Novel combinational therapies:Is the increased toxicity worth the possibility of increased benefit?

so I'd like to thank the organizers of this conference for allowing me the opportunity to talk to you guys about kind of novel combination therapies for the management of kidney cancer here are my disclosures so you kind of seen this list multiple times now ever since about 2005 we really have had 11 fda-approved drugs for the treatment of metastatic kidney cancer and this is really phenomenal growth and advancement within the field you know up until about 2005 or 2015 most of which have has really been single Asian therapy so back before 2015 this was kind of the treatment paradigm and if you had asked me like do we do combination therapy the answer would have been no what we really did was we took treatments and we used them kind of one after another in a very sequential sort of fashion so you you know progressed on one and then you move to the next and then if you work us on that you would move to the next so this is kind of looking at the different categories of medications in which the eleven can be classified into the first of which you know is has always been the largest group and this has really been based off of the mechanism by which the kidney cancer derives its growth and it's really targeting the blood vessels that feed the kidney cancer the second category is are the Amthor targeted agents and they are medications that work by changing the metabolism the kidney cancer that regulates growth and proliferation and more the new kids on the block now are the development of the immunotherapy is which you've heard multiple times work by boosting your own immune system to have your immune system better fight and recognize the kidney cancer now back before 2015 there have been multiple pro with multiple clinical trials looking at that as a possibility but up until that point we really the store was very simple like you combined the medications and we never really saw any increased benefit by using this combination I mean it seems like a very straightforward question like you know you take one from one category and you combine with one from another category you're attacking the cancer from two different directions and you would think that this is something that would work better but what we actually saw was when we combined some of these medications the amount of toxicity that we ended up seeing was significantly higher high enough that we actually weren't able to get to kind of high enough doses of the medications such that we could try to harness this sort of efficacy information so that's one of the greatest pitfalls is using combination therapy is whether or not we actually can get to both of the drugs which were initially designed to be used individually it's a high enough doses that we can actually use them in combination other times we've tried to combine two drugs that target the blood vessels and we've also seen by we saw great responses but unfortunately we saw a lot of toxicity that came along with it in which they weren't able to move forward just because of the amount of people develop toxicity from it so the first medication or first combination unit they're a combination that was fda-approved was the combination of Labatt and applause everolimus and this is a combination that takes one drug that targets the blood vessels that beat the kidney cancer and one drug that targets the metabolism so this was done in a randomized phase 2 clinical trial so at the time it wasn't designed as a registration trial that company wasn't thinking about using this to get FDA approval so it was a relatively small trial that took in about a hundred and fifty patients patients were randomized to either the combination of Lin bat nip at 18 everolimus at 5 or Lin bat Nevada higher dose at 1 four and everolimus at ten which is the fda-approved dose and they wanted to see whether or not there were the patients were able to be treated how long the disease progression free survival was and you know also to see whether or not they were stopped at unacceptable toxicity the fraud was designed to kind of look to see whether or not the length of response for each combination or each drug was better than ever lime is that's kind of the comparison arm so this is what they ended up seeing so they end up having about 50 patients in each group and then the patients who got combination when baton of everolimus had 43 percent of them had shrinkage of their tumor compared to 27 percent with own bangable own and 6% with everolimus by itself and this was thought to be statistically significant now most of these are what we call partial responses what a partial response really means is that you know you have greater than 30 percent shrinkage but you also have not it doesn't completely go away the other number to look at is how long was the duration response so as you can see the duration of response for the people who responded they had a median duration of response of 13 months and you know for the single agent arms limb fat and it was you know 7.5 months and then ever limas by itself was 8.5 months so even though there was a small percentage of people who had shrinkage of their disease if you did have shrinkage of their disease it did you know convey some good clinical benefit here another kaplan-meier plot that you've probably seen multiple times and what you do see is clear separation so the cyan color is the combination of Lombok no+ everolimus and you know on a whole the median progression-free survival is 14 point six months and then you know ever limas doing the worst with a 5.5 months and then magnify itself kind of in the middle but this in of itself doesn't really answer the question and we may not necessarily get the true answer the question of what if we used us to use them one after another like you know that's that type of trial often is we aren't capable of doing and so as a result you know we use these as kind of proxies like you go ahead and you get the drugs with kind of the highest possible response and you know you kind of you know assume that doing it this way is a little better this is looking at the overall survival numbers and you know because this trial was empowered to look at overall survival and overall survival gives us a better metric of what would happen if we use them sequentially but if you just don't have the numbers you may not necessarily see that you know from a numerical standpoint the combination of long diagonals everolimus was improved in comparison to people who got you know either everolimus by itself or limb Batna by itself so moving forward the new interest right now has really been looking at how can we combine the immunotherapies with other drugs because with the immunotherapy drugs that a lot of excitement has been centered around this and it does seem like using the immunotherapy is are a little bit easier to combine whereas the drugs that we've used for kidney cancer in the past we've run into a lot of toxicity issues with that so as you all have known on checkmate 205 this is a randomized clinical trial looking at Nivola map or opt Evo randomize against everolimus with a primary endpoint looking at overall survival with the key secondary endpoint of looking at the objective response rate so if you look from a progression-free survival standpoint by itself with single agent immunotherapy you know progression-free survival may not necessarily give you the tower answer because from the this you can see that progression for survival on Evo was you know four point six months everolimus was four point four what really does interest us about the immunotherapy is is the duration of the response for those that respond they sent teen tend to do much better and the idea behind combination there for this population is really to see whether or not we can either improve upon you know the response rates or to kind of see whether or not that long tail can be maintained and this is what we can see with this swimmer spot so a swimmers plot is basically every patient they get started on treatment and you kind of you know see how long it lasts for and you can see that quite a few people who were treated with new bola map you know we're still an ongoing treatment and kind of maintaining those results and this kind of bears out in the overall survival data which was the Oh at the end point in which if you got single agent you know therapy you definitely did better than not having gotten a single they become true name you know therapy so check me two one four was the first was one of the combination immunotherapies studies looking at if it will imatinib ola map which you've heard about and this was done in the first line setting but at the same time so this was a one-to-one randomization of getting combination immunotherapy versus the standard of care at the time which was Sutent patients were stratified based off of their risk stratification whether or not they had favorable risk intermediate risk or poor risk you know they were kind of put into separate buckets making sure that you know kind of the arms are balanced and patients who again treated until either progression or they developed kind of unacceptable toxicity related to the medications and this is where we see something very interesting so in people who had intermediate or poor risk disease and this is a very clinical sort of measurement of how patients are stratified you know the this has you know we're taking numbers that or that just come from a strong it in the blood that don't directly relate to you know the biology of the cancer and taking metrics as also in terms of how you feel as a patient and again like that gives us some clue about you know the cancer and being able to you know see differences in the treatment approaches well and what we ended up seeing is for at intermediate pour rust disease they did better on the combination of two immunotherapy drugs than they did on the standard vegetative therapy at the time you know with a forty two percent objective response rate versus twenty seven which was statistically significant however for people at favorable risk disease we actually saw a reverse trend so for people with favorable risk disease you actually did better just going with run-of-the-mill synonym this is the drug that would just approve like at this point you know around ten years ago and giving you more drug doesn't necessarily mean that we're getting better effects and in terms of you know the percentage of people that are responding so this is one of the things that we always have to look a look at before we start you know jumping into just like you know combining things that random and implementing them is really to be able to make that comparison and looking at you know what are the groups that are going to benefit from kind of getting additional treatment and you know because the general treatment always comes with a little bit of additional risk so within the intermediate or risk group this is the overall survival data and then you can see that the curves separate pretty nicely in which you know people who had intermediate porous disease you know at the time in which they evaluated you know the median overall survival hadn't yet been reached while as the people who are created with Sinitta biood sunitinib in the first line setting had a median overall survival of twenty six months so then the question becomes another possible combination is what if we take one of the drugs that you know targets the blood vessels because we know the response rates and the people who clinically benefit from that medication seems to be rather high and we paired it with one of the immunotherapy drugs and see whether what the response rates and clinical outcomes would end up being and then there is some rationale for making this combination so one immunotherapy drug is the drug at tehsil as a mouth and one drug is Bevis as a map and the rationale for combining really is the drugs that target the blood vessels probably have some effects on the immune system also you know it's very tough for us to know in advance what the exact mechanism by which we see this cooperation but you know whether or not it's you know increasing immune cells ability to present the cells or opening up the tumor so that more immune cells can come in or just decreasing be a number of mune cells that inactivate the immune system that really still remains kind of an open-ended question I don't think we necessarily have the definitive answer but without having that definitive answer it doesn't really change the fact that we do have clinical studies that can give us some insights about information about efficacy so in the phase 3 clinical trial comparing this combination to sunitinib in people who expressed PDL 1 so this was looking at as a primary endpoint you know expression of the marker that the immunotherapy targets you know we saw you know good separation of the curves and you know an improvement in progression-free survival in comparison to sin it at the eleven point two months versus a seven point seven and from a toxicity standpoint because a test the immunotherapies in general haven't had that many side effects in Bevis ism have you know for medication that targets the blood vessel and you know makes it relatively easy to tolerate and you know has been you know combined with multiple agents including give different chemo therapies you know and uh and has also been combined you know successfully with the m4 targeted agents overall showed less side effects that people find to be bothersome in comparison to send Aetna granted you know there are some other targeted agents that you know may be a little bit easier to tolerate than this in a net but you know the comparison wasn't done against that group and in this you know we do see you know some evidence that you know doing this type of combination from a patient standpoint in terms of you know tolerability we see benefit however there is certainly the inconvenience standpoint of when we were talking about doing IV infusions on an average week basis so right now there are multiple phase 3 clinical trials really looking at the use of immunotherapy plus checkpoint inhibitor you know with you know pretty much almost all of the different tyrosine kinase inhibitors or anti-angiogenesis drugs that you know are available so there's the clinical trial with lung bat nip which is a large phase 3 it's looking at Lin Batna plus member Elizabeth temporal is about being the immunotherapy against Lin Batna plus everolimus ever being the fda-approved combination in the second line setting random guys again soon it nib for exited there's been two clinical trials that are completed accrual so and we're kind of still waiting for the release of those results one is with exhibit plus PEM bro the other one is a voluma a balloon map is just a tear for an immunotherapy that can be combined with the exhibit and then the Bevis ISM a Plaza tezo as I had mentioned before and then also up and running right now is the combination of Kappa Zeta plus an Ebola map randomized against in it them so right now we don't have phase 3 data for this sort of t ki io sort of combination but we can gather some quick glimpses at what we may expect however you know a lot of caution has to go into looking at you know data from phase one and Phase two trials because historically speaking you know our results have all sometimes been a little bit better perhaps it's patient selection perhaps it's just the small numbers of patients so we don't get as clean up a look so this is a fifty-two patient study in which about 56% had an objector response so this is a very like you know as you can see from the waterfall palat like almost all the patients did end up getting shrinkage their tumor even beyond you know the 58 percent because the 58 percent looks at that dotted line and that that cut off right there and what we still don't yet know is whether or not this objective response truly predicts for how long the progression-free survival is and from your standpoint as a patient like and I've told all my patients this when they've gotten TK eyes is you know it's all we know shrinkage is always better than growth but what you are interested in is not necessarily shrinkage but how long the drug is effective for like you know what you the last like just because you get shrinkage and then the next skin afterwards the disease grows right back like you know you didn't care you got shrinkage like you know I think that what you want is the medication to work on a kind of a more ongoing sort of basis so this is another one of these clinical trials looking at this type of combination and this is with an badenov plus member ellisa mob and this is a trial that looked at patients that were both treatment naive so having not gotten any previous treatment in patients who got previous therapy so they got a tki beforehand what they end up showing was you know it's a small trial of you know 30 patients if they looked across the entire 30 patients 63% had an objective response if you looked only at the treatment naive patients so that so the patients who hadn't got any previous therapy 83% of them had to rank each of their tumor and then if you looked at the patients who got previous treatment then about 50 percent of them had shrinkage of their tumor and as you can see from the waterfall plot you know there's not good prediction on whether or not you got previous treatment whether or not you know you had more frança tor less shrinkage and then the other thing that we again often look at is PDL one status and then you know as you can see from the random smattering of colors like you know PDL one status didn't actually well predict whether or not you're going to get shrinkage of her tumor you know with this sort of combination the question is you know what is the toxicity like you know so when we look at toxicity and when we look at combinations you know it's probably to be expected that you're going to get talks is the the odds of you're going to get the toxicity of the two treatments what the issue really becomes is also like do you get additional toxicities when you have combinations to the two drugs interact in some sort of way that you know in the same way that we you would like them to enhance their efficacy there's also the possibility that the drugs may end up enhancing their toxicity related to each other and at least that underly follow-up they didn't see any safety signals to suggest that there were unexpected talks at his toxicities related to the medications and this is their update in which they looked at progression-free survival especially when we look at small small trials like this the medium progression-free survival on here was 18 months however the actual you know that's a very wide curve and you know it only takes a couple people to change how long that number is measured so we really do have to wait for the phase three clinical trial to make you know firm assessments on you know what the true progression-free survival will end up being for this combination another one the combinations with kappa Plus nuvola map and this was done either without or in combination with a pollutant map so this was only 13 patients again you see kind of within the same ballpark you know around 50 some percent of people have frankish at their tumor most of which being partial responses and the question really becomes you know how long is this and the duration of response going to be looking at so this is really going to be a really important look that we're going to get in October of this year for one of the first trial first phase three clinical trials with the TK eyes and immunotherapies with a voluma plus exit nib you know we know from the press release that this is a positive trial but what a positive trial means we don't yet know so we're kind of anxiously awaiting to see what those results will end up being and like you know whether or not you know this type of combination will end up being better than and you know kind of supplant you know the current clinical approach so in summary you know I think that combination therapy and RCC is really a promising future approach you know we don't yet know whether or not the using these in combination is going to be better than using them sequentially but we do have some hints to say suggest that that might be the case and then right now kind of the big question in the room is for the multiple TK oh you mean no therapy combinations you know we've seen these impressive you know response rates like in whether or not those response rates are gonna translate into either cures which would be great but you know whether or not they would otherwise translate just to you know longer responses you know anyways that's thank you so much for your attention and I open the question [Applause]