Systemic treatment options for patients with metastatic non-clear cell renal cell carcinoma

thanks for having me speak here today I would like to say thank thank you to the kidney cancer Association for supporting our research in rotini malignancies and so talking today about rare kidney malignancies in the beginning we we divided Guinea malignancies in clear cell and non clear cell and that's what we still do and we thought that you know the non clear star the papillary the chromophobe and the younger Saitama but actually the reality is much more complicated than that in 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 we know so carcinoma we before we thought it was either papillary or clear so 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 there one can find so about 90% of them are bona fide Arenas cell carcinomas but there are others as well you can find lymphomas you can have fine 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 percent of the cases when we say kidney cancer about 16 percent 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 mendler carcinoma which is about less than 0.5 percent of cases collecting that less than 0.5 percent of cases translocation carcinoma 1 percent 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 a 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 it's where we talked there for others because I've talked before what are the various systemic therapy options and systemic therapy as opposed to let's say local therapy which the surgeon and radiation is therapies that are going to go all over your body and potentially kill the cancer cells anywhere that they might be in your body and broadly do you have the targeted therapies like the oral TKE eyes or mTOR inhibitors that 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 unclear so subtypes and whereas in the past although even in clear so now we don't use it as often cytokine based immunotherapy like high-dose il-2 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 so histologies that are generally resistant to classic chemotherapy and maybe at least in some cases to targeted drugs that are used for clear so like you have papillary let's see papillary type two chromophobe heredity limiters 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 ones can be collecting that carcinoma or renal milder carcinoma or it's one of its subtypes RCC UMP or malignant Rab do tumors or Wilms toons so those are more often actually treated with cytotoxic chemotherapy and so when when it comes to targeted therapies in non clear cell tumors there are some studies some very important trials face two trials like the Aspen and the ESPN trial that compared the oral TTI sunitinib compared with the mTOR inhibitor everolimus and you know there's a lot of discussion about this data I'm not gonna go deeply into it but I'm gonna tell you that the general impression is that the data slightly may be favoring sniffing it but regardless the efficacy of both agencies modest and keep in mind that those two trials accrued non clear cell of any histologic subtype so it wasn't specifically to say to just papillary or chromophobe it was anything that was non clear so with a few differences between the two there are some data of modest efficacy of the tkx sitting there based on a multicenter phase two trial in Korea after progression of temsirolimus so there is some efficacy there there are retrospective data with cables and a nib with show at least disease control in patients most of whom have progressed on other targeted therapies and actually and Matt Campbell led this retrospective study they were actually interestingly enough to patients who were treated with cables Antony who had progressed on a pure med inhibitor kappa's Anthony B's known to target Mette but it can also target other pathways so patients have progressed on met but then had one of them had partial response and the other one had stable disease with capacity so even if you have progressed on a tki targeted once in a pathway don't rule out that using another TK i 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 you know it could be just the mere fact that drugs like caboose Anthony may target other pathways and the tumor may be driven by other pathways it may be or also how people its person is an individual so it's patient metabolize a drug differently so the way somebody might metabolize one drug might be different from the other a third reason can be just pure randomness you can never ever exclude pure randomness on how a patient might respond so talking now about other targeted therapies in non Clearasil tumors there were actually some really nice studies prospective studies in papillary renal cell carcinoma the second most common kidney cancer one tried a met vgf are two inhibitor called um for retinol it showed not not a very profound objective response 13.5% might be better in patients with germline met mutation but importantly this was a a Phase two trial that was able to enroll 74 patients so it showed that it is possible even when you're occurring patients with one specific histology to get data from 74 or even more patients another trial looked at the arm arc rosante name again not very large some objective in response rate but the trial was specific to even more even more specific papillary type one so again it is possible to develop design and around trials for each specific histology Cibola tanam objective is response rates seven percent maybe 18 percent in med driven disease and this is how my driven disease was was was defined and car data but we 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 the four papillary patients with papillary renal cell carcinoma that are testing some of these oral TKIs and here I have even more so here I have quite a few trials and I have their NCT number so you can look at clinical trials.gov either some of them are for either clear cell and not clear so they don't distinguish some are any non clear so but some are even he's told the specifics so you see there are some that are for papillary only we have some trials for we know medullary carcinoma and some similar other subtypes so there are there are trial options for patients out there so talking a little bit about immunotherapy and how how what is the role of immunotherapy non clear sir in non Clearasil histologies so I really like this slide which you know makes very simple what PD 1 and PDL 1 is all about it basically hides the tumor cells from the good immune cells and and and you need to have first of all though these good immune cells in order to kill the cancer cells if you don't even have the good immune cells around even if you remove this there will be nothing to to kill the actual tumor so that's something import 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 in your 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 is to have lots of good immune cells and very few zero bad immune cells so my general impression you know at least of a few subjects and and these are these are these are you know typical scenarios that can be applied for other subjects as well with some clear cell renal cell carcinoma you have a lot of immune cells on average and many of them are good some some of them might be bad but if you give immune checkpoint therapies you have a good relative probability of of having efficacy popularity you still have immune cells in there you have in yourselves that issue but few of them it's a little bit more cold as we call it chromophobe on the other hand is much more cold it tends to be much more cold and not have neither the Barons northern are the good ones other ones like collecting the carcinoma in America Sonoma 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 we can 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 some 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 chromophobe we really need to bring immune cells and in in the mix here with other ones like collecting that we might need to remove a lot of the bad players before we see some good efficacy with with immune cells so let's talk a little bit now about its histology and what is a general approach that you know we typically use at MD Anderson for its histology so with popular in the circus now but first of all type one 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 mad pathway type 2 tends to be the more aggressive one so this is the one that we usually will we'll see in the metal clinic having metastases how usually treat like most of them if possible we try to enroll patients from clinical trials let learn more about these cancers optimize their therapies as I mentioned before immunotherapy can sometimes work and remember nivolumab a nickel emu map was broadly approved for any renal circus Noma although the trial was done in clear so the FDA approval is for any renal circus trauma so you can you can easily get approval to use this for these patients because we have prospective data for force knitting if that can be used we have retrospective data for other ticki as like Cabos additive as well there also you know some studies like a recent one in European urology by Monty Pal where if you do molecular testing and you find certain fusion such as this you can have really profound and durable responses so in those cases molecular testing might be 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 you can try that with chromophobe that one generally tends to be more indolent than papillary type type two especially however if there is sarcoma 2d differentiation it can be very aggressive as I said few immune cells in these tumors so Karin immunotherapies are less likely to work how to treat this again clinical trial always should be something to consider and then oral TK is sometimes there is some evidence that mTOR inhibitors especially might work in these malignancies especially if there are mutations such as this one so that's how broadly an approach we use then there are those that we call translocation 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 a tfe3 translocation there is the TF eb translocation which has a better prognosis than the one above us based on the current data there's another one that's not exactly a translocation it is it is a this molecule being affected TFTP but is an amplification this one actually tends to be more common even though we recently identified its existence and tends to build a 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 some clear cell but it's worth a try and then oral and then oral TK is some retrospect the data have actually shown good disease control rate in these cancers and then there are the ones that we associate with former and hydratase deficiency so that's a protein involved in 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 that leiomyoma ptosis 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 and your germline but you still might have developed this disease this one can be very aggressive how to treat again clinical trials there is there are some very promising data in this histology there is a trial at the NIH trying devices I've seen plus erlotinib showing a very good objective response rate so this this this is always a nice option to keep in mind collecting that carcinoma also I'm 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 were chemotherapy and platinum-based chemotherapy the old old-school cytotoxic chemotherapy may be preferable rather than pills but there are some retrospective data that the oral TT has like kappa xanthine if may achieve disease control clinical trials against always be an option immunotherapy may not be as effective but we've seen some cases where where it has been so if no other options I think it's it's worth a try we know mendler carcinoma extremely aggressive probably the most aggressive of them all occurs mainly in in young in their mid-twenties 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 tumor suppressor as I mentioned most commonly in individuals who have sickle cell trait sickle cell disease or others sickle hemoglobin Apophis but it can rarely about ten times less likely 20 times less likely or curing patients without sickle hemoglobinopathies and for now we're calling this when it's happens in patients without you nope nobody's RCC ump how to treat the the current commander P would be platinum base our toxic chemotherapy in our experience there are no responses of this malignancy to sunitinib preservative exceeding or any of the oral t k eyes or mTOR inhibitors so keep that in mind and there are clinical trials like the ones that I mentioned before where of targeted therapies plus chemotherapy or immunotherapies 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 unclear so histology so basically this is what we call sarcoma toyed and rhabdo ad 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 so 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 rhabdomyosarcoma so if it looks like a you know a classic sarcoma we call it sir coma toyed or if you call if it looks like more like Arab DeMayo sarcoma the cells look like that we call it Rab going it's not going to be a hundred percent of the cells necessarily but even if it's just a few of them that change the progresses because this this these cancers have started to evolve into something different and generally more aggressive and and in our experience and published experience the prognosis is worse if the original histology was non clear so as opposed to clear so but but in both cases the prognosis is is worse how to treat targeted therapies are often not as effective even in patients who originally had clear so we 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 gemcitabine 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 chromophobe they may be the most resistant to immunotherapy and now you guys understand why that would be but with the other histology is clear like clear so we've seen some profound responses in some cases and so moving forward there is clearly an unmet need to do 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 chromophobe they've been very useful and helpful to us to design the next treatments for these patients and there are similar efforts currently underway some tile although and are smaller skills for some of the other the less common ones and now the other thing that I want to tell you is don't be don't be disappointed just because a cancer is rare sometimes the bigger the better philosophy is not always correct we I wanted to point out the law of diminishing marginal return returns remember that its additional patient on a trial adds less value information-wise than than the previous ones 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 we do and if you want to read more about it here is am 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 dichotomize data and that can make us lose precision we do not adjust very often for variables that are predictive in our analysis in in rare malignancies we need to do that we need to be more careful with how we analyze data because it's patient is it's it's data from its patient is very very precious and also another thing we need to to get more data to be more precise we need to increase the resolution of our outcomes so broadly based outcomes like survivor or PFS etc do not give you as much precision especially for decision making because what we've all been talking about throughout the day is that it's patient is individual and so when we decide as doctors we don't just take into account the survival curves etcetera that 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 [Applause]