In this presentation from the 22nd Annual Perspectives in Thoracic Oncology, Dr. Tsao discusses both the existing standard of care and novel therapy for patients with mesothelioma. Earn CME credit for a related activity at the following location:

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Good afternoon everyone thank you so much Cory for that very kind introduction so we will go ahead this is my COI slide this will be my outline for the talk today will do very quickly some background about mesothelioma we’ll go over what is standard of care clinical practice right now we’ll go into the medical and ecology aspects in terms of systemic therapy and then I’m gonna give you an overview

about what’s happening in the disease in terms of where the field is going forward with and what drugs were using and then in the very last part we’ll do resectable disease first and then we’ll go into unresectable okay so very quickly as everybody knows mesothelioma is a very challenging disease the white part here is sort of the depiction of the tumor it’s like the orange peel around the orange and so as you can

imagine it’s very difficult to get an R 0 if impossible for mesothelioma but we still do have different surgical techniques that can try to achieve that usually we have a large latency period from the time of asbestos exposure it’s 20 to 50 years so it is very difficult and challenging to predict when a patient might necessarily develop mesothelioma in general women always have better outcomes there are several different main primary sites of mesothelioma we’re going

to talk only about pleural mesothelioma but there are peritoneal testicular and pericardial we do treat those differently but that’s not going to be the subject of today’s discussion there are three main histologic subtypes of mesothelioma this is actually very relevant now because some of our agents are only going to be designed for specific histologic subtypes so now you have to know what your means that the glioma is so it’s either epithelioid or sarcoma toyed

biphasic means you have components of both now we do know there is PDL one IHC expression it tends to be expressed more in sarcoma toy tumors there’s a lot of different genetics that are underway one of the biggest discoveries over the last I’d say decade has been the discovery of bap1 germline mutations this is a very small proportion of patients and they generally do tend to be a Western European Caucasian descent we suspect that

there may be a founder genetic mutation from there but we do know that a good proportion of bap of mesothelioma patients have bap1 dysregulation and so although we don’t change our therapy at this point in time it may be that we have agents that are specifically designed against bap1 deficient tumors which is about 30 to 40 percent potentially of our population visa patients there are several different clinical biomarkers I would say I wouldn’t worry

too much about these for right now we don’t utilize these at this time but we will in the future and as I mentioned before PDL 1 Hz expression just like we do in other solo tumors is also seen in mesothelioma it generally does pretend a poorer prognosis and we do tend to see this more in the sarcoma toy tumors okay so what is our current standard of care practice in the clinic so

in terms of chemotherapy for resectable disease there have been no randomized controlled trials so we are doing this primarily from the belief that tri modality therapy is going to be beneficial for our patients we didn’t have very good system make there appears before but if you look at this table these were primarily platinum based doublets that were utilized in the new atrovent setting and as you can see here unfortunately our median overall survival with tri

modality therapy wasn’t that great we do know though that if you give systemic neoadjuvant chemotherapy that are more likely to have a better overall survival outcome but the NCCN guidelines are currently this where you can give four cycles assist PEM either as neoadjuvant or as adjuvant therapy before tri modality or by modality therapy and so again no randomized trials but we do this as standard of care practice we do not give the platinum doublet

with anything else right now but hopefully as we move forward in the field that may change now in unresectable disease almost any chemotherapy has been given to musa Thelema patients and you generally don’t see very high response rates combination therapies have been better historically but essentially the only fda-approved agent agents have been platinum pemetrexed for unresectable mesothelioma now in Europe and South America they do use route to track said it’s the same thing as pemetrexed there’s

really no major difference and we certainly always an unresectable disease substitutes this platen for carboplatin and that’s very reasonable now the Maps trial so this was a study that was conducted by the French inner group back in 2006 and 15 is when they presented at 2016 was the publication so this was system with and without Bevis is a map and then they continued the Bevis is anitha’s maintenance therapy after six cycles of the

platinum doublet now this trial gave a better progression free survival by over two months and an improved overall survival by two months and across the board it appeared that most patients on the study gained benefit with the triplet regimen an addition quality of life demonstrated no decrement and so it definitely appeared that the addition of Elvis’s Neb improved survival as well as quality of life for our patients so based off of this the NCCN

guidelines were amended so you now can give sispann and bev and get it paid for by insurance Bevis ISNA will not be getting regulatory approval not because the results weren’t accurate but unfortunately this was not conducted as a registration trial and so the companies were unable to file with the regulatory agencies for the drug but right now you can still get this covered for your patients so the usual standard restrictions apply for Bevis ismap

no one with a recent CVA or you know heart attack in the last six months no one with frank mop ptosis or bleeding diathesis should receive the Bevis system but if you need to reduce bulk for your patients and they are a very good performance status the ACOG PS zero to one you can certainly give this triplet regimen and it’s covered via the NCCN guidelines and by insurance in the salvage setting there is

currently no fda-approved agents but we’re going to talk about the NCCN guidelines which is just recently been amended in the last month and a half to include Pemberley Zeb and IPPY nivo as Salvage therapies from use athili ama so we’ll talk about that in the ongoing clinical trials section okay so what is happening in the field and where are we moving so these are currently some ongoing clinical trials in the neoadjuvant settings so remember I

mentioned we’d haven’t made very much progress in tri modality therapy or median best meeting overall survival is 25 months in our curable population which isn’t great so there’s several trials ongoing incorporating immunotherapies we have swab 16:19 which is set to open which is looking at suspend at asel is map followed by surgical reception with and without XR t followed by maintenance at asel ism at for a year so we’re following along with what non-small-cell

lung cancer is doing in addition we’re also looking at the combination of immunotherapy with radiation after surgical resection to see if we can’t improve survival for our patients the Canadians have been doing something called the smart trial which is chemo radiation followed by surgical resection they have had a very good response rate as well as overall survival and their initial set of patients they’ve done about 60 ish patients and so we are hoping to

see more data from them this is an ongoing larger trial being done in Canada right now I would say though do not attempt to do this off protocol because this is obviously incredibly challenging to do surgical resection over such a large field that’s been radiated there’s been an adjuvant vaccine study that demonstrated an improvement in PFS and OS using a wt1 vaccine and there’s currently efforts underway to try to convert this into a randomized international

phase 3 study there’s a lot of intraoperative and intrapleural strategies that are under investigation right now I would say I just listed them here but there’s a lot of gene therapy being looked at and also PDT but none of them have really made it beyond to phase 3 so I would just keep them in mind that these are things that are underway ok so what about the metastatic setting so everybody knows that the

hallmarks of cancer all the different dysregulation of the pathways that you can do so right now in the field of music a glioma there’s a ton going on with anti-angiogenic s– as well as the immunotherapies and also looking at cellular metabolism as well and so when we look at the emerging frontline trials I do want to touch on a couple specifically the cisplatin pemetrexed an attendent study called Lumi me so that was just

presented at ASCO this last year so this was this Pam within well-attended which is an oral anti-india genic inhibitor it targets veggie far and pdgfr and fgfr and then they gave him the tentative maintenance afterwards now when you looked at the intent to treat population median overall survival and PFS it was very significantly different for PFS there was a trend towards overall survival benefit there’s about a four month improvement absolute numbers and this trial was

not powered for overall survival but it was for PFS so lumi meas oh is now in the phase three study which is a registration trial and so if that does hold up with the Phase two new tentative will then become likely a standard of care for mesothelioma in the frontline setting so this is definitely something to look out for I believe the phase three is already two-thirds enrolled and so this is definitely something

that to watch out for now I do want to make a quick point and that is this will only be probably for the epithelioid patients because the phase three study is only enrolling epithelioid mesothelioma so remember I said you now have to know the different histologic subtypes of misa and this is partly why so when your clinical practice if an attendant gets approved you have to only you can only give it probably four

epithelioid patients because that’s how the trial is designed now quickly there is no predictive biomarkers for any anti-angiogenic so this is a little problematic but until in the absence of that predictive biomarker the registration approval will probably just be for any epithelioid mesothelioma patient now we don’t know whether or not Bevis is Neb will be different from the oral veggie for TTI’s there’s another drugs to do that swag is putting forward which also targets veggie

fara pdgfr we also don’t know if it’s the maintenance effect that gives us our survival benefit and if we just gave maintenance PEM would we see similar data maintenance pemetrexed is not FDA approved in mesothelioma but I will confess I do give meat and it’s pemetrexed in my patients that are not on protocol and I’ve gotten it paid for but throughout the rest of the world this is not the case and technically you’re

not supposed to do that but you know you do what’s best for the patients so there’s also the question about whether or not if we combine the anti-angiogenic s– with immunotherapy is would we get an even better outcome for our patients and so there are a couple of studies ongoing right now throughout the world that are looking at that combination of anti-angiogenic s– and immunotherapies okay so what else is going on in music

a glioma so I do want to touch on the atomic trial so this again is for biphasic and sarcoma toyed only mesothelioma patients and that’s using a drug called a deep egg 20 and so this is an agent that basically depletes your cancer cells of arginine and usually in by phases they can start coming to acne as though there’s a paucity of arginine in the cells so when you deplete it they die

off and so there was a Phase two trial that was published I think in Lancet that showed a significant benefit and biphasic start coming toward me as though so this is also a registration trial it was the theives 2/3 that’s ongoing right now throughout the world mesothelioma neste gated so you can see here from this table there are lots of different ways of targeting mesothelioma whether by monoclonal antibodies cart t-cells by vaccines and the

reason why everyone is interested in Mesa fillin targeted agents from euzeth a glioma is that music a glioma tumor cells Express me as a villain and so the Artemis trial is ongoing right now it’s system with and without Emma tuckson mob they’re looking at overall survival as a primary endpoint and so that is a frontline trial for all comers that they’re hoping to see a benefit now what about amino therapies so there’s quite a

few immunotherapy trials ongoing right now but we cannot give sispann with an i oh right now there is no data for that and you’re probably not going to get it covered by insurance so you know that question that they asked earlier don’t do that yet so most of these trials have just been initiated I don’t anticipate anything’s going to read out at least for the next six to nine months but maybe by

world lung next year we should start to see some of the preliminary efficacy data maybe from the Australian trial first so in addition there is an epi nivo frontline trial compared to chemotherapy and so this is a frontline study that’s rapidly accruing and so we probably will get a readout on that hopefully in the next year of some preliminary data now obviously there’s a whole ton of studies in the salvage setting looking at

all these different agents and some of these are typical musical and targeted agents as I mentioned before the only thing I would say is that there have been this study right here and a tuma map versus Naville beam unfortunately that was a negative study so that was unfortunate and that was just presented at world lung in terms of the salvage setting when you look across the board at all the different checkpoint inhibitors and then

also I’ll touch on the map study as single agent checkpoint inhibitors it’s pretty consistent we see about a 20% roughly response rate in these patients and we don’t have enough data to know whether or not it correlates with PDL one but we are seeing that trend but I think we still have to look at the microbiomes on these patients and tumor mutation burden to really know who’s going to be the best responders

to single agent checkpoint inhibitors combination immunotherapies are also being looked at right now at world lung there was a presentation on nittany so also at ASCO and world on the maps to trial which I’m going to touch on in a minute and then they initiate study was presented at World on in the selvedge setting very significant response rates probably about 25 to 27 percent disease control rate looks very good I would say not you

know clear whether or not this has to correlate with PDL 1 IC expression like I mentioned before we’re all knowing that I’m across all the solid tumor types that microbiomes tumor mutation burden as well as PDA one might be more relevant so the maps to trial was presented at ASCO and world on and this again was mesothelioma patients who have progressed after one or two lines of prior therapy and they gave neva versus epi

nivo this was not designed to be a comparative trial though they had two parallel designs with their stats analysis but it being evil gave you about a twenty five percent response rate and the disease control about fifty percent and so this is something that we’re definitely looking forward to seeing more data on however based off of this information the NCCN guidelines were actually amended to allow epi nivo in the salvage setting and also

Pemble is map was also included in the NCCN guidelines so like i mentioned we don’t have any initial definitive survival data but OS does look promising from maps to there’s a randomized trial that is currently being from what I’m told in France being under developed under way and then we don’t know if it correlates with PDL one IC status but I think we’re going to learn a lot more from the frontline if you

Nev o trial about that and then as I mentioned before it beam Evo has been included in the salvage setting for your Meisel patients so you can now give it and it is covered by insurance if you give them the NCCN guidelines you do have to fight a little bit that you can get that for your patients and as I mentioned before Pemble is mat is also included as well based off of

the response data from the oven and publication so a ton of IO trials and miso are underway and all of you will have our slides later so that you can refer to this if you need so to conclude the anti-angiogenic s– in my opinion definitely have a role in mesothelioma and i do consider them as a standard treatment option you can right now give bevacizumab and insurance covers it will see about an

attendant it’s very important to ultimately from a research perspective identify the patients that benefit them so we reduce cost for our overall healthcare system and then we also have the question about whether or not iOS can be added at some point now the immune checkpoint inhibitors I do think are going to change our standard practice for me so you’ve already seen on the NCCN guidelines we can give epi knee though and we could give

PEM bro and so we’ll have to see whether or not moving them front line will be beneficial or not right now you can’t do that but as the trials come out over the next year or two we may see adoption of that practice and as I mentioned Epping EVO is being looked at in the front line setting versus chemo and so we’ll have to see and so I think that this is

my last slide yes

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