 I'm Rhonda Bitting, I'm a medical oncologist from Wake Forest in Winston-Salem and I am going to talk with you this morning about sequencing of therapy for metastatic kidney cancer and as a little bit of a caveat to this, I could say almost anything because there are a lot of therapy choices for kidney cancer and there's not really a right or wrong way to way to do this but I will try to answer the questions that the field has already answered and then I'll draw your attention to some of the questions that remain in the field that we still need we still need help answering and then just so that we're all on the same page and speaking the same language I think I'm the first person today talking about advanced disease so I'm talking about metastatic cancer, cancer that has spread that is seen on imaging outside of the kidney and so I'll go ahead and get started so this is a good time to be a kidney cancer doctor it's been a there's a wealth of options available to us and things have changed very quickly over the last 10 or 15 years so as you see here in the slide even over just the last two or three years we've had new drugs approved for the treatment of advanced kidney cancer and we basically have almost an embarrassment of riches we have drugs that fall into five different categories we have drugs that treat that use your immune system to fight the cancer immunotherapy we have oral agents that target different pathways the VEGF pathway which I'll talk a little bit more about the mTOR pathway we have combination treatment and we have oral drugs that target multiple pathways and so we have a lot of options the drugs that are shown in yellow are the ones that were approved over just the last two years and with all these options brings a lot of questions as to what drug to give to who when and I'm not going to go through this other than to show that we know we've learned about 15 20 years ago now sort of more about the biology of how kidney cancer works and we know that there's two main pathways that are important for the development of kidney cancer and the and the spread of kidney cancer and those are the VEGF pathway which is shown here and the mTOR pathway which is over there the pathways the point of in either case is that when those pathways are active cancer cells grow proliferate so the goal of treating based on those pathways is to block the pathway to block the signaling so that cancer cells can die and so as I go through this I'm going to go through some of the questions that have come up in the field over the last 10 15 years and one of which is now that we understand that these pathways are important for kidney cancer is there one that is better to target first so should we target the VEGF pathway first or should we target the mTOR pathway first when we're trying to treat patients that have advanced or metastatic disease so this has been asked in multiple ways and for the most part has been answered we say in general we know that in first line therapy targeting the VEGF pathway is better there's been probably the most definitive study to show this is this study that I mentioned here where everlimus was patients were started either with everlimus which is an mTOR inhibitor or Sunitina which is a VEGF pathway inhibitor and then when they progressed they got the other drug and it essentially showed that it was better to start with the VEGF pathway inhibitor in general now there are some exceptions to these rules but in general that was better another question that has come up is does it matter what type of kidney cancer you have so the most kidney cancer is clear cell kidney cancer about 10 to 15 percent is considered non clear cell kidney cancer and non clear cell kidney cancer has a little bit of a different biology and so the question has been asked is it better to treat with a little different drugs if you're treating a different biology but at this point in time we still believe that starting treatment with a VEGF inhibitor regardless of the underlying subtype of the cancer is the right way to go so is it better to target VEGF or mTOR when you're starting out well we think and we think VEGF but there are some exceptions to this rule which I didn't really get into but across the across the board we usually start out with the treatment that targets the VEGF pathway so if we know that there are two pathways that are important in the biology of kidney cancer wouldn't it make sense to just try to target them both at the same time and maybe if you could target both pathways you would have a better effect on the cancer so this question has also been asked many times in many different ways over the last 10 or 15 years combining the different VEGF inhibitors that are shown here the ones that are approved including some that never did make it to FDA approval and combining those drugs with the mTOR inhibitors which are either termed serolimus or everolimus and across the board we've determined that this combination might be better for treating cancer in terms of the effectiveness on the cancer but in general is considered to be too toxic for patients and I thought that this question had been sort of definitively answered until a couple of years ago when was a little bit of a surprise to me there was another study that was reported that used this drug when batonib which is a VEGF inhibitor but also hits a couple other targets and combined lenbatinib with everolimus and mTOR inhibitor and patients were randomized to receive the combination therapy or each of the drugs individually and it was shown that patients receiving the combination therapy which is this blue line here had improved progression free survival when you combined the two drugs versus either alone so this combination therapy is actually now FDA approved so the question can VEGF and mTOR inhibitors be combined safely the answer is yes certain drugs and certain patients the toxicity is still pretty high and then importantly this approval is only in the second line setting so the question that we started out was what do we start with when we're treating advanced disease so this is still not an option for when you start out to treat advanced disease so if you're supposed to start out with a VEGF inhibitor which one is the best this question has also been asked in a number of different ways over the years and two VEGF inhibitors were compared directly head-to-head pazopinib and sunetinib and in this study where the patients were randomized to receive one or the other we've shown that the effectiveness against the cancer is similar regardless of which drug you choose but there is a difference in side effects inside effect profile and so that led to another study where patients started out receiving one drug and then had a little bit of a washout period switched over to the other drug and at the end of all of this were asked which drug did they prefer taking and 70% of patients preferred pazopinib over sunetinib for a variety of reasons as shown here mostly better quality of life less fatigue less taste change less GI side effects so which VEGF drug is better to start with well in terms of fighting the cancer they're about the same but patients generally find that pazopinib is better tolerated than sunetinib now a caveat to this question is that this is only talking about clear cell renal cell carcinoma when you're talking about non-clear cell or the other more rare types of kidney cancer most of the data still sits with sunetinib and so you can't necessarily assume that these the same thing holds true so if it's non-clear cell sunetinib is still the way to start so we have kind of understood that either pazopinib or sunetinib are accepted as the first line treatment for metastatic kidney cancer but importantly multiple of these studies have shown that only about half of patients will be well enough to go on to receive second line therapy and so that really highlights the need to get it right when you're picking the first line therapy and so the question where there's been most action in the most recent years is can we do better than single agent VEGF inhibitor in the first line setting for metastatic disease and we have a few a few ways in which we've shown that we have that we can do better so this study is is the Cabo Sun study that has recently reported and is comparing patients with new diagnosis of metastatic disease to receive either sunetinib a pure VEGF inhibitor or Cabo Zantinib which is a multi-targeted oral agent that is already approved for kidney cancer but it's approved in later stages and so this study was looking at it when you give it when you're newly diagnosed first line therapy and they did show that at least in intermediate and poor risk patients and I'll talk a little bit about what that means in a minute that there was an improvement in progression free survival the blue line there in patients who were receiving Cabo Zantinib and so this is now an option for the well this is now not yet FDA approved but soon likely will be in the frontline setting and is an option in some patients for starting out treatment for metastatic kidney cancer and where probably the most excitement has come recently is in immune therapy in the frontline setting and I'm not going to talk about the details of immune therapy because I think we're gonna you're gonna hear about that in more detail from Dr. Amin in a little bit but I'll just go through a little bit about this study so Nevolamab is a immune therapy medicine that is already approved for kidney cancer in second line and beyond and this study looked at that drug combined with another immune drug called Ipollumamab and compared that to patients receiving Sunitinib in the frontline setting and so patients were randomized to get the combination of immune therapy or Sunitinib oral VEGF inhibitor and I'm showing you here again the data only for intermediate and poor risk patients which I'll define in just a minute but we see that the overall response rate was higher in patients receiving the immune therapy as shown over here with 42 percent of patients responding including a higher likelihood of complete and partial responses as measured on on imaging and patients are able to remain on this treatment longer which is what's shown over here also patients who are receiving the combined immunotherapy live longer which is the gold standard when we're looking at the these studies and they also have less side effects and a higher quality of life so now we have two studies that have compared either Cabozantinib or immune therapy in combination to the standard Sunitinib VEGF inhibitor and specifically have shown a benefit in patients who have intermediate or poor risk disease and so this is a sub grouping that's based on these things which basically is related to the time that metastatic disease is diagnosed how functional the patient is and a bunch of lab abnormalities or having normal labs will tell you whether you have risk factors to be considered good intermediate or poor risk and then these risk groups have been shown previously to correspond to the prognosis from the cancer so the question we ask is can we do better than VEGF inhibition in the first line for metastatic kidney cancer and the answer is yes we can at least at this point in time we know that we can give Cabozantinib and or nivolumab with ipilumumab well we can't actually do that yet because that's not neither of those are FDA approved yet but they're likely to be in the coming months so we have options but specifically for patients that fall fall into those risk categories so what do we do with the patients who who have good risk kidney cancer well at this point would they still get the tried and true VEGF inhibitor Pizopinib or Sunetinib so if I were giving this talk a couple of years ago it would have been a little bit simpler in the frontline setting patients would either get Sunetinib or Pizopinib then after that they would either get Exitinib which is another VEGF inhibitor or Everolimus an mTOR inhibitor and after that if they were well enough to continue on therapy they would get whatever they hadn't gotten yet this year it's a little more complicated and specifically which I didn't really get into because i'm talking more about the first line treatment but this year the last year or so most of the action has been in the second line setting where there's been three new options approved that have been shown to improve outcomes and survival for patients so in the first line setting patients are still getting VEGF inhibitors in the second line setting if they're well enough to go on to additional therapy they may get immune therapy an oral multi-targeted agent or this combination therapy that I had mentioned a little bit ago after that they may go on to get whatever they didn't get in the second line or then the other VEGF inhibitors and mTOR inhibitors that are out there and then if they're well enough whatever is left and I'm sure most of the clinicians in the room can attest that there are patients who are going through all of these treatments and and then some so I have a patient who treated through 11 lines of therapy and it's hard to even imagine so this is actually possible where patients are getting all of these all of these drugs over time now if I come back next year to do the same talk it's gonna probably have to be completely different because I think in 2018 the landscape is going to change again and this time I think it's going to change more in the frontline setting so the newly diagnosed metastatic disease where I think we will have more options so still if they have good risk disease VEGF inhibitor is where to go but intermediate or poor risk patients will have the options of being treated with immune therapy or kaboziansanib and then from there it's really who knows what what to do next after that we don't have any answers to these questions yet these are questions that are going to be hopefully answered over the coming years but there's a lot of options for folks moving forward and I could try to tell you the the right way to give to do this or the best option but I really at this point have no idea so there are there are factors that come into play having to do with with the science but also importantly with the patients so depends on patient symptoms the extent of their disease how well they're tolerating therapy how well they responded to the previous therapy so there's a lot of factors that come into play as to the best decision about sequencing therapy so I'll stop and just talk for a minute about a case of mine and I put this in here because I think looking at survival curves and trials that talk about improving survival on the order of a couple of months sometimes gets a little bit almost seeming negative so as oncologists we look at this data and we get really excited when we talk about patients living longer and we see survival differences but when you really look at the numbers one of the hardest concepts that I hardest conversations I have with patients is trying to explain what it means if we see in a study that somebody on average that patients live about two months longer with one therapy versus another patients will ask well two months should I should I risk the cost or the side effects or the inconvenience or whatever just for two more months of life and it's important to remember that these are averages and this is data that's compiled for us in the field to better understand the data but on individuals it's different and there are exceptions there are people that do better than the averages and people who do worse than the averages and so it's I wanted to stop for a minute and just talk about how this might look for a patient whenever you have all these options so this is a patient of mine who I started taking care of in 2014 he was about a year out from his original diagnosis of kidney cancer and had metastatic disease at that time. He received Sunit Nib in the frontline setting I think he was on the Cabo Sun study actually and he developed some painful metastases in his bones he got some radiation for that eventually progressed and went on to second-line treatment which was with a vegev inhibitor Exit Nib in 2015 if you remember my landscape this is kind of where we were so he started with Sunit Nib he went to Exit Nib and he had a rare serious side effect from Exit Nib had to stop and ended up getting some more radiation for painful metastases and right around the holidays about two years ago he was in the hospital with extra more with more symptoms he had disease in his spine and his lungs he was really sick and so we sat down together and talked about whether it was time for hospice and he had a goal and his goal was to get to this Disney cruise his whole extended family had planned a Disney cruise like 30 of them and it was in March and at this time it was January and his goal was that he needed to get to this cruise so we talked about what to do he decided he wanted to try additional therapy so we started Nevolumab which had just recently been approved at that time and he made it to his Disney cruise he was still in a wheelchair at that time he had also when we had started he was on a lot of pain medicines he had a catheter in his lung that was draining fluid within a couple of months that catheter was able to come out he ditched his wheelchair he started tapering down his pain medicine over the summer he was very active out chopping wood working in his garden hardly on any pain meds he gained about 20 pounds he was doing great that was last summer I just saw him last week and he's still still on Nevolumab it's been almost two years he's getting his 47th cycle and he's doing great and this is just highlighting the fact that we're lucky as clinicians in this in this field because things have changed so quickly so in 2015 I didn't think I had a whole lot that I could offer him and now here we are almost in 2018 and he still has a whole bunch of options ahead of him when when he needs them so it's it's a good time to be in the field so in conclusion we've had 10 drugs that are FDA approved since since 2005 there's more to come including likely in the next year we now have long-term survivors who have metastatic disease and so this is great but we can still do better and we need to do better so we need biomarkers that help us figure out which drug to give to which patients when and we need more data about how to take all these drugs that are out there and put them in the right order or the right combination so that we can improve outcomes even further and then I didn't even mention the fact that in some cases there's a role for surgery even in the setting of advanced or metastatic disease and we don't really know how to incorporate that into all this new data either so I think the standard of care will change over the next year but we have a lot of options and we still have a lot to learn. Any questions? Thanks. Go ahead. Yeah there's a couple of different ways that this can be defined a couple different risk classifications the most recent studies have used this international metastatic renal cell consortium definition which has to do with the time to metastatic disease so if you develop metastasis less than a year from your original kidney cancer that's one risk factor this one is about performance status so how functional you're able to be what your labs look like whether you have anemia whether your calcium is high whether your white blood cells are specifically your neutrophils are high whether your platelets are high so all of those factors are things that we as clinicians assess at the beginning of sort of metastatic disease diagnosis to help understand the prognosis of the patient well depend probably depends on when the diagnosis was because things have things have changed but right now I treat most of my patients with with vortrient when they're first diagnosed sounds very reasonable did you have a question uh a lot um they're they're okay good good yeah there there's a lot I think um there are both basic science research for us to understand more about the biology of the cancer to help make decisions there's a lot of research in looking at clinical trials about using all these agents in combination and how best to actually use the drugs and then kind of in between that there are studies looking at whether there's biologic factors about the patient that you can use to help predict which drugs to use so biomarker type studies any other questions all right thank you very much