 Okay. It's really a pleasure for you to be here, for me to be here today. I'm sorry that I am changing the topic a little, but it's my wedding anniversary and I really do need to go home. So my topic is how does histology alter treatment? And we know that with increasing understanding of VHL and HIV and the pathway and the consequences of VHL mutation, we have many new targeted therapies for patients with clear cell carcinoma of the kidney. However, kidney cancer is definitely not a single disease and only some 75% of patients actually have clear cell, some 10 to 15% of patients have papillary carcinomas, 4 to 5% chromophobe and there are many other types of kidney cancer with completely different pathologic and biological and molecular characteristics. Kidney cancer is not a single disease. We know that papillary type one may be driven by MET, papillary two by alternations in the fumarate hydratase gene and oncocytic with alterations in the succinate dehydratase gene, the FLCN abnormalities may be important in chromophobe and oncocytoma. Kidney cancer is a metabolic disease and we can have alterations in MET, alterations in the FLCN gene as in chromophobe cytoma in the fumarate hydratase gene as in papillary type two, the succinate dehydratase gene, the microchlamia transcription factor genes, TSC1 and P10 genes. What they all have in common that they're all associated with abnormalities in the cell's ability to sense oxygen, iron, nutrients or energy and I think that by looking at how we can evaluate these metabolic and understanding these fundamental metabolic aspects of kidney cancer we hopefully will be able to provide the foundation for the development of novel approaches, but I think it's important to remember that kidney cancer is a metabolic disease. Now papillary, there has been much hope and there still is hope from results from the cancer genome project but what we know today about these diseases comes primarily from work that we know from the different hereditary family lines and hereditary cancers. So papillary type one kidney cancer is, we know a lot about hereditary type one papillary cancer familial syndrome. It's a germ line mutation of the C-MET gene and they have patients have a 90% chance of having thousands of tumors that are bilateral and you can see that the histology is different than other histologies and the treatment of choice is actually active surveillance of the small tumors and weight and do surgery when the tumors are 3 cm because they do develop these bilateral tumors. In the sporadic tumors 13% of them will have C-MET mutations and these are often less likely to metastasize than the clear cell cancer and again surgery is the standard of care. Again showing bilateral kidney cancer is an autosomal dominant hereditary papillary variant. Now type one papillaries often mix together many studies with papillary type two cancer and these are completely different. They're really different tumors. Papillary type two is made up of a number of different non-type one papillary cancers. We know from genetic studies that hereditary liomyomatosis, germ line mutation of the fumarate hydrotaste gene can be involved. This is an aggressive disease. Nobody thinks about active surveillance until they have a 3 cm relation. Wide resection, wide resection is recommended and this is a perfect example of where we can see the Warburg effect. The Warburg effect is where aerobic glycolysis comes into play. This is one of the reasons why people have thought to treat papillary type two with combinations of EGFR and VEGF blockade. The sporadic tumors are not well characterized but these are very very different from papillary type one carcinoma. The hereditary variant can be associated with uterine myomas and cutaneous liomyomas. Again that's an autosomal dominant. The chromophobe carcinoma, 4-5% of all renal cancers. The inherited syndrome is Hogue-Dubais and the germ line mutation is in the FLCN genes and more than 90% of the families. These are generally indolent tumors unless they're associated with sarcomatoid features. Then sarcomatoid which will be in Victor Grunwald, we'll speak about later, once they're associated with other tumors can have a completely different course. But here again we speak about a slower growing tumor, active surveillance until 3 centimeters and then surgery. And here you can see with the FLCN gene mutations you can see oncocytomas, oncocytic renal cell carcinomas and chromophobe tumors. These are all very different tumors. Now collecting doc carcinoma or Bellini tumor is another kind of tumor. It occurs rarely but I see quite a lot of them. It occurs in less than 2% of cases. It's a highly aggressive tumor. It comes from the collecting ducts in the renal medulla. And it responds transiently to therapy for transitional cell carcinoma. It doesn't respond to sonitinib and patients often come in on therapy with sonitinib. But we really don't know the clear role of targeted therapy because no studies have really clearly been done aimed on this disease with targeted therapies. So in terms of collecting duct tumors and Bellini tumor the largest study that I found was done by Stefan Udard published in 2007. It was a phase 2 study of 23 patients in which he gave gem cytobine and cisplatinum or carboplatin. And he did find a 26% overall response rate, the PFS of 7.1 months and overall survival of 10.5 months. So this is the largest study that we have. He's told me that he's now planning another study with the combination of the vessism. I'm not sure if this will be just a French study or if other of us will be able to participate. But we really don't know what to do with this highly aggressive tumor. Renal medullary carcinoma occurs in young patients of African descent with sickle cell trait or with hemoglobin SC disease. It's an extremely lethal disease. Some transient responses to chemotherapies for transitional cell carcinoma have been seen. Since there is some over expression of DNA topo 2 it's been thought that Adryomycin and Etoposate might be useful. And we don't have any support for the use of VEGF or mTOR inhibitors in this disease. Last year I discussed the XP-11-2 translocation carcinoma part of the Microphthalmia transcription family of cancers. The TFE-3 tumors first discovered recently in the 1980s. Primarily as a tumor of children and we rarely see it in young adults. I had had a 20-year-old patient that I presented last year. And this was the first case ever described by Marston Linehan and his group in a 21-year-old college student in which they did the genetic studies on her. It was the first case of a TFE-3 kidney cancer and translocation. And it's a different family of tumors with a different history and perhaps they do respond to senitinib somewhat. And these family of tumors can be inherited or sporadic as well. And then there's the unclassified renal carcinoma that's usually an aggressive tumor. It's a really heterogeneous group and we're not sure about the role of targeted therapy. I'm leaving apart sarcomatoid tumor and mentioned. So we have an international database consortium prognostic model looking at thousands of patients. 252 had non-clear cell. These patients tend to be younger, have lower hemoglobin, higher neutrophils. But they do have a significantly worse outcomes than patients with clear cell renal carcinoma. And these are the studies that we have right now with senitinib and seraphimib. We have retrospective study done by Chouiri with senitinib and seraphimib. He did this in a few really excellent centers in the United States. Excellent pathologists reviewed the pathology and often changed the pathologic diagnosis on many of the patients. He did get together 53 patients. The overall response rate was about 10%. It was higher in the chromophobe than in the papillary. And senitinib had a PFS of 11.9 as compared to 5.1 months with seraphimib. From Martin Gore's extended access program with senitinib. Again, there were non-clear cell carcinomas. They not really defined what exactly was their pathology. And there was a median PFS of 7.8 months, but a decent median overall survival. And the seraphimib expanded access program reported in the United States had a mixture of papillary chromophobe collecting. And as I showed you, these are really different tumors showing 40-week survival. But all of these studies point you to the fact that there is some activity with these drugs. These are the phase two trials looking at senitinib in non-clear cell carcinoma. I'll talk again about revos later trial afterwards. But in most of these trials, you can see there's one from France, one from Memorial. There are some responses in these patients. Many of them have papillary, but many of them have mixed tumors. The study from Korea by Lee had the highest responses of 36% response rate and 26% in the papillary carcinomas. The chromophobe that were lesser, fewer of those patients did better. Taneer at MD Anderson has put together 57 patients. Again, a mixed, really mixed group of patients showing a 5% overall response rate, but a 16.8 month overall survival. So the SUPAP study is a phase two study with senitinib in patients with both type one and non-type one papillary carcinoma based on all these data that senitinib should be working in papillary renal cell carcinoma. And the other thing we heard a lot about was temserolimus. And based on the Huda study, 20% of the patients did not have clear cell carcinoma. These 20% of patients seemed to have done better than the patients with clear cell carcinoma if you look on this graph. And temserolimus became the de facto treatment of choice for a while. For these patients, but again, they're not really specified who are all these patients. They have different non-clear cell histologies. This led to the evarolimus trial, another mTOR inhibitor, another RAPALOV called the RAPTOR trial, with the primary endpoint being PFS at 6 months for patients with advanced papillary tumors. Now, Ellen Rabeau presented the results of the SUPAP trial at the ESMO meeting in 2012 and Bernard presented the results in 2013 at the ECHO meeting. And you can see that in many centers, they got together quite a lot of patients. This was not an easy task. 60 in the SUPAP trial and 92 in the evarolimus trial. In the SU-10 trial, there was a 5.6 month PFS, an overall survival of 12.5 months. In the evarolimus trial, the investigator found a 7.6 months progression-free survival, but a central review, this was only 3.7 months. The overall survival, which can't be changed, is 21 months, which is important. So I think that we know the investigators often, let's say, overestimate what the central review often underestimates or whatever, but that both of these drugs do have activity in papillary carcinoma. Again, the problem of mixing these two, papillary type 1 and 2, which are completely different diseases in all of these trials. And if you look at the record 3 trial that was evarolimus, and Sunitinib versus Sunitinib, followed by evarolimus, clearly the non-clear cell patients did worse, and patients did a little better with the Sunitinib than they did with evarolimus on this trial as well. So the Mozart and his group at Memorial have now looked together at putting the rapalogs together, and they mixed together the non-clear cell and the sarcomatoid. I'm only going to speak about the non-clear cell. There are 62 of those patients with non-clear cell carcinoma, given either evarolimus or temserolimus, and what they found was a PR rate of 5% with the rapalogs and 56% stable disease. So here you can see this graphically presented better. Again, the unclassified patients, most of them had stable disease. There were some patients who had partial response, either with evarolimus or temserolimus, papillary the same. There were two patients who had a partial response, and the majority of patients had stable disease, and chromophobes, well, there was stable disease seen in these patients. So again, if you look here at the Memorial data on the non-clear cell patients of the 62 patients, the median PFS is 2.8 months, and the median OS is 9.1 months. So, I mean, this is again a study that mixed sarcomatoid and non-clear cell. Again, I think because these patients are less, this is what's being done. This is a retrospective study, but that's what's out there. And what was particularly seen in this study was that the Rappelogs do have some activity in sarcomatoid and all of these non-clear cell histologies, but what really was more important for overall survival was the MSKCC risk group, more than the histology. So these are two other trials that are ongoing because we really don't know in the non-clear cell histology if we should be using sunitinim or evarolimus upfront, and this is a study that's led by the Duke group. It's called ASPIN, and it's for patients with papillary or chromophobic non-clear cell carcinoma. It's ongoing, but it's not recruiting patients anymore. 108 patients randomized between upfront evarolimus or sunitinim, the primary endpoint being progression-free survival. And a very similar study by the MD Anderson group. It's also called the ESPIN trial. Again, this study is ongoing, but it's not recruiting, and the eligibility criteria here are much broader. Again, 108 patients are randomized, but here they're including chromophobe, papillary, collecting doc, translocations, sarcomatoid, and unclassified. So it's a similar study, but with different groups of patients in it which will definitely affect the results. Now, foritinib is a very interesting molecule to dual-vegep receptor and MET inhibitor. And Tony Chouiri studied this along with the group from the NCI, and they showed that they looked at intermittent dosing and daily dosing, and what they saw most important of all was that the patients who had, the 10 patients who had germline MET mutations, there was actually a 50% partial response rate. So these were the patients who really responded the most, and you can see this on a waterfall plot. I think this was shown earlier. The ones in purple are the ones with the germline mutations and MET, so clearly an excellent drug for this disease, which I think has been dropped by the company because perhaps it's not interesting enough. Lawrence Alvege and Bernard Escudier have just recently published their work on MET as a potential target across all papillary renal cancers showing copy number alterations being gained in 46% of type 2 renal cancers and in 81% of the type 1 papillary cancers, 11 somatic mutations of MET gene in 51 type 1 papillary renal cancers and 4 new mutations. So this supports investigating MET inhibitors in papillary renal cancer in correlation with the MET activation status. And just one other drug, or Lottinib, based on some studies with C225 monoclonal antibody against EGFR in the laboratory, the SWAG embarked on studies in papillary carcinoma or Lottinib, and they enrolled 52 patients with an overall response rate of 11% and showed a 64% disease control and median overall survival of 27 months. So this isn't also a drug that probably needs a further study. So these are just some of the ongoing studies in non-clear cell carcinoma, the pitopin is being studied in papillary carcinoma, axitinim is being studied in non-clear cell carcinoma after patients have had temserolimus, BEV is being combined with everolimus and it's also being combined with Lottinib in papillary renal cancer, both the hereditary and the sporadic types, and Tvancinim or ARC197 with or without or Lottinib in papillary cancer. So just to finish, in terms of non-clear cell renal cancer these are distinct tumor entities, they have different genetic abnormalities, they have different phenotypes and they have different biology. And further work clearly needs to be done to understand the pathogenesis. There is no established standard of care and in some cases an aggressive surgical approach is justified in selected patients. The VEGF-TKI's and MTOR inhibitors have shown safety and efficacy in the extended access protocols and in some prospective phase two trials. There's a role for the C-MET inhibitors in patients with germline mutation of C-MET. The role of VGF-R inhibitors is being explored and in my mind all patients with metastatic non-clear cell carcinoma should be referred for enrollment on clinical trials. Thank you very much for your attention.