What novel therapies are on the horizon for metastatic renal cell carcinoma? 2019 and beyond

thanks Philippe and thanks everybody for staying it's a familiar role the last speaker usually after the hotel check out anyway the biz it'll be on the Internet I guess they don't get a lot of jokes on that so what's on the like we can make a separate bloopers so what's on the horizon for next year I'm going to have some kind of forward-looking statements in the SEC sense of the word and let's let's have a look and come back next year see if I'm right sometimes I'm right and anyway here's a couple slides in a way we have a firm 6:00 p.m. commitment you can move that clock I'm gonna I'm gonna win it so so here's anyway thanks for staying there's a picture of my my grandmother and my great grandparents from about 90 years ago there so that's some staying power that's in we visited Moldova so that's in Moldova they did not stay in Moldova so that was like the last I work with drug companies I like drug companies they've got good medicines as they've brought us here today so there's some of the ones we work with details matter I've been preceded by many excellent speakers and will not go over some of their good points but the details matter here's some of the histology differences here's some of the anatomic differences that we might find and knowing that it almost seems unfair to just say well here we are at the kidney cancer Association you know it started in the same location in the kidney so we should treat it the same well they're not the same here's some of the risk factors we know the patients with more problems there have a disease with a different natural history a faster natural history our versus a slower one molecular details matter sometimes there's a drug which exactly fits on to a particular target well if the targets there you have a chance this targets not even there then time to move on and try something else sometimes we like talking about medicines but we had good presentations about the local therapy local therapies can make all the difference clear cell kidney cancer in particular sometimes will have a very irregular pattern of spread there might be a one problem area you fix that problem area and you're done you don't really have to do anything I have a patient ten years out presented with the tumor it is in his leg and in the kidney took care of both of those and nothing happened since then other times there are brain lesions kidney cancer can spread to brain but it just sits there sometimes it's much worse other times it's just sits there you take it out move on and very early on one of the trials though just looking at an open-access program for sarandon identified that people with brain pattern and spread they track just along with people with no brain pattern of spread I I have patients who had interleukin 2 treatment who are a decade out after having had brain pattern of spread and there's no disease left so it's a pretty different in that sense that sometimes you just you don't need a drug at all just a strategy sort of the talk about what happens in a trial versus what happens to a patient and I know with my colleagues of many remaining still in the back we're interested in in general concepts but as soon as we step into the room really only interested in one person so it's it can be a little bit of a different experience so here's a cartoon with a bunch of colored spots and you average them together and it looks something like that but you know you can't go back and make little mini minimis out of the trial here's some of these risk factors which we're going to go over now just to say this this figure which we all saw before shows that more risk factors is worse and it's embarrassing to say we're making some progress with it but the dominant factor on how well people do is whatever they walked in the door with we're changing that but these are some of the risk factors which we've had experience with how many prior treatments as the patient has well pharmaceutical companies love this the FDA loves this and long times you'll see one L or two L first line or second line or immune therapy naive or checkpoint naive well guess what cancer doesn't care it just depends what you have walking in the door so it's a good way to organize things but it's not quite biologic here's here's a nice diagram of looking at the two factors prior treatment or not at a good risk or high risk or low risk and the trial says they come along they kind of carve out subsets of patients and we reach some conclusions and they're good conclusions they're a good conclusion for the patients within that set and as they get a little bit outside the set you might be extrapolating a little bit but you can still say well it looks like this drug is better than then that one and then a real life comes along you say we're gonna use this trial and your next three patients they're not in the group so there's a bit of judgment involved and this is not special to kidney cancer but just something to remember of EGF receptors I think you've had a good schooling on this the B jefra Thep receptor pathway what's ahead for that well the old role was a lot of single agent treatments and some sequencing strategies intermittent strategies Sennett nib the dominant drug for a decade was a mostly prescribed at 28 days on or 14 days off turns out that's hard to tolerate and many patients wouldn't complete the whole 28 days and then they'd stop and wait a couple weeks and get started again but actually more rapid cycling 14 days on a 7 days off seems to be better tolerated and probably works better and make it more drug into the patient so many of the trials that used us in it nib as a comparison they may have actually handicapped us in it nib arm and in real life this didn't matter that much but on the trials you might have had this in it nip send in losing by a bigger margin than it otherwise would have why wouldn't it it matter in real life your oncologist probably knows this already and would adjust your schedule if you were on a regular on a regular treatment adjust your schedule to make it meet you this is not unique to Senate nip many other of these medications some schedule adjustments here's another cartoon with a VEGF receptor pathway there's a tumor cell and there's some of the VEGF drugs blocking the VEGF receptor the money is probably on the endothelial cell or the tumor cells themselves have some of that here is len vat nib also blocked so this the fgfr receptor not all cancers have this not all clear cell kidney cancers have this but it may matter for some here's a Cabos antenna it blocks a seemeth and axial and those are actually more dominant targets on the tumor cell so there is some sense that blocking the VEGF with a VEGF drug may be something that could be salvaged with kappa xanthine if so we're seeing a lot more kappa's ant ative in 2019 talking about immune therapy we had a good good education on that here as well on the immune therapy the pd-1 pathway was used mostly in isolation and il-2 and interleukin 2 another one also used in isolation these are proteins on the white blood cell surface also ctla4 and the drug in this case so it works on the immune cell and the immune cell has to do what it was born to do which is attack something but the drug isn't really attacking the cancer directly so let's talk about one partner which i think is gonna be a big partner in 2019 and beyond to use the catchphrase and that's the il-2 receptor and it's not choice to say that the how to receptor is gonna be a big deal in the future because it was a big deal in the past you know Lucan - i mean it's got a really low number - is one of the proteins that white blood cells make to communicate with each other and there is a receptor on the lymphocytes T lymphocytes s cd4 T lymphocytes cd8 T lymphocytes natural killer lymphocytes il-2 receptor and it gets the il-2 and it changes its behavior it divides more it goes to attack more interleukin-2 receptor is used in a lot of lymphocyte based treatments we talked for a minute about car T cells so the car T cells are the patient's own T cells taken out of the body expanded expanded with what with interleukin 2 and Riaan fused back in after the patient's own white blood cells have been kind of wiped out to clear the stables and and the patient gets a few doses of what of interleukin 2 to help those lymphocytes to expand now we don't have car t-cells that are available for kidney cancer therapy the antigen matters a solid tumor car t-cells have been slow to develop as the technology but that interleukin-2 receptor is what's on those cells similarly till cells tumor infiltrating lymphocytes this was initially tested in kidney cancer the tumor is taken out interleukin 2 is put on there it grows out the lymphocytes and they have a population of lymphocytes which were at least smart enough to get into the tumor then those re-infused back into the patient and at the point they're put back in their given interleukin 2 so interleukin-2 receptor is something that helps support lymphocyte activity which is what we're interested in we have some combinations of medications that use interleukin-2 receptor and pd1 receptor at the same time they're listed here so member lizardom ad with high-dose il-2 that was a single arm study we're finishing that up at the Moffitt Cancer Center next are in Nivola map neck cards were in the engineered aisle to drugs I'll show you that that together with Nivola map and epi luma map as well that's also in initial testing and ALK s 42:30 an engineered il-2 also in early testing with the PD one so here's a native il-2 it's just a small protein it's got a three-part receptor illustrated there with the blue green and red which is beta gamma and alpha and il-2 little oval there attaches on there the alpha parts a special part it doesn't really stick into the cell but it stabilizes the il-2 on to the other part of the Howell 2 receptor there's two kinds of il-2 receptors just the beta gamma or what the Alpha also the cells we think are attacking the cancer have just a beta gamma one called the intermediate receptor here's a cartoon showing the native il-2 which is now pink in this illustration and you can see either binds the two the two part one or the three part one with the alfa attached so it stays on longer here's one of these Alchemy's 42:30 this is a completed it's a single agent testing and man and now it's going to be doing combination testing so it's a phase 1 trial phase 1 trial but you're kind of getting a good deal on both drugs you get the ALK s42 which is an engineered il-2 it's got a il-2 receptor alpha pre attached onto it in a single chain and this is how they did it with a little permutation of the protein sequence which is pretty interesting if you have a PhD in biochemistry but otherwise it's just a cartoon there and then that trials being given together with the preamble is a map which we know already is active in kidney cancer here's another one a necked are hectares the company next are to 14 so the sequence of interleukin 2 which is a small protein has some different amino acids six of them are a con called lysine and lysine is particularly good for attaching things to it so in this case they've attached a thing called PEG polyethylene glycol so polyethylene glycol is a big long molecule you may recall it seeing it on your ice cream ingredients it's used as a thickener anyway it's not it's not toxic it just sits there however it's so big that the il-2 is effectively a prodrug it's like the drug is in there but it's got these extra pieces the attachments are not particularly stable and they pop off and then when it's down to one or two that's good enough and it can fit onto the receptor so this is in a trial with a dozen different diagnoses kidney cancer included and there's been several complete responses already reported with that the frequency of complete responses we don't want to especially speculate on that is a low number of patients but they're definitely out there I have one one patient who's done quite well with that there at least a dozen other ways to engineer il-2 here's one which has only been tested in the test tube it hasn't even made it to Mouse testing and what they do is they take the lymphocytes out give them an il-2 receptor which doesn't fit il-2 it only fits this special aisle to then they give them a special il-2 it only fits on to there and what's the advantage of that you could take your lymphocytes out and only have the population that you want to respond to that so maybe their cd4 cells which we have a regulatory function you don't want them to see il-2 well you could use this special engineered combination we'll see if that comes out that won't be in 2019 however so as far as on lymphocyte targets and you've seen most of this before just highlighting the aisle to receptor there with the il-2 and the other engineer dial to is on the left side of the slide and on the right side the pd-1 and PDL one those are ones we've talked about before what those are kind of the brakes and then I'm the right lower corner there's the tremor loom a band epi luma map which box ctla-4 which is part of the priming response so looking at PD one happily for me and the time these are the same slides you've seen before this is the same key paper here with initial therapy of those two medications together versus a Sinitta nib and just going through it briefly we see that the balloon map Nivola map combination was better with some complete responses observed on the other hand in the favor of favorable risk subsets which was a smaller subset it was planned to be a smaller subset but the senate nip appears to be better for those patients especially if they don't have the PDL one protein so anyway as I said the details matter the evolution of how to pick patients for which of these drugs and the reality is really we're just picking which drug first because if one doesn't work we're going to take a step back and try the other and there's a graphic there and here's the same lines that we saw before with the blue map d'Avola map graphs on the right there again a trial we've already seen the emotion 151 with a Tesla the Matt Bevin is a map the PDL 1 and the VEGF receptor sorry Jeff antibody versus an endeavor again with the combination doing relatively well here's another one we've seen as well with AXA to nip the VEGF antagonist pill with Pemberley zoo map and just a striking number of proportion of patients who really get their tumors to get smaller as Jolie just mentioned we get a lot of graphs with tumors getting smaller and we have to take a step back Mike talked about this Mike Harrison about what do patients really want a paper which I didn't put in here we BMS and I worked with them and they took a survey to ask patients what they really wanted and it was a little bit anticlimactic turns out patients really want to live longer and you get a graph like this and it becomes like an ironic question says the patient's want to live longer how come from the day they're diagnosed till the day they die all they talk about is how big is the tumor well that's the only accessible thing we have there so they did with that that's again one of those graphs graphs there here's a big question here is a Juventus and it Nibin now Omaha stalked about this trial the S track trial the single positive adjuvant trial we see the blue line the patients who got synonym had a lower rate of reoccurrence as compared to the patients who didn't get to knit nib but the overall survival is about the same on both arms they've updated it it's a few patients ahead on the Sutent upfront arm as opposed to the placebo upfront arm but still not a significant difference so is this 2009 technology playing out or is this 2019 well there might be some subsets that do particularly better where it makes a big difference so this has been looked at at a few different ways the first was just a generally easy answer which is that whether was a t32 more a24 tumor patient had symptoms or no symptoms or high-grade Fermin or not it came out to be about the same so that didn't add much information but two of the other subsets analyses give some hints so in this one from dr. Rainey as the main author here we see that there's a this 16 gene recurrence score and they didn't have that many patients on it but you can see that at least in the placebo group it really matters which what your score is on the other hand in the treatment group the lines are closer together so where do you know that the treatment group had a better progression free survival but also that the lines get closer together so at least for the worst group which would be the red line on the on the left panel it probably makes a bigger difference so the people in the worst group it makes it looks like it makes a bigger difference that they should really be on something besides observation now this is a secondary analysis on a fraction of the patients but that's at least a hint on that and then similarly looking at markers in the tumor we already knew that PDL one seems to be a marker for patients with a higher progression rate and looking at this here we can see one line standing out which is the placebo patients that had PDL one on their tumor that blue line on the right graph there so well that's a hint maybe to help us out on adjuvant selection patient selection there's three large very large very slow adjuvant studies accruing now check again this won't be in 2019 this will be in the 2023 24 of them make it a read out whether starting those immune therapies very early helps I have a trial here and this is just for a general interest on how there are we had set up that trial there it's finished accrual and we wanted to get at least 45% major response rate we've got a lock on 60% so it does look again that putting those two types of immune therapies together seems to be better than one now as a single agent sorry a single arm trial we don't want to really make any comparison statements and we know that picking the patients carefully is probably the best way to could get a good response here's some art from my trip to Moldova clinical trials.gov clinical trials.gov I guess at least one person in the room thinks it's hard to use I use it all the time but I think we'll work with KCA maybe get some tutorials on that it's true I can't know all the trials there are if you look on this here it says there are 280 4824 research studies in 204 countries so yeah you'd have a pretty psychotic doctor who had a really working knowledge of this but you can use it to look up some things here's one we can look up this is a CB 839 that Calif era's product the glute amination inhibitor we had a good presentation on that and a couple trials we've combined with that or open the first two are open I think the third one is just a planned trial their epic sino stat that's an H stack inhibitor H stack inhibitors probably 20 H that trials have been coming on in oncology a couple have approvals and hematologic malignancies but they're all still waiting to hit the big time for solid tumors so this is a combination that everybody gets pies open if it's a face retrial but it either get positive and nothing or they get positive with the new drug added on so that the is a registration or trial and it should be a couple years to accrue the exciting thing is it's an H stack inhibitor which has nothing to do with all the other things we were talking about so kind of a new angle on this here's another H stack inhibitor called atenist and you might remember antenna status a partner drug with il-2 this was a single arm trial which did relatively well and antenna stat only blocks H stack one coordinate with radiation therapy and other destruction destroying stuff that really gets the attention of the immune system changes of a lot of things in the tumor and in the immune response and there's about eight different trials in kidney cancer probably another 20 and other diagnoses as well so I think those will mature we'll get some more standardized protocols that some of the thinking is that getting to a higher dose with a lower number of fractions maybe something that really makes the immune system sit up and get stimulated but those are details that we need to work out the ID the idea of using them combinations with the PD one drug and something else so at least a two-part two immune therapy that's going to be something we see a lot of not clear cell type cancers I hate to always give the not clear cell type cancers kind of a quick wrap-up but we at least for the first time in many years have several trials these are directed at cement and these are gonna be slow trials that come around but we may actually get some targeted drugs which really focus on that so what's the target a year for 2013 do we do a defect it's order on there but I think it'll pop down there it is so I think il-2 receptor it's on every lymphocyte in your in your body he's got il-2 receptor we've got the PD we're kind of you know running strong in the age of the PD one type trial and I think that aisle two receptor we've been using it as a single agent we used it in till therapy and cartee therapy and I think that we're gonna see it have a resurgent not just as a single agent il-2 but aisle to receptor as a partner for these other immune therapies as the immune the immune area kind of overtakes everything so anyway thanks very much and thanks for the kidney cancer Association for organizing this I want to encourage all of you you know in your own health but also to the extent you can you can advocate and work with the Association is it's here for you and you can be here for it and I think jeans gonna give us a couple genes outside good thanks thanks to gene bureau for organizing and Gretchen will give us some closing remarks thanks [Applause]