The Role of Immunotherapy in Advanced Pleural Mesothelioma Thierry M. Jahan, MD

Thank you very much for the invitation Dr Cameron and I go way back if I'm doing this today it's actually because of him so I'm going to blame everything on him Bob and I met when he was a fresh faculty and I was a fresh faculty at UCSF we met on the wardens and realized that nobody at UCSF was remotely interested in thoracic malignancies so two decades later for good or for worse we are so I'm gonna touch a little bit upon some of the immunotherapy approaches and I'm gonna finish talking about the CRS 207 vaccine trial because we've been very involved in that UCSF and have treated quite a few of those patients so it's a very interesting story that is a just starting to unfold as we speak so real quickly did mesothelioma though low incidence for all of us who live in port towns and in towns where there had been quite a bit of asbestos-related activity it is a major major problem because while those activities may have ceased and may have ceased a couple of decades ago there are their damages persist way beyond the disappearance of these industries and the prognosis for this diseases is still abysmally poor where the median survival about months and five year survival that is well below five percent so clearly there's a lot of work to be done Dr

Levski showed you the stroller really the granddaddy of them all this was the trial that that really led to the approval of pemetrexed and as a standard of care for mesothelioma I clearly the backbone of pemetrexed cisplatin really is is is here at least it's the best game in town and it takes upon us to try to build on it this trial had a slight separation and curves there was about a three more me and survived but was actually very interesting is that not only was there a survival benefit but there actually was a quality-of-life benefit that was noticeable in terms of pain management but also in terms of breathing and there was some physiologic measurements done to go with this including increases in mvc capacity for these patients that was actually a significant improvement and really assisted in why some of these patients did a little bit better than than what we would have expected since 2003 a lot has been going on but a lot of disappointments as well so these affiliate my biology we know that mesothelioma has does induce a really high level of VEGF expression vascular endothelial growth factor in fact when you look at different tumor types patients with that VEGF have the highest circulating levels of that VEGF so that I mean people patients with mesothelioma have the highest levels of circulating VEGF which is really makes it seem like it should be an important factor when you look at the respective specimens mesothelioma specimens have very large numbers of microvessels so that angiogenesis really is an important phenomenon for this tumor so the last decade and a half has seen a lot of activity looking trying to test all of the molecules that would target the the VEGF axis and you can see from this list which is really a partial list that none of these have made a major impact and it looks like the oral tyrosine kinase inhibitors targeting vegf may not work as well the exception to this may be an intent which is undergoing much further evaluation than any of these molecules because the phase trial was so provocative when you look also at respected mesothelioma specimens they tend to stay in very intensely by immunohistochemistry for EGFR when you actually tease that out a little bit further you don't quite see the same story that you'd see in lung cancer were you can actually have a driver mutations that explain the sensitivity of lung cancer to targeted therapies mesothelioma you never see targeted mutations so that you do activating mutations so that you not you see no activity when you try to target the VEGF exes the PDGF access also would seem to be a very good target for mesothelioma there's a lot of PDGF overexpression and preferentially the the the beta part of the gene is more expressed in the alpha which is more expressed to normal tissues and yet targeting it with drugs like imatinib or vatalented doesn't seem to have as good an effect as you would have expected so none of these agents really has made it into primetime so despite this is there any progress Dr Olevsky presented the results of the maps trial and the maps trial is some progress there had been an earlier attempt by Dr Kindler at all to test the addition of service is a map to chemotherapy but this was the trial was pre pemetrexed days and it was a genocide of being based chemotherapy backbone which is probably not as effective so Dr Kindler’s trial ended up being negative it was a smaller trial it was it was a consortium trial so it wasn't just a single institution study but it still ended up being a negative study nonetheless it had a provocative result that in a unplanned analysis if you looked at the circulating level of their VEGF and and were able to devise a cut point between high and low patients who had low expression of veggie for the ones who seem to be responding to this is a map whereas the very high level of education did not seem to respond to to the addition of a system that result has not been tested prospectively meanwhile this trial came along with a better chemotherapy backbone to to base the use of bevacizumab and indeed it was positive with an improvement in median survival about months or so Dr Sturman made a point earlier about whether this this trial really was applicable and should be should serve as the as the control arm at least the the active arm and disarm in this trial should serve as the the control for future studies and and that certainly is something that is being considered in an number of trials the problem has to do with the use of bevacizumab in elderly patients it's very difficult in people over to receive this drug cardiovascular morbidity cerebral vascular morbidity are are clearly a problem interestingly enough with this amount of bulky mediastinal disease there were very few hemorrhagic issues seen in this trial whereas in lung cancer the minute there's Mia style involvement or contiguity two large vessels there is a a significant risk for hemorrhagic morbidity and mortality not seen in this trial go so indeed the the control arm in this in in this study had a much better result than what we're used to seeing if you remember the Vogelzang study had a control arm with platinum alone of about nine months in this study and and the and the treatment arm with pemetrexed answers platinum had a survival about months here at the control arm would just platinum and pemetrexed had a survival of nearly months now we're not quite sure why that is it that we're now caring for these patients better than we were years ago is that that perhaps the population here was a lot younger than the population of Vogelzang trial the median age and Vogelzang was around was over to meet in page and this trial was about so clearly there are this isn't an important trial it it does make services the map an agent to be considered but it doesn't in my mind established it absolutely as a as a panacea for all for all patients so a dozen years later we have not really gone that far beyond the backbone the response rates are still around twenty-five percent the median survival is still around months to months if you have a particularly more active companion the five-year survival is still well below five percent and again Bevacizumab is not applicable to the whole mesothelioma world alright that's that's a very important point to be made so what's even more daunting is that we still don't have a decent second line approach for patients once they progress through the pemetrexed platinum backbone so what's next so we're entering an age of Golden Age of immunotherapy there's been through the FDA approval of of a number of molecules in diseases like measles of melanoma and non-small cell lung cancer and now in bladder cancers we actually have quite a lot of molecules to play with and there really have been some new understanding of the tumor identity and the way the tumor is sort of shield itself from the from the host's immune system all this leads to exciting new possibilities so very briefly i'm going to recapitulate the efforts of titans in the field of tumor immunobiology in a fairly simplistic cartoon but i think it does illustrate a little bit what we're trying to talk about in target so you have a tumor that's there and this tumor has a life cycle just like normal cells as well and a number of these cells are gonna die whether they die of their own volition through senescence or whatever or they die through other body factors the result the result is that you're going to be releasing a cancer cell antigens these antigens are going to be taken up by dendritic cells and process inside these dendritic cells to turn these dendritic cells into antigen-presenting cells these cells are going to translate to the to lymph nodes where they're going to expose a whole population of t cells to the antigens that they are that they learned to identify from from the tumor once in that compartment t cells are exposed and and sort of learn how to recognize these antigens and you know when I explained this to patients usually tell them it's it's akin to giving a dog is sent and sending it on a on a hunting job these T cells are then going to translate and and traffic to the tumor through the circulatory system usually blood vessels but also they can do so through lymphatics and once they get to the site they have to exfiltrate these structures and get into the tumor itself where they can hopefully exert their activity and end up killing cancer cells obviously this is a process that has quite a lot of checkpoints and and regulatory mechanisms as you can see in green are a number of stimulatory factors in red number of stimulating factors there's several areas that were particularly interested ctla- is a is an area that is particularly interesting at the level of the lymph node and it it it is basically active in the expansion of that T cell population that now has an idea of what the what to look for and then the pd- PDL one axis is more is more a tumor site issue where the the activated lymphocytes can be turned off through an interaction with molecules that target these receptors and explains a little bit why it is important to look for the presence of ppl one and tumors to see whether they could potentially be targetable with some of the new agents that going that direction if you Raphael Bueno published very interesting article in nature this year basically looking at the expression of mutations in a number of tumor cell types and clearly in the yellow box you can see mesothelioma is at an end of that spectrum that is less immunogenic this is very important because in general the more immunogenic a tumor is the more likely it is to respond to some of these agents that target the immune system and in particular you have here a number of lung cancer variations and head neck cancers which are if you will environmentally caused cancers to a certain extent through the use of tobacco there's a great deal of mutagenesis that that happens from the the -plus or more carcinogens in tobacco smoke that actually make these tumors a lot more visible to the immune system even in lung cancer when you have patients who have lung cancer who are never smokers their response to these interventions as much less robust if you will then those patients who have actually developed lung cancer through three smoking mesothelioma is an environmentally caused cancer with asbestos but the mutagenicity of asbestos is much more complicated and doesn't yield the same amount of mutations if you will then the other very complex biochemical mutagens when you look at the PD-L1 expression with mesothelioma looking at a number of different retrospective analyses suffice it to say that there is PD-L1 one expression in mesothelioma and more interesting there is a greater PD-L1 expression in sarcomatoid mesothelioma which is is going to be interesting for future therapeutic interventions and PD-L1 one expression correlates very well with a poor outcome the more pn expression you have green line here at the the worst the outcome is patients so here are some initial efforts at targeting the PD-1 PD-L1 access and believe Dr

Sterman is going to cover that as well in more detail this was a trial from that was presented by one of his colleagues Dr Alley, Evan Alley from University of Pennsylvania this was keynote which was a basket trial this is a trial design that's actually very interesting you end up accruing patients in very different very different indications in sort of unique groups and keno had was one of the first trials to have a pure mesothelioma group which is where those patients were treated we actually participated in the study and tell some very interesting activity so the patients had their usual mesothelioma presentation they needed to have a good performance status they need to have measurable disease and for this particular study they needed to have sent in tissue to assess for the presence of ppl one it did not require heavy presence adjustments required pl positivity so this is what you look for under tumor cells and these patients were treated with a pretty hefty dose of federalism and now we're using a little bit less than that and those patients who had a response continue to treat for up to months or until progression or intolerable the the development of intelligent toxicity those who had confirmed progression stopped and classic mesothelioma population median age a little younger perhaps than what we used to see but around overwhelmingly male overwhelmingly Caucasian excellent performance status overwhelmingly epithelioid with few sarcomatoid biphasic and this was a pretty heavily pretreated all all of them and had some kind of cytotoxic therapy prior to starting this is the response assessment using a modified resist which is a technique that is especially designed for mesothelioma assessment when you use conventional radiologic techniques it's a lot harder to figure things out but this modified resist allows allows me that mesothelioma clinical trials to speak the same language anyway using this technique about -percent of the patients were on this side of the waterfall plot in a wonderful plot you want to see decline which is why these are negative percentages you want to see the tumor get into negative percentage points and the-the-the more people on this side of the of of this black line the better off you are here in this is called a swimmers lane plot really looks at the duration of the response and obviously the longer the line the better the duration but this is a very healthy swimmers plot for first attempt at immunotherapy and median survival curve as you can see me in survival was about median disease-free survival is about six months not perfect but certainly a very good signal what was actually very surprising in this study that was that the PD-L1 at one expression was absolutely not associated with the response people with low expression responded people with higher expression responded there didn't seem to be a clear-cut relationship now this may be because this was a small trial but this is a signal that warrants quite a lot more interest this is a patient who has pure sarcomatoid means this is one of my patients with a fairly large tumor over here between these arrows and after a three or four infusions of pembrolizumab this area is not there and I believe this big conglomerate may be reduced to just this about a year-and-a-half later this gentleman is still receiving pembrolizumab and is doing actually quite well these he really has no symptoms attributable to the meso his only problem is that he's developed toxicity from the pembrolizumab and had to go on a fairly long break for about – months due to the developing a very significant skin toxicity is very interesting manifestation yesterday where a lot of gloves now because his hands are very scaly from the pembrolizumab and looking at other continuing efforts in there these are the three minute studies so far this is actually a second study that was done with nivola map which is a very similar molecule to pembrolizumab pembrolizumab is made by Merck nivolumab is made by Bristol-Myers so competing molecules this is a European study that is still ongoing again you're seeing similar partial response similar conditions control rate so very these are probably not going to be very different overtime here is a different molecule both pembrolizumab and nivolumab target the PD-1 receptor which is located on the surface of the t-cells this molecule development targets the PD-L1 receptor which is more likely to be located on the surface of the tumor cells so and obviously it's going to have the same similar effect it's just targeting the other side of the bridge so to speak and trying to hit the receptor that way what may be different is that because you're targeting the tumor itself you may be developing and antibody-dependent cytotoxic effect once you hit a receptor on the cell and it can trigger other responses from the immune system which which can kill the cell just because you you find an antibody so this is maybe an effect that is actually important for the future and this molecule develop apps have some activity demonstrated in line cancel and a number of other other carcinomas so the design was very similar this was also a basket trial and had a little bit more patience but similar eligibility criteria the dosing was what had been determined from expanded studies expanded access not not expanded access expansion phases of phase one studies using looking at response safety progression-free survival and the expression of the PDL one marker in the in the tumor tissue and over here the results were a little bit less encouraging than they were but still a positive waterfall plot nonetheless which I'll show you in a minute there were five clear partial response here they're swimmers plot measured in weeks and over here you'll see the waterfall plot there's obviously a lot more a lot more patients on the under not so good side of the waterfall plot but some very deep responses here on this side of the waterfall plot and this is something we call a spider plot which gives you an idea of the time to the response and how long the response last below this line is actually what we define as a radiographic response under this line is what we consider stable disease in the middle so you can see that there's a lot of lot of green and even some green turning into orange fairly late in the game so these patients are deriving clearly benefit even though radiographically they're not necessarily going down they are deriving a significant benefit the slides by the way where the slides that repeat Hassan presented at ASCO here to the progression free survival did not seem to depend on PD-L1 expression which was again a little bit surprising and is something that warrants further investigation in the future so when you put all three studies together in one table you can see that the effect there is clearly an effect but we're just not quite there yet a minority of patients are responding rather than a majority even though on paper we should see a lot more a lot more activity looking at a different target so we've targeted the with the PD-L1 axis approach we're targeting things that are happening in the tumor and that are maybe that may be driven directly by the tumor by targeting ctla- were targeting things that are happening perhaps a little bit away from the tumor they may still be influenced by the tumor but they're happening more in the lymph lymphocyte lymph node reservoir rather than the actual tumor site itself from tremelimumab is an anti CTLA-4 molecule very similar to ipilimumab which was approved for mesothelioma some years ago it was in fact the first immune targeting therapy approved for for cancer indication in a really really long time tremelimumab is made by a different company than ipilimumab and in a couple of small phase one studies done in Italy in particular we saw that you could get some very nice overall survival in patients who had been heavily pretreated before almost fifty percent survive the year when this is a population that doesn't really have a second line option it's nice to see that you can prolong survival with this approach so these two trials really suggested that it would be worth testing this and larger on the larger scale trial in a randomized fashion and this is the determined study that Dr Kindler presented at ASCO a very large study patients what was dramatic about this study was how quickly it accrued normally as patient study in lung cancer would take probably three to five years to accrue this study in mesothelioma which is up a hundred times less common then then lung cancer this study accrued in months which was really fantastic it was a double-blind study it was a two-to-one randomization is double blind but because of the side effect profile of the drug you very quickly if you're patient was actually getting active drug it does cause some some solid side effects this study was open to the perineal disease as well and patients were randomized to getting tremelimumab every four weeks for seven doses than a maintenance of ever every 12 weeks or placebo IV and the primary endpoint was overall survival I wasn't progression-free survival which sometimes the FDA frowns upon unfortunate here's the the patient population very similar to what we've been talking about again mid to late sixties mostly epithelioid advanced stage for the most part at least in second line by definition these patients that had to have seen some chemotherapy before some of them had had more than one regime and then virtually everybody had seen prior pemetrexed and everybody had a decent performance status this survival curves as you can see has really no significance play in it and the hazard ratio of point was really not statistically significant again this was a little bit disappointing but it may have to do with CTLA-4 not being quite as good a target by itself as a as PD-1 so in second third line this was not effective the safety data that we saw the safety signals in this study were consistent with what we would have expected with tremelimumab we didn't see anything more than what we would have expected but what was really remarkable is that if you have an exciting concept in a sighting study you can accrue to it very very fast even in an in an orphan disease like mesothelioma that has not as many patients to to draw upon so how are perhaps tumors defeating some of our efforts well one of the problems may have to do with gender generation of insufficient number of t-cells and this is a problem at this level in this compartment another possibility is that even though you generate themselves none enough of them make it to where they are where they're needed and finally once they get there and this is the whole PD-1 PD-L1 one-story the t-cells are inhibited in inside the tumor microenvironment not only can the tumor do that but there's a number of cells that are that are modified by the tumor that can actually lead to some in inhibitory signals and you can see that this at this level the list of stimulants is is much less than the list of inhibitors so since we've identified a number of these possibilities there is a tremendous amount of work on going to try to optimize what we're doing with these molecules and what I've shown you are very crude very early efforts to try to get at these these questions another possibility is to target this means a feeling receptor which is differentially expressed on these affiliate micelles Dr Olevsky talk to you a lot about me so feeling the direct directed monoclonal antibody efforts over here i'm going to talk to you about this means you're feeling vaccine with CRS 207 which is a modified Listeria its modified in the removal of two genes which account for some of the nastiness dead Listeria does to people Listeria was a was a very important pathogen at the turn of the century in fact Listerine was kind of developed a try to fight listeriosis and every once in awhile it raises its ugly head in food preparation there was a list listeria outbreak not that long ago in commercial salad preparations and a few years before that in in cheese and when people consume these tainted products they can actually get pretty sick and part of that is because Listeria will invade and this is actually a very nice little representation of the story does it invades the cells and then it invades other cells the red Listeria here are the the wild-type Listeria where's the blue ones are the CRS 207 modified Listeria so you can see that the red ones are kinda going all over the place and even trying to get inside and adjacent cells whereas the blue ones are actually staying very very put this is an actual micrograph from from the company that produces this vaccine the design of the study was fairly straightforward patients once they met eligibility criteria and started treatment received two doses of listeria administered intravenously two weeks apart and these patients come into the infusion center they get they get their Listeria infusion they usually get very significant rigors the they shake quite a bit and usually these rigors are well mitigated by giving a little bit of Demerol mostly they have an unpleasant day with fatigue some nausea and and those rigors but usually by the third day which is when we see them they're actually doing quite well once they do their first to vaccinations they go on to receive six cycles up to six cycles of pemertrexed/cisplatin with CT evaluations every other cycle to make sure that people are still responding to treatment once they make it to the six cycle then they receive another to boost of vaccine and if they still haven't progressed by then they go on to receive maintenance dose of vaccine every eight weeks so we see them back and and we scan them every eight weeks to ensure that their continued to respond now the protocol was modified with the addition of one dose of cyclophosphamide that low-dose milligrams per meter square which is not a very big dose of cyclophosphamide administered one day before each of these vaccines here here here and with the boost the purpose of this pre dosing with cyclophosphamide is to try to perhaps neutralize the t regulatory cells compartment these are t-cells that actually blunt the effect of the immune response and trying to see if we can get them out of it so that cohort of patients is still ongoing it's met all of its accruals but quite a few patients are still being treated which is very exciting so again this population was a little bit older than what we saw in the trials the other trials that i showed you with which means that we treated people as old as and again mostly males mostly Caucasians good performance status one patient snuck in here with with perineal this is really a strictly pleural mesothelioma study and then the majority of these patients have epithelial if you had biphasic but by there's a requirement in the study that if they have by facing components should have less than fifty percent sarcomatoid because our commentary means a three-month does not really Express me feeling very well so there's actually some some justification behind that exclusion hear some of the adverse events this was extremely well tolerated o most of these are events the great three events really have to do with the fever being going high and the children rigors is being a little bit more debilitating at the time of admission of administration once the patient comes back to clinic either hours or hours after the administration there really isn't any more symptomatology to speak of so very very well tolerated and most importantly no infectious complications we didn't see any patients have persistent listeriosis in the whole CRS 207 program which included a whole a very large effort in pancreatic cancer there's only been one documented episode of continuing listeria presence in the body several days after the infusion and this is in a patient who received the Listeria against protocol recommendations through a chest port so the chest port got colonized and allowed for seeding of the stream when you give the Listeria peripherally there's absolutely no problems with a contamination colonization even if the patient still has that port case they don't get contaminated from the peripheral administration this is the kind of waterfall plot you want to see very little going up and most everything going down so this had a sixty percent response rate stable disease 35% for Disease Control rate of ninety-four percent this is good stuff we like that a lot and this is really not what you expect to see from pemertrexed alone this is the the spider graph you can see that there's very few dots above the the stabilization line and quite a few lots below the the response line this is really also the kind of spider plug you want to see and here are some very long responses in all the other swimmers plots that I've shown you this axis was weeks here we're talking about months so the duration is actually the response is actually a very durable and very effective response so this was a well-tolerated agent it worked very well with chemotherapy and achieved a more than ninety percent Disease Control rate the results are being confirmed in the second cohort that wordy been doing with the cyclophosphamide pretreatment future direction there is a phase three global drug that's been planned and interestingly to answer your question that trial actually allowed the use of bevacizumab and control and just ask sites to sort of the clear to declare whether that patient was going to get it and stick to it so you couldn't just like in the middle of it add bevacizumab if you felt like it and the trial is on hold due to the negative results in pancreatic cancer which is a very poor immunogenic cancer so the company is not a huge company and they're a little bit there dirt they sobered up a little bit after the the results for the pancreas study so that things are are being discussed what to what to do next but one clear direction that is going to be explored is combining CRS 207 with a PD-1 PD-L1 axis drugs and that's actually a study that I'm very much looking for that's going to be a very exciting possibility so clearly PD-L1 one is very much expressed in mesothelioma but most patients don't respond to this and we don't really at this point have good predictors on how to raise the response from chemotherapy as high as we can get it chemotherapy itself can change the visibility of the tumor by causing the presentation of neo of what's called neoepitopes and new antigens it may be that combining chemotherapy with these agents is going to be one of the the possibilities so there's a number of studies are being planned here's one that combines the Pem/Cis backbone with one of the anti PD-L1 antibodies here combining an anti PD-1 with an anti CTLA-4 also does make sense and that's actually a big study that were were participating in it's going to be opened in a just a few weeks here's another CTLA-4 PD-1 study and then a number of different I different options so immunotherapy approaches can be effective in mesothelioma at this point we're at the really at the early discovery stage and look to see a lot of efforts in that arena in the next few years it's going to really drive the next decade of research and in mesothelioma we really need to identify relevant biomarkers so that we can enhance not only the effectiveness of the approach but but really select people who are most likely to benefit from this and then obviously we need to keep moving forward and develop new strategies to optimize these results, thank you

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The Role of Immunotherapy in Advanced Pleural Mesothelioma Thierry M. Jahan, MD

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