 Thank you Chris for the kind introduction and thank you all for coming and thanks to the KCA for putting that together this conference So you heard from dr. Yonash about the different therapies that are at the up who for kidney cancer those drugs are approved based on The most common type of kidney cancer, and that's clear cell RCC I can tell you in a word about the non-clear cell histologies in a word. There's really no established Agent we use these drugs that dr. Yonash talked about the different Tyrosine kinase inhibitors or anti-vegeft therapies the mTOR inhibitors, but really We do not consider any of these as a standard of care because there has not been this large face-to-retrile Comparing one of these agents with something else to show that these drugs are really Beneficial so what are these different? histological sub types that we refer to as non-clear cell ryansoccasinoma, so You see the list here Apillary type 1 and type 2 ryansoccasinoma Chromophob there is a rare tumor called collecting duct or Bellini's tumor There is also another even more rare tumor that is Called renal medallary carcinoma that afflicts mostly in the u.s. African-American young patients who have sickle cell trait There is a rare tumor that's called translocation ryansoccasinoma or XP 11.2 That afflicts younger people as well mostly females and when we do not really know what the This disease is we refer to it as unclassified. That's really a reflection of our still You know lack of knowledge about the molecular aspect of this subtype of RCC so we Dump it into an unclassified basket and there are even some more rare tumors such as MTS or Mucinus tubular and spindle cell carcinoma and then some case reports have surfaced with even even rarer tumors now uncle Cytoma is a Benign tumor of the kidney rarely becomes aggressive and metastasizes And for all practical purposes, it's cured patients with this disease with this tumor are cured with surgery now with each one of these tumors Including the clear cell the most common type as well as the non-clear cell. I just listed There is also an added feature that can make the disease even more aggressive I Describe this as you know having a turbo charge on your vehicle makes it even more aggressive So that's the sarcoma to it the differentiation So there is a plethora of genetic alterations Interpining each one of these tumors And as I said, you know the non-clear cell basket of diverse histologies represents about 25% of all kidney cancers Populating type 1 and type 2 and the chromophobes are the most common subtypes with varying prognosis So you heard from dr. Nosh about the prognostic models that have been established And that's basically looking at patients with who have You know different performance status how they function how active they are how a how they're able to perform activities of daily living We look at the time of initial diagnosis of their kidney cancer and when they develop metastatic disease and require initiation of systemic therapy and we look also at laboratory parameters such as you know Hemoglobin, you know anemia whether they're anemic or not and whether they have high calcium in their serum and other laboratory abnormalities now, this is a model that is now frequently used Established by the international metastatic the answer calcium and that a consortium and they looked at these The patients who have the clear cell the most common type of reassurances and those who have the non-clear cell that I showed you earlier in the slide and what they found was Patients who have a non-clear cell rears or casinoma subtype are usually younger have more anemia and have usually a higher neutrophil count that's a form of a white blood cell count and There is this, you know their outcome is Worse and in that study again, this is a retrospective review of a large database the median survival of patients with Non-clear cell histology was about one year compared to about two years for patients with clear cell histology Now there have been some retrospective studies, you know several years ago now Published looking at the role of TKI is what you heard earlier These tyrosine cameos inhibitors in retrospective studies What's their role? What's the outcome of patients with these non-clear cell histologies when they were treated with these TKI's and as you see here in the slide the bottom line is that the Median progression free survival that basically Reflects the time from initiation of the drug until the disease progresses or unfortunately the patient dies and these Median progression free survival are short. They're shorter compared to what we observe In patients with the most common type of rensococcinoma the clear cell time Also, when you look at the response rate That is also a definition how much did the tumor shrink when except for chromophob, which in one study The retrospective study a small number of patients was associated with a 25% response rate When you look at the other the response rates are really low much lower than what we see in patients with clear cell RCC Now what about some of these earlier trials with synitinib in non-clear cell RCCs? Here is a list of four of them The largest was a study that we conducted here at MD Anderson and published four years ago and The bottom line here except for the Korean study and by Lee et al. here that yielded a response rate of 36 percent and 26 percent in the papillary histology the other trials show that the response rate in these tumors is Really low and again when you look at that median PFS It is about six months or less and when you look at survival in these two studies up here This one conducted at Memorial Sloan Kettering and this was a French study when you look at The survival it's it's really disappointing that the median survival of patients with metastatic non-clear cell RCC Treated with synitinib which is certainly a standard of care in the clear cell histology and one of the Earlier drugs if they approve more than ten years ago the survival of these patients is disappointing in that it is About 18 months or so So what about looking at mTOR you heard about the phase three trial of TEMS Rolomus versus interferon This is the only phase three trial that recruited patients with non-clear cell histologies About 20% of the patients who were enrolled on this trial had the non-clear cell histologies again the Median OS When you compare non-clear cell versus clear cell was comparable with TEMS Rolomus again better than what you see what you see with Interferon alpha which was used as comparator the French conducted a phase two trial with Everimus in pepillary RCC called the raptor trial and their primary endpoint of that trial was progression free survival rate at six months And here the data is median duration of exposure meaning use of everolimus in study was less than five months By investigated the patient the physicians treating those patients median progression free survival was about seven months And about half the patients a little over half had progression for word progression free at six months So really nothing really to write home about or be excited about What about another drug? This is a another tyrosine kinase inhibitor, but that blocks eGFR Epidermal growth factor receptor a drug that's approved for lung cancer adenocarcinoma of the lung. This was a small study conducted many years ago by the Southwest oncology group and in a 45 Patient trial the seven of those were in the miserable The response rate was 11% The Estimated six months overall survival was 87% and the estimated median overall survival was 27 months again the FDA did not approve this agent even though there was some promising activity in Pepillary RCC because of lack of a large Properly powered phase three trial The you heard from Dr. Raj about the Cabo Zantanib. This is actually a drug that was tested in Pepillary RCC Before Cabo Zantanib. It's a cousin to Cabo Zantanib. It is a drug that was manufactured by Exalixus the maker of Cabo Zantanib and it was tested in patients with Pepillary RCC Using two different dosing schemas either daily dosing or Intermittently five days every two weeks and the primary endpoints were objective response rate and the secondary endpoints Progressive free survival and overall survival 74 patients were recruited to the study and here are the the two cohorts with What the one with intermittent dosing and one with the daily dosing and then here when you look at overall response rate 13.5 percent and when you look at the median PFS about nine months interesting, but then you look at the biomarker results of this study, which is the most interesting part of the trial about 50% of the patients so five out of ten patients who had germline mutation of med that basically they have the inherited syndrome of Pepillary type 1 RCC and the Response rate was 50% when you look at the others patients who had the somatic mutation that is they did not inherited the germline mutation, but their tumor showed mutation in that Met oncogene one responded out of Five and that's basically 20% and then there were again low responses So the take-home message from this trial was yes There was some activity, but it appeared that the patients that benefited the most from this C-met inhibitor were patients who had the inherited Pepillary type 1 syndrome But the trial was not developed any further and we still are looking for a an agent that is Effective in Pepillary RCC. This is a sequel trial to the one I showed you earlier that we published four years ago and this trial we published just last year. This was a Collaborative study that we led here at MD Anderson Comparing two agents or FD approval for this cohort or this diverse group of non-clean cell histologies So we dubbed this trial the ESPN trial. It's everolimus Versus synitinib prospective evaluation in metastatic non-clean cell RCC so the Goal of the strategy the study was to compare synitinib and everolimus in these patients with the different histologies and We looked at for primary end point progression free survival in the first line. We did allow crossover at the time of Progressive disease with the first line agent Secondary end points were survival objective response rate PFS or progressive survival in the second line objective response rate in the second line But the main goal of this trial the main objective In addition to the clinical parameters We just our end points we talked about was to really understand the biology of these different histological and to create a biorepository Where we collect tissue from nephrectomy and biopsies on these patients as well as blood to really understand more About these diverse histological sub tabs of RCC. So here was the treat. Here's the treatment schema patients who with non-clean cell histologies Were randomized one-to-one to receive either everolimus or synitinib and at crossover take the other agent if they wish to do So and their condition permitted The trial what we was stopped earlier than the target goal of 108 patients because the data safety monitoring body looked at the results and at preliminary analysis found that Patients who were treated with synitinib had actually better Outcome than patients who were treated with everolimus So this was counterintuitive because we were thinking that for patients with non-clean cell histologies. They would be benefited more by The mTOR inhibitor everolimus based on that phase three trial that I showed you the term serolimus versus interferon trial so we Stopped the trial after 73 patients were in were recruited and Here are the results about a three quarters of the patients had prior nephrectomy About two-thirds had crossed over to the other agent and unfortunately over 50 percent of the patient had died But when you look at the responses Here you see that the response rate is very low less than 10 percent So less than 10 percent of patients receiving synitinib or everolimus in first line Responded had significant shrinkage of their tumors that we arbitrarily take a car off at 30 percent So that's really disappointing compared to what we normally expect to see with these agents Especially synitinib for example in patients with clear cell RCC So again, the results were disappointing in the first line and in the second line Interesting and you have the asterix there the patients who benefited the most from either drug Were patients with chromophob RCC, which is a rare Tumor that about five percent of patients with RCC will have And here are, you know, you saw similar data. I don't want to dwell on it The red curve represents base treated with synitinib the green curve patients Treated with everolimus and of course the curve that's on top looks like it's better But this was not statistically statistically significant so our Hypothesis initially that patients with these rare non-cluosal histologies will be best served best treated with better outcome When they would when they receive everolimus did not pan out so summary of that trial was Both agents everolimus and synitinib yielded modest efficacy in place with metastatic non-cluosal RCC There were trends for longer progression free survival in first line and longer overall survival with synitinib but this came at a cost of higher rates of Toxicity with synitinib compared to everolimus Chromophob RCC showed higher objective response rate longer progression free survival and longer overall survival compared with the other non-cluosal RCC sub types the Duke Center led a similar study in 19 at 19 sites in three different continents In three different countries basically U.S. Canada and the UK and they had Identical design of randomization That's a random allocation or assignment of therapy to everolimus or synitinib, but there were some differences in the eligibility criteria They did not include patients who had Sarcoma toyed clear cell who had sarcoma toyed De-differentiation or features and they did not allow as we did in our trial to allow pace to cross over After daily they have progressed disease with the first line but their Results were very similar again. You see here the couple of my curves You know the patients treated with synitinib are represented on the blue curve here and the everolimus on the red curve and pace is treated with synitinib had a better progression free survival longer Than pace to treat with everolimus Same thing with overall survival results again Consistent with what we saw in our trial So somebody for the aspen trial led by duke synitinib yielded a significantly longer progression free survival than everolimus And the benefit with synitinib was noted in patients with good and intermediate risk disease Peppillary and the unclassified subtypes. However, everolimus did Have good results in pace with poor risk disease Which is not surprising considering that mTOR inhibitors especially The study with them so all of us showed improvement in poor risk disease And then the chroma hope subtype as already alluded to now We are doing extensive molecular analysis on these tumor subtypes and it appears that patients with chromophobic histologies have a Higher than what is expected of TSC one mutation a mutation in the gene That's that's called tuberous sclerosis complex gene one and that makes these tumors chromophobic Sensitive to blockade by the mTOR co1 times Ramos or everolimus But both these agents result in short progressive survival times and low response rates and that basically Underline the importance of continuing research to find more effective therapies for these patients with non-cliosal histologies But this has to be based on a better understanding of the biology of these Tumor tops. Now, what about some of the ongoing clinical trials for pepillary RCC here? I list several for you This is a trial finished by swag looking at a semit inhibitor here with Erlotinib and the trial was negative In a couple interesting trials Conducted being conducted right now at the at the NCI This agent van detenib plus metformin and then be versus a map plus a lot of it in the Heritory Lyoma riansoccasinoma type. This is that those are the patients who have the inherited syndrome that leads to Development of a very aggressive popular type to RCC But this trial is also for patients who don't have the inherited syndrome They have sporadic popular RCC there have been some interesting results with this combination and I think this seems to be something that we need to validate and Moving forward conduct a larger trial to really see if this would be a standard of care in the future for patients with pepillary RCC An interesting trial that that was led or sponsored by AstraZeneca and was conducted in multiple sites here and in Europe Used a pure semit inhibitor for patients with pepillary RCC. This was a single-arm study of a 90 patient trial We await the results of this that a lot of tissue based Essays looking at the semit alteration and the impact of this agent. It's a pure semit inhibitor To see if we can identify a subgroup of patients with pepillary RCC that benefit the most from semit blockade What about ongoing clinical trials in not just pepillary but the non-clear cell in general and Here are some of these trials. This is being conducted at Memorial Combining the Vasusimab the anti-VAGF plus everolimus The core and there is if a Korean study as well as a study at Mayo Looking at Pesopony in this diverse Histological group and I think you know here. I'd like to pause and and emphasize a couple important Studies that we are conducting In patients with original medallion carcinoma. I mentioned to you earlier that this is a rare tumor. That's devastating unfortunately that afflicts Young people with sickle cell trait in the U.S. These are African American But we have seen some patients are actually Caucasian who have sickle cell trait who also can develop this devastating disease So until recently there was never a trial for these rare tumors and for in particular Carcinoma. So now we have two trials at MD Anderson one using a an easy H2 inhibitor This is the name of the drug. It's from a company Epizyme and we are conducting this trial in patients with metastatic rheumatoid carcinoma and we have seen already some interesting some promising Results two of the six patients. We have enrolled have actually responded to this agent So there is hope that hopefully as we continue developing this drug as we treat more patients that we will see we will see consistent result with activity of this agent in Patients with their mother carcinoma, but we know that from previous experience that there is no one drug That's gonna cure kidney cancer So we are working to combine an agent such as taste metastatic the easy H2 inhibitor with immune therapy So this is another trial that we have at MD Anderson here that we are conducting in RMC patients Using a PD1 antibody this agent from Merck in patients with RMC and there are some other Drugs that we have set our sight on to try to test in this disease So the last two three slides. I want to just tell you how I treat my patients with non-creasile RCC So for chromophobic RCC Those patients have usually a more indolent course They do live longer even without treatment But obviously the disease is not curable When it is in the metastatic setting but any VHF RTKI as you know the experience with synitinib and Pazopanib have Led us to believe that there is some activity with the VHF RTKI But these are patients as I said because of the TSC1 Mutation these are patients who are most likely Will respond to an mTOR inhibitor such as everolimus. I mentioned about RMC How would you how we treat patients with RMC? chemotherapy has been the mainstay and this is the same chemotherapy we we use for to treat patients with bladder cancer Some of the old cytotoxic agents have helped some patients But unfortunately the vast vast majority of these patients will have them progressive disease because they develop resistance and We know that chemotherapy is not a corrective therapy for these patients So a circum what about sarcoma toad this is a very aggressive disease And it can occur with any of these sub types How our approach to treat those patients have been to use a combination of cytotoxic chemotherapy plus tyrosine kinase inhibitors But this is a situation and opportunity where we could use an immune checkpoint inhibitor In this disease and and this is based on some observations in patients treated with these immune checkpoint inhibitors particularly the PD1 inhibitors where we've seen patients who have sarcoma toad The differentiation differentiation and more than 90% of their tumors respond dramatically. So there is hope that Immune checkpoint inhibitors will will hopefully once for all change the outcome of this dismal disease for all other Sub types it's clean clinical trials clinical trials and clinical trials. So my conclusions There is no established standard of care for patients with monthly cell RCC as I mentioned at the outset The anti-veg FTK is are less effective in monthly cell RCC than clear cell RCC Temtheromas which is a standard of care for poor risk disease is a poor standard of care for patients with non-clear cell RCC There may be a role for CMAT inhibitors in patients with germline mutation of CMAT in papillary RCC The role of cytroductive nephrectomy as Dr. Karam earlier alluded to is not Established is not defined yet for non-clear cell as it has been in patients with clear cell All patients with metastatic non-clear cell RCC should be referred in my opinion for enrollment on clinical trials There are data now that are available from the TCGA To develop rational targeted therapies based on relevant targets in chromophobic and papillary RCC But it's only through transformative biology driven trials that we can hope to Make a dent in this disease and improve clinical outcome trials with immune checkpoint inhibitors are planned And I thank you very much