Best agents for 2nd line and treatment of metastatic clear cell renal cell carcinoma

good afternoon everyone it's a pleasure to be here thank you so much for having all of us okay so my talk is entitled what are the best agents for second line and beyond in the treatment of metastatic clear cell renal cell carcinoma it's a mouthful it's going to pay you back right off of dr. Harrison's talk so dr. Harrison did a beautiful job of covering what we use frontline I'll go through all the other agents that are approved in kidney cancer and sort of how we think about them and stratify them in terms of what to do next sorry I just forwarded a bunch of slides these are my disclosures so you guys have heard a lot of this background already but as you know there are several different subtypes in kidney cancer the most common of course is clear cell kidney cancer which makes up 75 to almost 80% of what we see so most of these drugs are very well studied in clear cell disease and so that is the data I'll be presenting today and we've talked at length about the associated VHL mutation and clear cell kidney cancers and again there's two distinct patterns here there's the familial genetic VHL syndrome versus the sporadic VHL mutation that occurs in the majority of clear cell kidney cancer so what does the VHL mutation do it basically causes a state where that tumor cell does not have enough oxygenation it's hypoxic so there's a lot of different regulation of factors that try and grow blood vessels to that area so as to provide more oxygen and nutrients and so this veg F pathway becomes a very logical target for our cancer agents you heard from dr. Harrison and some of the other speakers today about our different strategies for risk stratifying patients as you heard there's the Memorial sloan-kettering score and the IMD C score and these have become increasingly relevant because a lot of our recent approvals in kidney cancer have been based on that patient's risk criteria and so this takes into account laboratory factors like anaemia it takes into account somebody's sort of performance status which is basically there strength and function on a day to day basis it takes into account sort of the timing of their diagnosis to the point at which their metastatic so this is the Memorial sloan-kettering score the IMD C score has a lot of similar criteria with some differences in the labs that we monitor and that helps us to sort of get in our minds a sense of the biology of a patient's tumor so is this somebody who we think will behave more indolently with sort of a slower tumor or is this somebody who we are worried is sort of quote unquote on fire where things are moving quickly and we need to kind of get to action very quickly so as dr. wood mentioned we didn't have much before 2006 and gratefully we have a lot of options now but putting it all together is something that is still very much a work in progress and sometimes the more we know the more we don't know about sort of what comes next and so dr. Harrison just covered the data kind of on the bottom right here where I'm so the Cabos on data and the checkmate to one for data brought Cabazon to nib and nivo it be into the front line setting very recently I've just highlighted a couple things to put on your radar there were two very recent studies that just resulted out that are combinations of immunotherapy and tki and so these have not been approved at this time but approvals may be forthcoming so just to keep in your radar it says ilysm AB InBev assume AB is a combination of immunotherapy and tki as is a valium AB and exit nib so a little bit more on the general categories of course the veggie forty key ice act on the veg F pathway there are seven approved agents in this category and I'll go into each of these his open and Bravo treants and it number Sutent Cabos antennae or code medics sorafenib above assume a bore Avastin lin bat nib or lin vemma exit never written light out in terms of immune checkpoint inhibitors we have nivolumab or opdivo a nipple uma map or your voice and remember dr. Harrison's analogy these immune checkpoint essentially ramp up your own immune system to better recognize those tumor cells as being foreign and something that needs to be cleared from the body is something that's not self tumor or protein I'm sorry not tumor protein mTOR inhibitors are a targeted therapy they work on a different pathway than budget far there are two approved agents everolimus and temsirolimus everolimus is approved single agent by itself or in combination with one Batna and then as I just alluded to there are a lot of combination immunotherapy tki sort of novel treatments that are coming down the pike and so I actually have a slide later with all six different combinations but that's gonna be I think increasingly important moving forward potentially and then of course you guys have heard about clinical trials there's all kinds of different novel agents coming along as well and so probably in a year from now this slide will be incredibly hopefully out of date things have changed so much in the last year even so recapping sort of in 2017 in the good and intermediate risk patients we use sunitinib or PES openiv primarily and in poorest patients there was data for temsirolimus after that frontline we sort of had this basket of other TK eyes I'm torn Heba ters immunotherapy to turn to in 2018 things really shifted with the advent of the data from checkmate 2 & 4 whoa sorry okay with the data from checkmate - one for nivolumab and voluma mAb is being very commonly used in the frontline setting now and so how does that change what we do in the subsequent line that's a new area of interest Cabo's Sun has meant that more patients are being potentially started on cab posing internet upfront and then these combos studies as they come out people may get treated with a combination of TTI and IO in the front line so in the second line here are sort of our major options and I'm going to go through each of these but Bevis is mad pose opener exit NAB over almost tensionless cousing of NIMH ofe so how do we think about these so dr. Harrison covered is there a bus frontline treatment it depends is there an ideal sequence after frontline treatment failure and as IO treatments are incorporated earlier what does this mean going forward we used to think of kidney cancer in a very linear fashion if one thing doesn't work we go to the next if that doesn't work or works for some time and stops working we go to the next and now with these immunotherapies the question is do we keep this pressure ongoing if it stops working do we try different combinations still incorporating that or do we not do it anymore so how do we overcome resistance these are all things that are trying to be answered at the moment with different trials so going through the agents sunitinib is an oral small molecule inhibitor of Vecchi far it also hits other receptors such as pdgfr most commonly it's administered as a pill that you take once a day 50 milligrams typically people take it for four weeks at a time and then a two-week break in practical data sometimes there's modified regimens where people may take it for two weeks and be off for a week depending on on their you know basically side effects and tolerance of the therapy and this was approved in 2006 it was approved on the basis of this particular trial where sunitinib was compared to interferon which was one of the early immunotherapies that we use in kidney cancer you guys have seen a lot of these kaplan-meier curves today so I won't go into too much detail about it but the way we think about these curves is basically we're comparing two different therapies to each other so orange line here was sunitinib the green line here is interferon and what we're looking for with these kaplan-meier curves is we're looking for separation of the curves that indicates that one is better than the other if they're crossing it really tells us hey you know was something really superior here and then we're also looking for the tale of the curve are we extending people survival for X amount of time because when we see that tail of the curve that means people are living longer pays openiv or vote ran is also in a bunch of our inhibitor also hits other actors and piss openiv unlike sunitinib is dosed continuously typically so people take comes in two hundred milligram tabs people take four tablets a day and they take it every day this was approved in 2009 and again and the original data you can seep is open it was superior to its competitors in our traditional kaplan-meier curves except it's veg F RC kit and pdgfr it started at 5 milligrams twice a day exit nib has a shorter half-life than most of these other agents which is why it's twice a day and most of the other TTI's are once a day and there's data in exit nib for dose adjustment up which is unusual for the TPI so you may notice your oncologist may mention hey we need to go up on this dose or down on this dose that's frequently done with next setting em there's improved progression-free survival with exit nib when it was compared to sera fin him in the second line and beyond setting Nivola map is a PD one checkpoint antibody as dr. Hass mentioned this morning originally it was approved for every two week dosing however recently we do have this approval for administering double the dose every four weeks which is kind of nice in terms of convenience for our patients it's less trips to the doctor to get the infusion since it is an IV medication and originally it was approved actually in the second line setting as a single agent so you heard a lot about the combination of nivo and it be in the front line but originally this was actually used single agent in later lines of therapy and that was on the basis of this trial which compared the volume AB and everolimus which is one of the mTOR inhibitors and Nivola mab had a clear overall survival advantage over ever Lemus now one thing that was really unique about this trial is this quality of life data that they collected and this is something that is much more frequently being done in kidney cancer trials now which is really great because we're paying attention to the symptoms and day to day effects of these therapies on our patients lives so not only did nivolumab have an improved survival but patients felt a lot better on Ebola map compared ever Lemus as well it had less side effects Kappas Nanton AB is a inhibitor of vag affair and it hits some additional targets called axial and met it comes in 2040 and 60 milligram tablets typical starting dose assists 60 milligrams a day and it was approved initially also in the second and subsequent wine setting after a previous tki therapy but with the Cobo some data earlier this year kaboo Santina became approved in the front line setting as well so the original data for sort of subsequent line setting for a cab as Antonia was with the meteoroid trial it compared cab is Antonia limas in patients that had previously gotten a cheeky I usually it was his open a person at nib and Cabos Antonov had a superior overall survival compared to everolimus and then I wanted to introduce you in the Cabo Sun data that dr. Harrison just presented to you guys not only did it show improve progression-free survival but you can look at the waterfall plots which the idea behind waterfall plots is they actually show you the change in tumor burden so at the you know at 0 is sort of where the tumor patient's tumor burden is at baseline and then on Cabos antony boron whatever treatment when you see bars that go up that means that you more grew when you see bars that go down that means the tumor shrank and you can see that a lot of patients really got change in sort of reduction of their tumor on cab byzantium you see that definitely what sue 10th to but sort of favored kilos Antonin Lin VAT nib targets vuja far FGFR pdgfr right and kit it is approved in conjunction with our alignments when you they actually did a three armed study for this agent so when VAT nib alone was compared to everolimus alone it was compared to the combination of both of them and the combination of the two led to both improved progression-free survival overall survival and response rate and so this is another therapy that we frequently utilize so putting this all together what do we choose I just named seven different or ten different agents for you guys how do we how do we figure out what to do in reality there's not a lot of head to head comparisons and with the rate that our approvals are coming out there will likely never be a trial that compares everything had to head to head where we can say X Y Z is the absolute best but in reality maybe that's not even a good question to ask because patients really end up getting multiple of these as I mentioned each of these hit different receptors so maybe if tumors are resistant to one the fact that you're hitting other receptors means that you bypass that resistance with one of the other agents and so really most people have at least several of these agents we also take into account a lot of patient specific nuances and so particularly for example with lab functions in a patient who has liver function issues we might not want to choose something like his open it which can cause a higher issue liver dysfunction with sites or volume of disease sometimes for example if somebody's got a lot of bony disease we have data that Kappos the internet works a little bit better in bony predominant disease and so we might favor that this side-effect profile we take into account quite often so while these are sort of a similar class um you know a couple of agents will have more diarrhea some will have more issues with rash on the hands or feet some will have more issues with blood pressure and depending on a specific patient's individual medical comorbidities we may want to avoid some of those and so we might choose something different I'm gonna go into a little bit of sort of the side effects of all of these agents in reality with kidney cancer because we have so many options we think of it as a little bit of a marathon and so part of our job and I think a really important part of our job is to help keep you feeling well as you're going through therapy we can't afford to let our patients get beat up on these agents because we have second and third and fourth line things we can try so we have to keep you feeling well on these so what I tell my patients is that with Tk eyes side effects are easy on easy off in that you're very likely to have sight if there's a very predictable pattern of side effects that occur but we also have pretty easy ways of troubleshooting them or helping you feel better on so what do we watch for we watch for blood pressure most patients on T KS are going to have an elevation in their blood pressure when we see it happening we take it as a good sign the drug is doing what it's supposed to be doing but of course we want to protect your heart make sure your you know other medical issues don't become exacerbated by this and so we do need to control it and change up your blood pressure regimen potentially diarrhea is another common one I have a whole slide dedicated to diarrhea in just a minute fatigue tastebud and appetite changes mouth sores and then thyroid issues are really common on all these agents and so your oncologist is likely checking your thyroid function intermittently with labs to make sure you don't need an adjustment of synthroid or something like that so diarrhea I find that imodium is grossly underutilized by most of my patients it's we tell people it's okay to take up to 16 tablets a day but if you're anywhere close to that we need to be hearing about it away before that is what I tell them and so if if you know for sure you take your tki in 30 minutes later you're running to the bathroom I tell my patients wake up take two imodium before you even start eating for the day if you're not in that boat if it's sort of more intermittent you can certainly use it as needed but don't be shy on the imodium because when you have severe diarrhea that's not controlled you're at risk of dehydration you're not absorbing things while you're gonna be fatigued and so you know prevention is really helpful there probiotics can help I will say we there's recent data saying probiotics are not good to be on with immunotherapy and so I do recommend them on tki but maybe if you're on immunotherapy maybe don't don't be on probiotics Metamucil is actually a really good trick and so it's funny because we think of Metamucil for constipation but if you take a scoop of Metamucil and stir it into something thick like applesauce or oatmeal it can really help bind up the bowels so that can be a really helpful trick and then sometimes we do have to adjust the dose that is not uncommon you don't have to feel bad if your oncologist says hey we need to go down by a little bit on your dose or we need to think about an alternate dosing schedule like take your meds Monday to Friday and give yourself a weekend break part of these strategies are to help keep you feeling well and so oftentimes we do need to rely on those adjustments to make sure we're keeping your functional status up to par hand-foot syndrome is also quite common with these basically a blistering type rash on the hands or feet it's particularly common in the feet because it's a weight-bearing area and really here moisturization is the key you want to buy a nice thick lotion really you know kind of greasy and moisturize the hands and feet twice a day at least if it's a really severe again we think about doing you know dose changes or breaks and then we also have prescription strength things that sort of help numb that up to make it more comfortable mouth sores and tastebud changes are another one that we see often a simple home remedy of what I call salt and soda which is a glass of warm water teaspoon of salt teaspoon of baking soda and just gargling with that multiple times a day really helps to prevent that and then again there are prescription strength things to sort of coat the mouth the taste bud changes are a lot harder and I'm sure many of you have experienced appetite changes where nothing tastes quite right there is a couple things you can do there's zinc supplements you can take and then there's something called M berry which you can order on Amazon but it makes everything taste sweeter 50/50 on this some of my patients love it some hate it but if you really are in the boat where things taste terrible you can try that immunotherapy side effects are a whole different ballgame okay we call them the itis a--'s I just means inflammation and so what's the what's this concept and immunotherapy we're allowing the immune system to ramp up and if the immune system gets overactive it can cause damage to normal self tissue or inflammation in some other area part of the body so immunotherapy severe side effects are relatively rare most of our patients feel really well on immunotherapy but when they're developing side effects they're often more subtle it's not like the TTI's where I said they're easy on easy off these are much less likely happen but when they happen they can be more nuanced and subtle and sometimes difficult to pick up upon however they can be quite serious if we don't catch them and so you'll notice your oncologists always have their radars up when you're on immunotherapy in particularly combination immunotherapy like the Eppley map and Nivola map we ask a litany of questions just you know making sure everything's okay are you having diarrhea are you having a rash are you having a cough are you having changing your energy level looking for signs and symptoms of whether that immune system is getting overactive the truth is it can happen in any part of the body which is why sometimes it's nuanced is that it's it's hard to pick up on but I'm gonna go through some of the more common ones that we watch her in just a second here so endocrine Appa these are basically a change in in hormone levels of some kind so thyroid is a common one but on the volumen nuvola map in a blooming map one of the things we watch for is actually dysfunction of your pituitary gland where your adrenal function can can be affected and so people feel very very fatigued they can have issues with sort of their blood pressure and so that's a big one we watched for it's not common at all but one of those things we don't want to miss colitis or inflammation in the in the colon causing severe diarrhea is another one if it's relatively mild you know sometimes it can be sort of managed with sort of supportive interventions but if people are having more than seven bowel movements a day that suggests the colon really is very inflamed and then typically we need to get involved with systemic ways of calming down that immune system anytime these immune mediated adverse events happen we're looking at something like steroids to calm the immune system down steroids are a first pass sometimes it works but with these immune related events sometimes as we taper down stories those symptoms can rebound and when that happens we sometimes need to reach for other rheumatologic type agents to keep that immune system under check so don't be shocked if your oncologist mentions other agents that typically you think of for autoimmune diseases we often use those in these subtypes of vents pneumonitis or inflammation in the lungs is exceedingly rare however if somebody develops cough or issues with oxygenation or getting winded when they exert themselves it's something again we don't want to miss because it can get very severe hepatitis refers to basically inflammation in the liver so every time you go in for your mayo therapy your oncologist is probably checking your labs and part of that panel we check is going to look at liver function tests to make sure there's nothing like that going on the 3 in red at the bottom are the ones that I hear most often on a day-to-day basis so I kind of mentioned some of the more rare stuff but the day to day stuff we hear a lot about our sort of joint aches and pains so people often say hey you know I've always had arthritis but all of a sudden I feel way more creaky it's a lot worse those are typically managed with lower doses of steroids or other rheumatologic agents but again a quality of life issue thyroid I've mentioned and then skin rash which can typically be managed with topical steroids I want to take just a moment to touch on some interesting upcoming data you have a whole lecture dedicated to novel treatments coming up but just some of the data that's just coming down the pike so combo IO tki treatment and then as we use more of these immunotherapies in the front line what happens to the response to these T key is in the second line and Beyond and so there are currently six actually probably even more now trials ongoing combining different io s and T key eyes and what this chart is showing is this is these gray bars are showing the disease control rate that refers to the tumor is either stable or shrinking and you can see in all of these combos that we're hitting somewhere between eighty and a hundred percent so almost all these patients are deriving benefit from these combinations in terms of it being stable or shrinking which these are pretty unprecedented numbers in single agent TTI's or single agent immunotherapy so the combo does seem to be effective these trials of course I mentioned these front to the bevacizumab it says ilysm ab and exit number value map just resulted out and so we do have data to support them but one of the big questions going forward is what's this going to do for an overall survival trend in the coming five and ten years and it's just too early to know that still but a very promising sort of area that we're all excited to see what happens as immunotherapy is used more in the frontline you know we were all kind of wondering does this mean Tiki eyes are gonna be just as effective in the second line this is unpublished data but we just took a quick look at our cohort of patients at MD Anderson so we had we had way more than this but we had 42 patients who were treated with upfront IO in the context of a clinical child before it was approved when when all the immunotherapies in the front line were in clinical trials you know there were 42 patients we collected that had either stopped deriving benefit or had progressed her HUD adverse events and then went on to receive a TI so that exact scenario a frontline immunotherapy second-line t ki and really our patients did really well on it they had minimal issues with adverse events and when you look at the water flow pot every single one of the patients had reduction or stability in their in their tumor burden in the second line T ki so you know it's early days in this setting but it does suggest that the T key eyes have not lost efficacy by not being used frontline that there's still a valid very good option in second line and beyond so looking ahead thankfully we have a lot more options than we used to combination options are exciting but we also have a lot to learn about when someone becomes resistance resistant how do we sequence these things what's the optimal sequence how do we better select who's gonna respond to T ki who's gonna respond to IO who's not going to respond and sort of tailor individual therapy the standard of care will continue to evolve which is a good thing but it also means that each time that changes it affects what we do down the line I think personally tell everybody and quality of life are huge here and that's a big part of what what I deal with on a daily basis with my patients in clinic is we have to keep you feeling well to keep getting to the next best treatment and predictive biomarkers as I mentioned are going to be key in terms of right patient right treatment there's so much work being done on it it's a huge area of controversy and interest and so hopefully in the coming years we'll be a lot smarter about what we're choosing I really want to take a moment to thank our patients and their families you know our you guys show a tremendous amount of grace and courage and hope on a daily basis and that's that's pretty amazing in the difficult situation and so you guys are a true inspiration to us to keep working and trying to improve things families as well caregivers being absolutely a vital part to keeping our patients happy and healthy thank you to the KC a and and also to my mentors and friends at MD Anderson I wanted to highlight a couple of my my I have their permission to show their pictures and everything this is Bruce who we were not sure we'd be able to get him to surgery here he is after a very successful surgery he's recovered in eating a Texas shaped pancake this is this is Mike and he six years ago was was diagnosed with advanced disease and is doing amazing on his current therapy his scans show no sign of cancer he's a professional racecar driver and has won six or seven major series he's also in the world poker tournament in Las Vegas every year and so he's he's really enjoying every moment to the fullest this is Maria whoo right around the time of diagnosis of advanced disease with a very rare tumor type not clear cell but um was was found to be pregnant she is doing okay but her her baby is now nine months old happy healthy cutest baby you've ever seen and then a very very special shout-out to Nick Harmon who's here today with his wife Kem Nick joined the Texas game wardens in 1985 he retired just earlier this year after 33 years of service I wish I'd actually showed you guys more pictures but he was out on the bay rescuing sea turtles while on active you know treatment for kidney cancer and when Nick got diagnosed one of his buddies told him well unions just need to get bit by a radioactive spider like spider-man and you'll be you know fine so Nick really took that to heart every single he's gonna hate me for shyness but every single clinic visit he comes with spider-man boxers or a spider-man t-shirt yeah and so you know we're gonna keep working to find that magic spider bite so thank you guys all very much [Applause]