 Thanks for having me speak here today. I would like to say thank you to the kidney cancer association for supporting our research in rare kidney malignancies. And so, talking today about rare kidney malignancies, in the beginning we divided kidney malignancies in clear cell and non-clear cell. That's what we still do, and we thought that the non-clear cell are the papillary, the chromophobe, and the oncocytoma. But actually, the reality is much more complicated than that. Within the papillary spectrum, there are actually two different types that we can divide in. There are other malignancies that we didn't even know about 20 years ago, like translocation renal cell carcinoma. Before, we thought it was either papillary or clear cell, something else or unclassified. There's collecting that carcinoma. There are many others. And so, here are some of the many histologic subtypes of kidney cancers that one can find. About 90% of them are bona fide renal cell carcinomas, but there are others as well. You can find lymphomas, you can find metastatic cancers that go to the kidney, etc. And all of these will require different management and very often vastly different approach from the clear cell renal cell carcinoma. So, just broadly, clear cell renal cell carcinoma is about 75% of the cases when we say kidney cancer. About 16% of cases is going to be papillary, papillary type 1 and type 2. That's the second most common kidney cancer. Third most common is chromophobe, about, let's say, 7%. And then you've got the other ones. You've got renal medullary carcinoma, which is about less than 0.5% of cases, collecting that less than 0.5% of cases, translocation carcinoma, 1% of cases, rare. But for the people that actually have these diseases, they are the most important kidney cancers. And so, you've seen this slide in various iterations before. And what I wanted to point out is that we've had fantastic progress in finding new therapies and FDA approvals in what we call renal cell carcinoma. But the vast majority of these are applicable to clear cell renal cell carcinoma. So, for a lot of these drugs, we don't have nearly enough data on how they would work in non-clear cell in other subtypes. And in some cases, we actually do have data that they don't work. And so, broadly, we've talked before, other speakers have talked before, what are the various systemic therapy options? And systemic therapy, as opposed to, let's say, local therapy, which is surgery and radiation, is therapies that are going to go all over your body and potentially kill the cancer cells anywhere that might be in your body. And broadly, you have the targeted therapies like the oral TKIs or mTOR inhibitors that have been described before. Another option would be the immunotherapies, again, mentioned before. But also, for some non-clear cell renal cell carcinoma, typical classic chemotherapy may be applicable. We don't do that for clear cell, but we might need it for non-clear cell, certain non-clear cell subtypes. And whereas in the past, although even in clear cell now, we don't use it as often, cytokine-based immunotherapy like high-dose IL2, it can work in clear cell, but it generally does not work as well or does not work at all in non-clear cell renal cell carcinoma. So that's important to keep in mind. And broadly, here I have in this slide some of the non-clear cell histologies that are generally resistant to classic chemotherapy and may be sensitive, at least in some cases, to targeted drugs that are used for clear cell. Like you have papillary type 2, chromophobe, heritadelematose-associated, SDH deficient. But there are some others that are actually sensitive to chemotherapy and are more likely, although not always, to be resistant to the targeted drugs. And that once can be collecting that carcinoma or renal medullary carcinoma or it's one of its subtypes, RCC-UNP, or malignant rabdoid tumors or Wilms tumors. So those are more often actually treated with cytotoxic chemotherapy. And so when it comes to targeted therapies in non-clear cell tumors, there are some studies, some very important trials, phase 2 trials, like the Aspen and the ESPN trial, that compared the oral TKI sunitinib compared with the ENTER inhibitor everolimus. And, you know, there is a lot of discussion about this data. I'm not going to go deeply into it, but I'm going to tell you that the general impression is that the data slightly may be favoring sunitinib, but regardless, the efficacy of both agents is modest. And keep in mind that those two trials accrued non-clear cell of any histologic subtype. So it wasn't specifically, let's say, to just papillary or chromophobe. It was anything that was non-clear. So there were a few differences between the two. There are some data of modest efficacy of the TKI exitinib based on a multi-center phase 2 trial in Korea after progression of temsirolimus. There is some efficacy there. There are retrospective data with kabozanitinib with, so at least, disease control in patients most of whom had progressed on other targeted therapies. And actually, and Matt Campbell led this retrospective study. There were actually interestingly enough two patients who were treated with kabozanitinib who had progressed on a pure metinib. Kabozanitinib is known to target met, but it can also target other pathways. So patients had progressed on met, but then had one of them had partial response and the other one had stable disease with kabozanitinib. So even if you have progressed on a TKI targeted in one center pathway, don't rule out that using another TKI may sometimes help. And that can be, you know, just to talk a little bit more about that. That can be due to many reasons. It could be just the mere fact that drugs like kabozanitinib may target other pathways and the tumor may be driven by other pathways. It may be also how people, its person is an individual. So its patient metabolizes the drug differently. So the way somebody might metabolize one drug might be different from the other. A third reason can be just pure randomness. It can never, ever exclude pure randomness on how a patient might respond. So talking now about other targeted therapies in non-clerosol tumors, there were actually some really nice studies, prospective studies, in papillary. We know cell carcinoma, the second most common kidney cancer. One tried a met VGFR2 inhibitor called foretinib. It showed not a very profound objective response. 13.5% might be better in patients with generalized med mutation. But importantly, this was a phase-to-trial that was able to enroll 74 patients. So it showed that it is possible, even when you're accruing patients with one specific histology, to get data from 74 or even more patients. Another trial looked at chrysotinib again. Not very large objective response rate, but the trial was specific to even more specific papillary type 1. So again, it is possible to develop design and run trials for each specific histology. Sevolitinib objective response rate is 7%. Maybe 18% in med-driven disease. And this is how med-driven disease was defined. Encouraging data, but there is clearly an unmet need to do even better than that. And so there are ongoing trials, and I have some here for you, for papillary patients with papillary or rhinococcinoma that are testing some of these oral TKI's. And here I have even more. So here I have quite a few trials, and I have their NCT numbers so you can look at clinicaltrials.gov. Either some of them are for either clear cell or non-clear cell. They don't distinguish. Some are any non-clear cell, but some are even histology specific. So you see there are some that are for papillary only. We have some trials for rhinometalluric acenoma and some similar other subtypes. So there are trial options for patients out there. So talking a little bit about immunotherapy and what is the role of immunotherapy in non-clear cell histologies. So I really like this slide, which makes very simple what PD1 and PDL1 is all about. It basically hides the tumor cells from the good immune cells. And you need to have first of all these good immune cells in order to kill the cancer cells. If you don't even have the good immune cells around, if you remove this, there will be nothing to kill the actual tumor cells. So that's something important for you guys to keep in mind. And so tumor tissues may actually contain or may not contain the good immune cells and may sometimes even contain bad immune cells, meaning cells that actually suppress even further their immunity. So the ideal scenario what we really want to do before we even try to give the immune checkpoint therapist lots of good immune cells and very few or zero bad immune cells. So my general impression, you know, at least of a few subtypes and these are typical scenarios that can be applied for other subtypes as well. With clear cell renal cell casinoma, you have a lot of immune cells on average and many of them are good, some of them might be bad. But if you give immune checkpoint therapist, you have a good relative probability of having efficacy. Papillary, you still have immune cells in there. You have immune cells in the tissue, but fewer of them. It's a little bit more cold as we call it. Chromophobal, on the other hand, is much more cold. It tends to be much more cold and not have neither the bad ones nor the good ones. Other ones, like colectic dacrosinoma or renal mather casinoma, also are hot in the sense that they have a lot of immune cells, but they may have a little bit more of the bad players in there. So that means that when it comes to incorporate immunotherapy approaches in its subtype, we have to use a different strategy. So for clear cell, we can activate the good immune cells, remove the bad ones as well, but activating the good immune cells can often give us good results. For papillary, we need to activate the good ones, but we also might need to bring a few more immune cells in. With chromophob, we really need to bring immune cells in the mix here. With other ones, like collecting dacrosinoma, we might need to remove a lot of the bad players before we see some good efficacy with immune cells. So let's talk a little bit now about its histology and what is a general approach that we typically use at MD Anderson for its histology. So with papillary and dacrosinoma, first of all, type 1 tends to usually be less aggressive, so less likely to be metastatic, but it can be. And it's more frequently associated with what we call the MET pathway. Type 2 tends to be the more aggressive one. So this is the one that we usually will see in the metal clinic having metastases. It's how we usually treat, like most of them, if possible, we try to enroll patients on clinical trials learn more about these cancers, optimize their therapies. As I mentioned before, immunotherapy can sometimes work. And remember, nevolumine and epilimumab was broadly approved for any renal sarcosenoma. Although the trial was done in clear cell, the FDA approval is for any renal sarcosenoma. So you can easily get approval to use this for these patients. Because we have prospective data for synitinib that can be used. We have retrospective data for other TKIs, like cuposatinib as well. There are also some studies, like a recent one in European neurology by Monty Paul, where if you do molecular testing and you find certain fusion sets as this, you can have really profound and durable responses. So in those cases, molecular testing might be useful. And they actually did a liquid biopsy, not even two more tissues. So even if you don't have access to the tissue, you can try that. With chromophobe, that one generally tends to be more indolent than papillary type 2, especially. However, if there is sarcomatode differentiation, it can be very aggressive. As I said, few immune cells in this tumor, so current immunotherapists are less likely to work. How to treat this? Again, clinical trial always should be something to consider. And then oral TKIs. Sometimes there is some evidence that mTOR inhibitors might work in these malignancies, especially if there are mutations such as this one. So that's broadly an approach we use. Then there are those that we call translation renal cell carcinomas. They often happen in younger patients, especially women. They can be very aggressive. About 20% of these patients will have a history of prior chemotherapy. There are actually three subtypes of this, at least three subtypes that we know, and we're still learning about them. So there is the TFE3 translocation. There is the TFEB translocation, which has a better prognosis than the one above, based on the current data. There's another one that's not exactly a translocation. It is this molecule being affected TFEB, but it's an amplification. This one actually tends to be more common, even though we recently identified its existence, and tends to be more aggressive than the translocation one. How to treat them? Clinical trials. Immunotherapy can be an option. Again, not enough data. It probably is not going to work as well as clear cell, but it's worth a try. And then oral TKIs. Some retrospective data have actually shown good disease control rate in these cancers. And then there are the ones that we associate with fomorine hydratase deficiency. So that's a protein involved in cell metabolism in the Krebs cycle. And that one can be inactivated, either due to a germline, a hereditary familial mutation. And in that case, we call this, that is part of a syndrome called hereditary myomatosis and renal cell carcinoma, or it can be due to acquired mutations. So you may not have a family history. You may not have this in your germline, but you still might have developed this disease. This one can be very aggressive. How to treat, again, clinical trials. There is some very promising data in this histology. There is a trial at the NiAIDS trying bivisizumapsin plus erlotinib, showing a very good objective response rate. So this is always a nice option to keep in mind. Collecting that carcinoma. Also, very aggressive, usually found in older patients. So remember, this is one of those histologies that I said, oral targeted agents don't work as well. And on the contrary, this is one where chemotherapy and platinum-based chemotherapy, the old-school cytotoxic chemotherapy, may be preferable rather than pills. But there are some retrospective data that the oral TKIs like kabozzantinif may achieve disease control. Clinical trials, again, should always be an option. Immunotherapy may not be as effective, but we've seen some cases where it has been. So if no other options, I think it's worth a try. Renome medial carcinoma, extremely aggressive, probably the most aggressive of them all, occurs mainly in young, in their mid-treaties, African-Americans with sickle cell trait or disease. And if untreated, it can kill patients within weeks. It is similar to collecting that, but more aggressive, characterized by loss of this very potent tumor suppressor. As I mentioned, most commonly in individuals who have sickle cell trait, sickle cell disease, or other sickle hemoglobinopathies, but it can, rarely, about 10 times less likely, or 10 times less likely, occur in patients without sickle hemoglobinopathies. And for now, we're calling this, when it happens in patients without sickle hemoglobinopathies, R-C-C-U-M-P. How to treat this? The current recommended therapy would be platinum-based orthoxychemotherapy. In our experience, there are no responses of this malignancy to Sunita, Pazoponibaxidinibor, or any of the oral TKIs, or MTOR inhibitors, so keep that in mind. And there are clinical trials, like the ones that I mentioned before, where, of targeted therapies, chemotherapy or immunotherapists, that would be worthwhile. And then there is another type, which is a little bit different than the others, in the sense that it can occur in individuals that can have both clear cell and non-clear cell histologies. So basically, this is what we call sarcomatoid and irraptoid de-differentiation. So what happens there is this. You can have your original cancer being clear cell, or it can be any of the other non-clear cell histologies, but then that cancer basically changes. It evolves, and it evolves to look, under the microscope, more like a sarcoma, more like a mesenchymal tumor, or more like a raptomyosarcoma. So if it looks like a, you know, a classic sarcoma, we call it sarcomatoid, or if it looks like more like a raptomyosarcoma, the cells look like that, we call it raptoid. It's not going to be 100% of the cells necessarily, but even if it's just a few of them, that changes the prognosis, because these cancers have started to evolve into something different and generally more aggressive. And in our experience, in publicist experience, the prognosis is worse if the original histology was non-clear cell as opposed to clear cell. But in both cases, the prognosis is worse. How to treat? Targeted therapies are often not as effective even in patients who originally had clear cell, or who still have clear cell histology, but there are some notable exceptions. We've seen it. We've seen some very profound responses in some patients. In some cases, especially when we don't see responses initially, we might consider adding cytotoxic chemotherapy like gemcytavine, and this is based on some, both retrospective and prospective emerging trial data. And there are also emerging data that at least some patients, up to 15% in our experience, may even achieve durable remission with immunotherapy from the ones that have the original histology was chromophobic. They may be the most resistant to immunotherapy, and now you guys understand why that would be. But with the other histologies, like clear cell, we've seen some profound responses in some cases. And so moving forward, there is clearly an unmet need to do better. And how are we going to do better? How are we going to develop new therapies and new approaches? Well, first of all, there are some very important biological profiling initiatives, like the Cancer Genome Atlas, and they have improved our understanding of the molecular landscape of some of these malignancies, particularly papillary and chromophobic. They've been very useful and helpful to us to design the next treatments for these patients. And there are similar efforts currently underway, although in a smaller scale for some of the other, the less common ones. And now the other thing that I want to tell you is, don't be disappointed just because a cancer is rare. Sometimes the bigger, the better philosophy is not always correct. We, and I wanted to point out, the law of diminishing marginal returns. Remember that each additional patient on a trial adds less value information-wise than the previous one. So that means that if we're being very careful and very efficient with how we gather and analyze information, we can actually gather and understand these malignancies a lot, even with 30 patients, even with 40, or even even with less. And as I said, more cost-efficient studies with small sample sizes can produce more projected scientific value relative to cost than some larger trials would do. And if you want to read more about it, here is a good reference about that. And so as the quantity of information decreases because these are more rare malignancies, the quality becomes more important. And so we need to achieve more precision. We need to improve the quality of our information gathering. And so we need to do that. We need to let go of some old bad habits that are, you know, we started them historically because we didn't have the computational power in many ways to do something else. We dihotomize data, and that can make us lose precision. We do not adjust very often for variables that are predictive in our analysis. In rare malignancies, we need to do that. We need to be more careful with how we analyze data because its patient is, its data from its patient is very, very precious. And also another thing, we need to get more data to be more precise. We need to increase the resolution of our outcomes. Broadly based outcomes like survival or PFS, et cetera do not give you as much precision, especially for decision making because what we've all been talking about throughout the day is that its patient is an individual. And so when we decide as doctors we don't just take into account the survival curves, et cetera, that we show, we take into account other things that are very important. And so those actually do need to be incorporated in our trial design. So what I mean, I mean cost, loss, time trade-offs, willingness to pay, risk aversion, this can and should be incorporated in our trial designs. And if they do, they can actually help us make better decisions that are more informed with fewer patients. And that's it. Thank you.