 Okay, we are ready to start again if you can just take a seat. It's my pleasure to introduce the next speaker, Brian Dietrich. He's one of our senior fellows in medical oncology. He's been with us in our urologic program now for more than a year. And I'm really pleased to say that Brian will be starting his job next year. I'm passing over the baton to Brian to help take care of our urologic oncology patients at the VA. So he's going to be talking on the overview of medical therapy for patients with kidney cancer in my introduction slide. I told you that the last decade has really evolved with therapies for kidney cancer. So Brian is going to briefly touch on the tyrosine kinase inhibitors, which is the bulk of treatments that we use for patients, both when they first have diagnosis with metastatic disease and subsequent therapy. And then that will follow by an immunotherapy talk that we'll have in the next session. So thank you, Brian. Thanks, Dr. Schoenevest. Can everyone hear me okay? So like Dr. Schoenevest said, I'm Brian Dietrich. I'm one of the third-year fellows. I've been here at Stanford for five years and lucky to have Dr. Schoenevest as my mentor. So hopefully she's taught me a few things I can pass on to everyone today. So we're going to be reviewing what types of drugs we use in advanced disease and kidney cancer. So I'll start just going over what these kind of drug classes are and then how these drugs actually work and some of the thought behind why we use these over things like conventional chemotherapy as is common practice in other disorders and cancers. And then it's a very evolving landscape actually on kind of which treatment options are the best. And I'll go through kind of some of how the risk stratification that we create for patients when they're first diagnosed and how that plays a role in how we think about what the best first treatment option is and then which treatment options we may use sequentially throughout their treatment course. And then each of these treatments has some anticipated side effects that our patients go through and I'll review, at least kind of an overview on how or which side effects are most commonly observed in each of these classes. So in 2017, the three largest groups of therapeutics that we have is the first are these VEG F inhibitors which are essentially blood vessel blocking drugs. And we have a number of these that have been approved through the FDA with some of the most recent ones, CaboXantinib and Lenvatinib in the last few years and some of the earlier ones with Su-10th or Su-Nitinib. Yeah, back at least within the last 10 to 15 years this landscape has been evolving. The rest of the talk will focus on these mTOR inhibitors that still have a role and are particularly kind of highlights when we may consider choosing this, particularly in the first line setting with Tim Serolimus based on some of these risk stratifications that we do. And then I'll briefly go over some of the immune therapies and how this is kind of changing the landscape of what we would consider for first line therapy and then there'll be a whole talk dedicated to those. So how do these drugs work? So I mentioned the VEGF inhibitors work by blocking blood vessels. So we've learned a lot more about the genomics of kidney cancer and one of the most frequent mutations that occurs is in this protein called VHL or von Hippel Lindau that we see in over half of advanced kidney cancers when we do sequencing of our tumors. So in the normal protein it actually works to break down or destroy some of these transcription factors called HIF, which when present they actually increase expression in another molecule called VEGF. So VEGF works basically by creating blood vessels. So if we think of a cancer cell these kind of start off as small tumors and normally they're able to get their kind of nutrients, their oxygen from the surrounding blood vessels but as these tumor cells start to get larger they have a higher need for access in order to pull in more nutrients and supplies in order to survive. So one of the things that happens is they upregulate these transcription factors or these HIF factors and this ends up leading to higher levels of this VEGF that essentially creates additional blood supply that the cancer feeds on. So one of the main targets is all of this class of medications that work on receptors that end up blocking the activity of this VEGF molecule and that's where basically by killing off the blood supply the tumor can't grow and survive and we take away one of the survival advantages to the disease. So over here on the right of this slide is kind of this next group are these mTOR inhibitors. So these work basically through a signaling pathway. So all of our cells basically work by responding to signals from the outside environment or signals from outside the cancer cell. So these can set down cascades that basically end up sending signals to the center or the nucleus of the cancer cell in order to basically tell these cells to divide, to survive. So there's all these complicated proteins that result in this interaction. So two drugs that we actually use, the virulimus and temsirulimus block part of this signaling that gives these cells their survival advantage. And the last group of drugs that we use are these newest immune therapies which are the new kids on the block. So we've known for a long time in kidney cancer that this is a very immune responsive disease and this goes back to some of the earlier trials that Dr. Shah will be talking about where we used to use high doses of cytokines in order to treat kidney cancer and even had durable responses in a number of patients. So we all have an immune system that's kind of floating around and we go through a process basically called tolerance as our immune system develops where our body recognizes us as us and anything else as foreign. So cancer cells, by definition, they're not our tissue. It's a foreign molecule that's kind of in our bodies. So one of the ways that these tumor cells kind of evade our own recognition of our immune system is through this interaction of a group of molecules and probably the most well known are these PD1, PDL1 molecules. And a lot of you may have seen commercials for a lot of these new therapeutics that try to exploit this pathway. So with this, if there's interaction between PDL1 on a cancer cell and PD1 which is on one of our immune cells called a T cell this basically down regulates the immune system or basically masks our immune system from being able to see cancer as it was designed to do. So we take advantage of this by giving an antibody that blocks that signal so then the immune system can actually go in and attack cancers and that's been the more cutting edge and more exciting treatment options that's come along in the last few years and is used not only in kidney cancer but has approval in a number of malignancies. So before I move any further, I'm just going to go over a few basic definitions of just some terms that we use in advanced disease. So I know our surgical colleagues had already talked about nephrectomy which is the surgical removal of the kidney that contains the tumor and there's a role even in the metastatic setting where we'll consider actually taking out the tumor even in patients that have disease that has already left the kidney and gone to other locations. In certain patients we'll also consider removing one of those kind of tumor seeds that's already in another organ which is something we call them metastatectomy and that's something that can be considered particularly if we're doing scans and we see one kind of tricky spot that might be growing but we see no other areas. Sometimes we'll talk to our surgeons to see can we consider actually removing one single metastatic site if everything else on the scan looks okay. Something that we call adjuvant therapy that I'll just briefly touch on today this is when we would give a systemic therapy after a surgery and there's been some studies that have looked at some of these drugs in kidney cancer and then the term metastatic is basically equivalent to what we would say is stage 4 disease. So this is when seeds of the cancer have already left the kidney and have ended up in other locations like the bone, the lung, brain, lymph nodes essentially anywhere in the body and then particularly we can't talk about oncology without looking at a lot of our clinical trials that drive the recommendations for the treatments that we have. So kind of the best trials that we have are what we call these randomized trials and this is basically where patients are randomized to one or another arm or one of several arms on a study. The randomization is to try to kind of separate all patient factors evenly between groups. So we're really looking mostly at the disease entity and have basically equal patient populations in each. And then each of these clinical trials occurs on different phases. So you may have heard of these phase 1, 2, and 3. Phase 1 studies, classically, are answering the question what's the best dose of the drug that prevents a lot of side effects. And then these move into what we call a phase 2 study which is looking is there actually efficacy or does these treatments actually work within a particular disease where we're trying to answer a question. And then the largest are the phase 3 studies which are trying to validate that question and kind of actually come up with a new standard frequently by comparing it to a current standard that's in practice. So treatment of the metastatic disease, this is a common scan that we see in our patients when they come to our urologic oncology clinic. They'll have a scan that shows frequently enlarged tumor as you can see here in the left kidney. And then they'll have areas elsewhere on their CT scan or PET scan that end up having a biopsy that shows basically this is a common finding of what we call clear cell kidney cancer that would confirm metastatic disease in this patient. So the landscape has kind of changed over the last 15 years or so and this is all of the drugs that we have available to treat advanced kidney cancer. And as you can imagine when we have all of these treatment options then it becomes the question on which of these treatment options is the best to recommend for our patients. So these go back to 2005 when the first of these small molecules, these tyrosine kinase inhibitors or these blood vessel blocking drugs were approved all the way to even last year in 2016 when we're still finding ways to exploit these blood vessel blockers through therapeutic options. So which drugs are the best to give first or which do we consider for our first line or upfront treatment? So this is kind of a table that shows all of these drugs and how we kind of sort of triage them into our clinics. So the first thing that I frequently do is actually just think about what's the risk when we see a new diagnosed patient. So there's a few basically algorithms that we can actually plug numbers into. This is one example from the group over at Memorial Sloan Kettering where you can actually look at a few prognostic factors of a patient's disease when they're first diagnosed. So in this they look at basically how long it takes in order to start a first systemic treatment. What are some of the lab values on the blood work looking at a marker of hemoglobin, of calcium, another protein that's commonly seen in cells called LDH and then just the physical performance status or how well a patient looks. So there's different variants of these prognostic scales that we look at and they can be useful in kind of predicting how aggressive we think a disease is just from the get go and do we think that based on some of these models a patient is statistically more likely to have a worse outcome compared to if these factors weren't present. And this is just one, there's many other models that will change some of these numbers. One that actually substitutes LDH to look at some other blood cell counts in your white blood cells and platelets. But this is just an example on how we might stratify a person that can be useful. One for how we determine treatment options as well as if we're thinking about clinical trials in the upfront setting. We're looking more frequently at using risk as part of that consideration. So a few questions to consider actually when we're choosing the first line drug. And this is something actually we tend to bring up in patients that I think can cause a lot of anxiety actually as a side effect is do we actually have to start a treatment even in the advanced disease right away? Do we have a little bit of time and can some patients actually safely be watched off of any treatment? Another consideration is with these tyrosine kinase inhibitors I had showed this slide that there's many different options. So which one of these is the best and is there actually an optimal TKI to use first over the others? And then currently in 2017 while we're coming out with all these new drugs, these new immune therapies, is there still a role for some of these older mTOR inhibitors for the frontline treatment? So this is an article that was actually published a little over a year ago in one of our oncology journals, The Lancets. And this is from Brian Rini who practices out of my old stomping ground in the Cleveland area looking at basically if we take patients that have asymptomatic disease meaning they were diagnosed based on a scan that was either done for surveillance or another indication and then had confirmation of metastatic disease if we actually watch them before doing treatment kind of what's the typical trajectory on how long they would actually need or could be watched before treatment would be indicated. So when we talk asymptomatic these are patients that basically walk into clinic and look extremely well. So some patients with advanced disease will have either pain symptoms. They can have tumor that's blocking structures that can be causing problems. They could have symptoms as far as cough or other shortness of breath if the disease is in the lung. So these are patients that wouldn't need treatment for any other reason. So what they did on this study is basically no treatment was started and they did repeat scans at set intervals usually about every three months just to see how fast these tumors are growing knowing that kidney cancer in general tends to be one of the slower growing cancers. So can we actually if we only have a one centimeter tumor spot if that's going to be slowly growing over a long period of time can we avoid some of the initial toxicities of treatment knowing that compared to when we're looking at earlier stages where we're trying to cure the disease all of our treatment options are mostly trying to control so if we can get a little bit more time just by watching and avoiding the treatment side effects until we really need them is one of the considerations of this study. So this is what we call a Kaplan-Meier curve that we'll be seeing a lot of throughout the rest of the talks through the day which basically plots patients on a clinical trial so everybody starts here at 100% and then whenever an event happens on study that causes basically a drop off on the curve so an event can be depending on what the endpoint we're looking at so if we're talking about progression free survival an endpoint that we look at that's looking at how long does it take for growth of the cancer to be seen overall survival is another endpoint that we look at meaning how long until there's actually a death of a patient on a clinical trial so these two curves are looking basically breaking down at these favorable versus unfavorable groups looking at some of those prognostic models that I had mentioned so clearly if you have more unfavorable features it takes less time before we would actually need to require a treatment if we're just doing surveillance so on average those patients it took about eight months before the clinician and the patient felt there was some indication to start therapy while on observation versus it could be actually much longer in the low risk group or the favorable group sometimes more towards the two years so this is something that particularly if we look at a scan in a patient it's completely asymptomatic we may consider even just watching and seeing where we're at in another three months to kind of see is there actually significant growth of disease just to kind of buy a little bit more time and avoid some of the toxicities of our treatments for a little while longer so getting to the treatments I'll talk about at least review the clinical trials on probably the two most common tyrosine kinase inhibitors that we use the first is Sunitinib or Sutent and then I'll review Votrienter, Pizopinib so all of these target not just VEGF or the VEGF receptor which is these blood vessel blocking drugs but they have a few other off targets as well so the dose that was approved through the FDA was this 50 milligrams once a day on this four week on two week off schedule although when we actually use this in practice we find a lot of patients actually have a harder time with this administration and there's actually good data and alternative dosing schedule where we give the drug for two weeks on one week off and at least from everything that we know about using it in that fashion it's felt to be equivalent so a lot of oncologists both here and throughout the country have a different dosing administration and we feel that that is equivalent to what was initially approved in 2006 so this is looking at the Kaplan-Meier curve from the initial Sutent study when they were comparing it to basically the only standard that we had available at the time which is Interferon so kind of a rule of thumb when you're looking at these Kaplan-Meier curves back in the room and you can put your thumb in between the curves that's usually a positive study and tells us that there's probably a good treatment effect between those so you can see when we compared it to one of our older treatments Interferon clearly patients that took Sutent ended up having control of their disease for a lot longer and then if you actually look at what the responses are when we kind of grade these CT scans on patients that are coming back so anybody that's either been on a clinical trial or known somebody that has been on a clinical trial knows they get scans fairly frequently sometimes even more often than we would generally do and that's to take measurements to kind of assess what the response is so part of those responses are what we call these complete response and that would be when we actually would see no evidence of cancer on a scan and then more commonly at least with these drugs we see at least some reduction of what we call partial response is what they're looking at and with Sutent clearly had more of a response compared to the older treatment with Interferon and then this is the follow-up where they looked at survival the curves are not as far apart you can see there's definitely separation compared to the old standard with Sutent compared to Interferon so in comparison another Tyrosine kinase inhibitor is Votrientropizopinib so this is another blood vessel blocking drug that inhibits all these VEGF receptors as we had talked about and generally the starting dose of this would be several pills a day or 800 milligrams and the drug actually you can have higher absorption actually if it's taken with food so a lot of these drugs we end up taking short from meals for that reason and this was actually approved in October of 2009 based on improvement in progression free or taking a longer time for your cancer to grow compared to placebo and this is a little bit of a fuzzy Kaplemeier looking at that compared to basically a placebo or a sugar pill Eusepizopinib led to significant tumor control for a much longer period of time and led to approval of this drug as a treatment option so these are two most commonly used Tyrosine kinase inhibitors so patients would come into clinic and it's always kind of a toss up on which drug we would pick and raise the question is one better than another so this is the compares study that actually enrolled a large number of patients over a thousand randomizing them to receive either Sutent or Pizopinib on this phase 3 clinical trial so the Sutent schedule ended up being that kind of approved 4 week on 2 week off rather than one of the other dosing recommendations and what we learned from this study is that the two drugs are essentially equivalent to each other so this on the left is looking at a human free survival or how long it takes the tumor to grow and you can appreciate these curves overlap meaning there's really no difference between Sutent versus Votrient as far as control they both seem to work or one is not worse than the other and this is actually overall survival or chances of dying on either of the treatment and again they're very similar between those one thing that I noticed is they actually gave patients just satisfaction scores and quality of life assessments meaning did one of these treatments tend to cause more side effects than the other so one thing that was noted is that there's definitely differences in some of the side effects between the two so Sutent overall tend to cause a little bit more fatigue or decreased energy again this is on that 4 week on 2 week off regimens so definitely we can see some modification of those side effects with different administration regimen and then Pizopinib can cause some other side effects but overall patients on the study seem to prefer to tolerate Pizopinib a little bit better but there's different ways that we can give Sutents as well yes Votrient or Pizopinib based on the study when they were just asking patients which of these they had done better and there was another study where they actually had given both drugs basically they gave one group Pizopinib first and then Sutent and then switched and then just actually asked them which one they preferred and Pizopinib was tended to be preferred even on that study but again Sutent like I said can be given a little bit differently so that can take away some of that more of the side effects that Sutent had so moving on to Toricella or Temsirilimus this is the one of those mTOR inhibitors or one of those drugs that interferes with that signaling pathway that causes cell growth and division so this is one of the only IV drugs I think the only IV drug that we use out of these agents and has been available based on the study comparing it to one of our old standards interferon so this got approval basically looking at patients with the worst risk features so basically those risk stratifications this would be patients that we would predict would have worse outcomes and they looked basically comparing the old standard of interferon to using this mTOR inhibitor Temsirilimus alone took the combination of them looking at survival as the primary endpoint so this is the Kaplan Bayer curve looking at each of those arms and you might be able to appreciate sorry the figure is a little bit fuzzy that this green line is the Temsirilimus arm and that one was basically showed a longer survival compared to either the combination or using the old standard interferon alone so based on this this led to FDA approval and this is one that though it's tending to fall more out of favor as new therapeutics are coming along it's still a consideration for this poor risk group based on those initial parameters so one of the newer kids on the block at least within the tyrosine kinase family is kabosantinib so this is a small molecule that hits not only veg f but some other targets as well which can cause a little bit more side effects than some of the other kind of more direct veg f inhibitors so this was improved in March of last year for patients that had basically disease growth after being treated with a tyrosine kinase inhibitor and this is basically the phase two study that compared this drug kabosantinib to one of the oral forms of the mTOR inhibitors which was kind of one of our go to drugs and for second line treatment before we had a lot of these immune therapies so kabosantinib basically led to longer control of the disease compared to the other oral mTOR inhibitors so this raised the question is yeah so this has a few other offset targets can we actually move this up earlier and this is a phase two study called kabosun where they actually tried to answer that question by comparing kabosantinib to sutent looking at disease control or progression free survival as the end point and they were looking at basically patients with worse risk so on those risk models looking at intermediate and poor risk with about 80% being intermediate risk and 20% being poor risk on this study so kabosun kind of confirmed that definitely there is some improved disease control with kabosantinib as compared to sutent and response rates were also a little bit more there were a few patients that actually had dropped off the sunitinib arm maybe a few more than the kabo which raised the question is there a better schedule that could make sutent a little bit more tolerated but at least based on the data that we have there may be some role for kabosantinib in the first line setting especially in those intermediate and poor risk group patients although this as of today is still approved only for the second line treatment or in patients that have progressed after a prior VEGF so this Kaplan-Meier curve is looking at what we call progression free survival so each of those lines is an event where on study the patient would have a scan that showed some tumor growth or progression so yeah that's when that's what each of those hashtags mean versus some of the other curves sometimes we'll look at overall survival which would be a patient death that would kind of mark those so it depends on kind of what the axis on the curve is looking at so those are kind of the treatments we've been using in the past years and now more recently we've been using immune therapy drugs and have had those available for the last two years or so in patients that had disease progression on a tyrosine kinase inhibitor and this was a press release actually from September of last month looking at combinations of immune therapies for patients that have had no prior treatment or looking at this in the first line setting so I had started this talk saying that kind of the treatments we choose are evolving so this is kind of an exciting update that was presented just at one of our European oncology conferences in September so we're anticipating that there's likely to be an updated FDA approval for this that will kind of adjust which treatments we think about and can actually add this as one of those options going forward and Sumit will likely be talking more about this in his talk so just a quick slide on treatment effects while I'm finishing up so each of these drugs has a unique kind of class of side effects anybody that's seen patients on these tyrosine kinase inhibitors probably knows that the blood pressure is one of the more common effects that we need and our patients come to clinic actually with diaries monitoring their blood pressure definitely we can see other changes particularly in the skin and in hair particularly vortirant can cause some whitening of the hair and then this hand foot syndrome is another common side effect that we see with any of these TKI's and then we do frequent monitoring of their blood work as well just looking for abnormalities in liver function tests and any other changes in blood counts that would be concerning with the mTOR inhibitors probably some of the more unique side effects is this pulmonary effect that we can see and depending on the studies somewhere between 1 and 5% of patients may have what we call a monitis which is just inflammation in the lung that can frequently just start presenting with cough or shortness of breath so that's something that we pay attention to that may require an adjustment in treatment and sometimes even stopping it and needing to treat with steroids if there's a lot of inflammation to bring that down and then Sumit will be talking more about the side effects of these immune type therapies which fatigue is probably the most common that we see but then since we're taking the brakes off the immune system we can get some of these immune reactions where our immune system can attack essentially any part of the body almost like an autoimmune type disorder so he'll be going into that more details during his talk so in summary our treatments consist of three large classes of drugs the blood vessel blocking veg F inhibitors the mTOR inhibitors that work on this cell proliferation and by slowing down that cell signaling and then these newer immune therapy drugs Pizopinib and Suthent as of today still remain first-line treatment options although that landscape is continuing to change as more drugs are studied and become available especially in combinations particularly for the porous group Timserolimus is still a consideration for upfront treatments again they're tending to fall out of favor here and then I had mentioned that Cabozantinib there's some data on use of that as kind of a first-line treatment option although we don't currently have an approval just yet for that and then for any patient that's progressed after one of these initial treatments treatment with either immune therapy basically a different veg F inhibitor or even combinations of these with veg F and mTOR are all reasonable options and then we expect that this is going to continue to evolve as more treatment options become available down the line any questions there so you talked a little bit about risk factors and you talked about how you assess risk factors or can you say a little more about how you define good intermediate so there's a few different algorithms that we look at I just put the Sloan Kettering as an example and it's all based on some of those presenting variables so a lot of those are lab abnormalities all of them tend to include how long it takes from diagnosis to when treatment is started so all of those just give us a little bit of sense on do we think that a patient is more likely to have a worse outcome earlier that can be suggested by some of those risk models hmm hmm yes hmm yeah so the FDA they review all of these large clinical trials and then determine based on that proven efficacy if they'll give approval for the drug based on the yeah how well the drug works and what the safety profile of it is to what extent does the firm and great determine treatment options so at least as far as grade yeah it wouldn't necessarily impact yeah which treatment that we think it does play a role kind of in the risk of the disease itself hmm but necessarily we wouldn't choose one treatment yeah just purely based on the grade there's some data looking at like the histologic subtypes that Dr. had talked about particularly there's some data looking at chromophobe and there's some phase 2 studies that may suggest possibly using mTORS may have a little bit of a signal or more benefit compared to the VEGF inhibitors so we take all of that in consideration yeah when we're doing those initial evaluations do you know if there's going to be a discussion about the efficacy of radiation versus immunotherapy yeah I don't think we have a scheduled balance out of radiation one of our topics for today but I can speak to it a little bit we don't use radiation we think about radiation more like surgery it's really a local treatment so if there's any one particular area that's bothersome radiation is used so typically it's used for either bone disease that may be painful it's used again you know as an individual site but really when we think about systemic treatments when there are multiple sites and wall radiation might not be an appropriate treatment any other questions yeah most of them that medicine lasted like somewhere around 8 to 10 months and then you start noticing a dip is that correct that would be about an average expected time span which is why it's important that we have new treatment options and expanding treatment options because eventually all of these treatments have a set failure rate so we're trying to learn not only other therapeutic targets but then can we combine these to get further efficacy and then depending on how the drug works if someone has a lot of cancer compared to someone who just a little bit if the side effects are more intense or not as bad yeah the burden of the disease shouldn't really affect the side effects on the drugs but kind of depending particularly sometimes we can see some immune flares so if there's a lot of disease burden then particularly that's something that we'll pay attention to which has kind of been a more unique phenomenon we've seen with some of these newer therapeutic drugs as opposed to the VEGF we generally some of the older oral drugs we don't see that same type of flair sometimes with those Thank you so much Brian and thank you all for your questions we're really glad you were engaged