy. I mean, when we have multiple choices, we have not just one we could use, but actually several different therapies we can choose in the second line or third line. How do we choose? What are the things we look at? This is what I believe are the most important and I start with the top which is I believe the most important for me. And that's basically efficacy. As a patient as well as a physician, I want to make sure that the first thing I want to give to a patient of mine is this drug going to prolong their life? Is this first going to cure them? I mean, ultimately that's the ultimate goal. But if we cannot, if we don't have a curative therapy for every patient, can this drug prolong which is of those drugs prolong survival? The second is the study that brought this drug didn't have the highest level of evidence. Was that a phase three trial? A large number of phase treated? Thirdly, tolerability. Can patients tolerate this? And then cost is important. And then there is the convenience and oral agent versus intravenous. And then there are some important things that we should not forget and that's basically did the patients who are now looking at taking a second line or third line drug, what side effects have they had from their prior therapy? Are they having high blood pressure? Are they taking three, four blood pressure medications? Do they have diabetes? Is it affecting their kidney function? Do they have some immune problems such as, you know, do they have mysthenia gravis? Do they have past history of Guillain-Barre? Because those are things that can basically force you to go one line to one therapy over another or to prefer to use one therapy over another because of those things. So in an environment, in a time where value-based care is talked about, this is what I believe how these several therapies that I mentioned stack up. Everleam is by itself except for select few patients. I think you show data for clear cell at least. We're not talking about cremaphob. We're not talking about papillary. We're not talking about these other rare tumors. We're talking about the clear cell, the most common type of clear cell. So there is enough now studies. I showed you three that showed another therapy is better than Everleam. So it's hard for clear cell alone now too. There is little justification justification to use it by itself nowadays. So I would not go to it in the second or third line or fourth line by itself unless it's been combined with something else. Accident, I think, is still remains an option and I put it there. But I really believe that if you want survival the accident trial that brought accident did not show survival advantage over its comparator Saurafenib. But Linvatinib and Everleam as I showed you did. So I would go to that and I would go to either Nevolumab or Cabuzantinib. And there will be patients that I prefer to give Nevolumab to rather than Cabuzantinib and there will be patients that I would prefer to give Cabuzantinib rather Nevolumab and these things that I mentioned yetollorability what side effects and symptoms do they have from the prior therapies? Do they have immune disorders that make me worry about giving them Nevolumab and maybe prefer Cabuzantinib or do they have very bad blood pressure problem that makes me go with Nevolumab? So what are in the next three four minutes I'd like to speak about some of the emerging therapies. I showed you what's FDA approved what's on the market now for use for our patients but now what's on the horizon because obviously we don't want to sit and be satisfied with what we have but we are looking at pushing the envelope bringing some new therapies which clearly we're not tuning everybody with kidney cancer with these therapies so hopefully we will do better in the future so the here is a slide summarizing if you want some of the novel treatment approaches that we have right now and I don't I will take a whole hour to speak about each one of these or most of these so I'll be selective in what I will be speaking about but there are two novel exciting immune therapies that are different than the immune checkpoint inhibitors that you will hear about from Dr. Gao next and that one of them is Pagulated IL-2 or Nectar 214 this is the IL-2 that you know about that's been around decades this is a an improved version if you want a new formulation of interleukin-2 that doesn't have to be given in the hospital in the ICU setting but more in the outpatient setting and it can be more importantly combinable with something like Nevalumab for example or Pemronuzumab so I think we are conducting studies with Pagulated IL-2 and I think in combination with Nevalumab it's showing really impressive results and then that we have planned to move forward with this agent in combination with immune checkpoint another one that has been shown also to show good results as monotherapy and as well as in combination with immune checkpoint inhibitors is Pagulated interleukin-10 or AM-0010 this is Armour Biosensit a small biotech company out of San Francisco there is a class of exciting drugs HIF-2 alpha inhibitors from Piloton and we are going to open a trial that Dr. Yonesh will lead at our institution in using a couple of these you know agents that block HIF-2 alpha which is downstream from the VHL and upstream from VEGF so it's a a new class a new way of treating kidney cancer at least again clear cell where this will be most relevant but an important class of of agents that we are now going to push forward with is a class of H that target the the metabolism the metabolism of the tumor cells and the first in this class is a drug called calythera biosensis or CB839 glutaminase inhibitor and then there is a new sort of a different axle met VHF inhibitor that's called MGCD516 or Citrovatinib and that we will be doing a study with at MD Anderson so in the interest of time we just go quickly here this is a cartoon rendering of the tumor cells and how the tumor cells take its nutrients sugar as well as the amino acid glutamine so cancer cells require both glucose and glutamine for growth and survival the TCA cycle or CREP cycle is a critical source of ATP for cellular energy and several key biosynthetic intermediates for production of amino acids نقلوتات and fatty acids so in the absence of glucose the amino acid glutamine is the primary source feeding the TCA cycle so cancer cells become dependent on the glutamine metabolism for efficient growth and survival and glutaminase is a mitochondrial enzyme that catalyzes the conversion of glutamine here to glutamine that enters into that TCA cycle and the drug CB839 is here that's the one that's put in the brakes or blocks the conversion of glutamine to glutamate it blocks that enzyme glutaminase so here is the design of the study we're going to be launching here at MD Anderson this is a multi-central trial and it's a 252 patients who were treated with any number of prior therapies including Nevolumab including Cabosentanin and they will be randomized to receive everolimus which you heard about already another you know a trial taken using Nevolumus as a comparator but in combination with placebo versus everolimus again in combination with this drug CB839 that glutaminase inhibitor the primary endpoint is progression-free survival so the trial is not open anywhere in the nation yet but this trial will be open in the U.S. we will be leading it along with other sites and it will be open in Europe as well as Canada so this is an investigator-initiated trial meaning that we are opening it at MDN only we are leading it I'm the principal investigator of this trial and we decided to take the best two drugs for kidney cancer in the salvage setting Nevolumab and MGSD516 or Citrovatinib which is this drug that's similar to Cabosentanin so we wanted to take the best drug that targets the immune system which is the Immune Checkpoint Inhibitor Nevolumab and the drug that's the best for targeting the cell the the signaling that the tumor cell uses and we combine these two so patients who had one or two PRAR therapies with either Citrovatinib Pazopanib or interleuk into but as long as they did not have an immune checkpoint inhibitor mTOR inhibitor or Cabosentanin they come in and they get treated on this trial and we have this is a trial that we're going to collect a lot of blood and biopsies before treatment is given and on therapy and at the time of progression this is going to be a very informative trial and we hope that if we show that the combination is better than Nevolumab alone or better than Cabosentanin for example what we know of these two drugs because I showed you data we pretty much know what you can expect if you treated patients with kidney cancer in the salvage setting with one or the other drug we pretty much know what to get if we get here double the responses with the combination then we can expect to get with either one alone then this trial is going to move forward for a phase three and we hope that that will be a positive trial as well so what is my forecast for the next say one two three years how do I see the landscape shaping up so you heard from Dr. Yonesh that Cabosentanib could be FDA أكبر in the next few months if the review of the scans confirm the results that were reported by the investigator and if Cabosentanib then gets an indication not just in the second line third line but in the first line that's going to shake up the field but there are several trials and maybe Dr. Gow is going to mention about these trials in his talk that basically are in the first line setting and they are using combinations of an immune checkpoint with an immune checkpoint inhibitor or an immune checkpoint inhibitor plus a target agents targeting this angiogenesis the blood vessels and here are those six trials نيولوماب plus ايبيلوماب versus سونيتينيب we participate and led that trial here at MDN and the results are still pending there's another one that also complete accrual using this immune checkpoint inhibitor اكبرزلوزوماب or the centric plus بيوزوزوماب versus سنيتينيب and these are three trials that are now ongoing using an immune checkpoint inhibitor with the same agent اكبرزلوزوماب here and these two trials and what I showed you here previously نيولوماب plus ايبرلوماب so and this is a trial that hasn't opened yet but it combines نيولوماب كبرزلوزوماب versus نيولوماب ايبيلوماب and كبرزلوماب again in all those trials the comparator that's being used is سنيتينيب because first line so I think the results of these and what the FDA is going to do with كبرزلوماب regarding its position in the first line will really shake up what will happen in the very near future maybe in a year or two years certainly by three years what was going to happen in the salvage setting but there will be also entry of new investigational agents in the second line space will affect the field so some of the trials that I showed you that the group timing is نيولوماب cb 839 نيولوماب نيولوماب نيولوماب the drug that I showed you نيولوماب cb 516 so if these get FDA approved they're going to come here and occupy space but there are some challenges and unmet needs particularly predictive biomarkers we still give all these therapies to all patients say with yourself and we don't know if they're going to respond or not because we don't have biomarkers we don't have predictive factors whether it's from the blood or the tumor that we can take a piece of the patient or the kidney tumor that tells us they're going to respond to this drug better than the others so we don't I showed you that PDL1 was hopeful that it would be a predictive but in رياساكس نيولوماب unlike lung cancer it was not a predictive factor so there is really a pressing unmet need to identify predictive biomarkers to help us select these therapies to patients better to bring us to really the era of precision or personalized oncology rather than give the the same drug to everybody knowing well that only a percentage of patients will respond and not all patients respond and then the the really unmet need and it's a subject that's near and dear to my heart which is the variant histology because I've been focusing on this this group diverse group of tumor types that so far we have not an industry has not really paid a lot of attention as well as academic centers because they're rare tumors and I'm talking about chromophob I'm talking about pepillary I'm talking about renal medullary carcinoma collecting tuck or bellini's tumor so those are they constitute about 20 25% of tumors of kidney cancer but unfortunately a lot of the data a lot of the trials I showed you and Dr. Yonah showed you and what you'll see you'll hear from Dr. Gow has been conducted in clear cell the most couple of time but there is hope we are we and others are and finally industry is listening and has come on board and we will be launching some of the trials in these variant histologies such as pepillary we have already launched some trials in the renal medullary carcinoma a devastating rare kidney cancer that afflicts young african-american with sickle cell trait thank you very much