Update from Recent Mesothelioma Clinical Trials: Olga Olevsky, MD

Good morning everybody and thank you for being here I'm very excited to be here we had a very exciting year in mesothelioma 2016 really asked all there were multiple presentations so what I'm going to do is I'm going to give an overview of the agents that we have and that are available and then we will have very exciting detailed lectures on immunotherapy and on dendritic cells so let's see so of course so mesothelioma is of course the cancer of the lining of the pleura and perineum the diagnosis is made histologically sometimes it can be confused with adenocarcinoma so we use the immunohistochemical markers that characterize mesothelioma since not a lot of pathologists see it because it's so rare so immunohistochemical markers that are important cytokeratin five and six Calretinin WT-1 those are positive it's TTF negative and CAC EA negative have been several germline mutations that have been worked out in mesothelioma we do know that there is a clustering of cases that is observed but then families and therefore there could be a genetic component the important mutation that has been becoming more and more prominent is called BAP1 it's BRCA associated associated protein it is a tumor suppressor gene that is missing in germline mutations this could also be a somatic mutations that can be acquired and in this particular individuals that asbestos exposure is particularly damaging and they are the ones that can develop the disease so chemotherapy this was sort of our first line of defense and prior to 2003 all sorts of agents have been tried and there have been no standardized therapy 2003 was a big year for mesothelioma there were two international trials that demonstrated the combination chemotherapy as his platinum and pemetrexed versus is platinum alone were quite successful and very good and both of these trials showed that there was significant response rate in an increase in overall survival this was the trial that was done in the US pemetrexed and cisplatin vs cisplatin alone it was a phase 3 trial where 456 patients were randomized into two groups one group 226 patients got combination therapy the other group got this cisplatin alone and there was a difference in overall survival and progression-free survival the combination arm had a 12 months survival and cisplatin alone a nine point three months survival so that time this established that the combination therapy was the gold standard and this was a standard of care for many many years pretty much up until now so as you saw the survival was 12 months with combination chemotherapy so since 2003 up until now the goal was to develop new agents to look at immunotherapy and to see what can be used in second line to prolong survival and additionally what can be added to the chemotherapy backbone working so the first the first trial that was done this was very exciting this was done in 2015 this was a Maps trial so this was a medicine me this mesothelioma avastin pemetrexed and cisplatin study so this was a multi-center study that was very similar to the previous one where avastin of acid or in vascular the seal oil derived growth factor was added to the chemotherapy backbone there were four hundred and forty-eight patients in the trial those were the patients that were candidates to receive avastin or bevacizumab they were not allowed to have any cardiovascular toxicity and they had to be no more than 70 years of age those patients were randomized to receive pemetrexed and cisplatin and bevacizumab versus pemetrexed cisplatin and placebo they were treated for six courses and if they had stable disease they continued on unto bevacizumab and those were very exciting results that we haven't seen for many years the progression free survival there was a statistically significant difference 9

6 vs seven point five months and more significantly there was a significant difference in overall survival 188 vs 16 months we have not seen those kinds of numbers for many years so this was very exciting and when we looked at all the subgroups all the subgroups benefited from avastin whether regardless of performance status histology gender age and the quality of life was also not changed and certainly was about similar was not worsened with addition of the avastin so based on the maps regimen this made it into the NCCN guidelines and so for the patients that are bevacizumab eligible the guidelines now recommend using the combination chemotherapy of cisplatin 'um pemetrexed with addition of bevacizumab with following for six cycles and bevacizumab can be used as maintenance therapy until disease progression so several questions I came out of the chemotherapy trials the first one can carboplatin be substituted vs cisplatin and the answer to that question is yes this was answered initially in the extended access program where patients were given those different regiments and there was no difference in overall survival and total time to progression one-year survival rates were similar this was recently confirmed by very large multi by a meta-analysis that was presented at ASCO by the MD Anderson group they looked at three large databases medline embase and cochrane they looked at overall survival progression-free survival over overall response rate they had five studies they had 11 perspective five randomized and 12 retrospective studies and again in five studies with comparative arms there was no statistically significant difference in overall survival the response rate was greater with cisplatin demand payment rx8 but disease control rate was the same so the conclusion was that pemetrexed and carboplatin is not significantly different than pemetrexed and cisplatin the next question that was also asked and is currently still not answered is whether pemetrexed maintenance is useful and the study again is looking at trying to use maintenance like we use in lung cancer with pemetrexed after four cycles of our combination therapy and the studies to finish a cruel in june of 2017 so moving on to second-line therapy there is no currently approved fda salvage therapy and several options are available to us none of them are excellent there is pemetrexed where patients can be retreated at progression gemcitabine in vinorelbine monotherapy and of course that's why this is where we're looking at clinical trials so multiple agents multiple biologic agents multiple immunotherapy agents have been tried and I'm gonna the agents that are highlighted in red I'm going to try and briefly review today we will look at tyrosine kinase inhibitors and immunotherapy and at miscellaneous agents like anti mesothelin agents and ADI peg 120 so the first study the first agent that we're going to look at the study is called Lume-meso the agent is called Nintendinib it is a vascular it is a triple angio kinase inhibitor and it inhibits vascular endothelial growth factor platelet-derived growth factor and fibroblast derived growth growth factor many studies were done previously preclinical trials and in vivo it's significantly prolong survival in mice and inhibited cell growth as a single agent and in combination with cisplatin and it showed an additive not a synergistic but an additive effect when used together with sis platinum in preclinical trials so this is the first abstract that I'm going to discuss from ask of 2016 it was presented by Dr Scagliotti they took chemo naive patients from 25 countries they had 87 patients in the phase 2 trial and they're planning to recruit 300 to 450 patients in the face 3 trial so they're using the combination therapy backbone cisplatin and pemetrexed and they're adding a nintendinib on Days two through 21 again every 21 days for six cycles and if there is no progression after six cycles patients will be given and tendon it which is oral or placebo so currently the trial is ongoing there in the face three trial and their primary endpoint is progression-free survival so this should be reported in the next several years so we're going to switch gears and we're going to talk about a different class of agents we're going to talk about anti mesothelin drugs most as Dr Cameron mentioned most of these have been worked out at the NIH by Dr Effete Hassan so several agents are currently available so just to review this briefly mesothelin is a cell surface glycoprotein it is cleaved from a larger precursor protein and mesothelin is located on the surface of mostly epithelial malignancies even though it can be present on normal cells so several mesothelin agents are currently in clinical trials and we will talk about four of them the first one is a monoclonal antibody against mesothelin the second one is the immune attack scene where the variable portion of the monoclonal antibody has been conjugated to pseudomonas immunotoxin the next one probably is very familiar to on colleges in the audience it's an antibody-drug conjugate which is very similar to TDM one it's the antibody that is attached to IDM 4 or Mateos annoyed toxin and this is that mesothelin vaccine this is a vaccine against using the mesothelin antigen that has been using a listeria vector so the first trial that will talk about again presented at ASCO in 2016 is called Artemis after the Greek goddess of hunting it's a chimeric monoclonal antibody that bides mesothelin Dr

Hassan has done a previous trial it's called Amatuximab some up with cisplatin pemetrexed pemetrexed and it had a adequate safety profile the median overall survival was fourteen point eight verses fourteen point three months without the antibody and historical controls and what they were able to show that higher trough levels were associated with higher overall survival and progression-free survival in their previous trial so the trial that they're doing right now again they're using different doses and they're using this is platinum pemetrexed backbone and they're adding a maximum at five milligrams per kilogram every 21 days for six cycles versus placebo if there is stable disease they're adding the patients are going to go on to continue Amatuximab weekly or until disease progression and the other group will get placebo the trial is currently ongoing and we don't have the results of this trial yet but this is something to watch for this is the again the Pseudomonas toxin which is a recombinant protein that links the antibody to the toxin so initially this was the idea that these are the mesothelin receptors on the mesothelioma cells so the taught the antibody would bring the toxin to the cells and this was supposed to result in cell death and even though originally they had very good results that were limited by the development of the neutralizing antibody to the compound so this limited they are experiments so what they were able to show that we're able to develop a regimen which is similar to a bone-marrow induction transplant regimen of Penta Staten cyclophosphamide and by priming patients with this regimen first they were able to eliminate this neutralizing antibodies and go on with their sales what they were actually quite surprised the kinds of results they got from using this conditioning regimens so they felt that not only were they eliminating the neutralizing antibody there were also probably eliminating the T regulatory cells that for suppressing the immune system and therefore they actually were able to show this is the water plot of their pilot trial where they had very good results and this is the picture that Dr Hassan has showed at a previous meeting well there was a patient with quite a bit of disease before treatment it did not get much better right after treatment but this was result at eight months and again they're also they have published their results of trying to add them you know toxin to pemetrexed and cisplatin backbone The next agent is the vaccine the live attenuated Listeria monocytogenes vector vaccine so idea the idea again is that it's a vaccine engineered to express tumor-associated antigen mesothelin which is expressed in mesothelioma it stimulates the development of specific t-cells against mesothelin expressing tumors they the phase two trial has been completed and again this was presented in ASOC that this was a frontline trial the patients were given two boosters of the vaccines two weeks apart prior to getting chemotherapy subsequently they got six courses of combination chemotherapy cisplatinin pemetrexed and then they got two more boosts of the vaccinations there were three weeks apart and if they were clinically stable they continued the vaccinations every eight weeks this was a small trial they had 36 patients that they could evaluate they had ninety-four percent these control they had three percent of complete responses they had fifty three percent of partial responses and thirty-nine percent stable disease so meet their median overall survival was 20 months and their conclusion was that it was a vol tolerated vaccine the plans were to go forward with the phase 3 trial but I'm not quite sure what is happening with that because we were going to participate in that trial and then suddenly it was not at UCLA anymore so so the final agent that I mentioned is the antibody-drug conjugate where again the antibody is attached to the DM 4 moiety and this is the trial that was presented by Dr Raffit Hassad ASCO 2006 this is called Anetumab ravtansine a hundred and eighty patients with biomarker staining for mesothelin and those were the patients that progressed on first-line therapy and they were given the antibody drug conjugates every week required for every day all right I self can acquire arginine by two pathways it was an internal agree a pathway to cells and the cells used the enzyme called Arginine Deaminase that cells can also acquire as an enzyme external so gives herself blocks that Arginine synthetase and therefore they rely wholly of external supply of arginine there is an enzyme which is called arginine deaminase that catalyzes the conversion of our arginine into citruline so it's depletes the supply of arginine The native ADI that is present in the circulation is very in half life is very short biogenic so a compound a regulated compound has been engineered that makes the enzymes less immunogenic at the significant prolonging of it's half-life ADI-PEG 20 can be administered IM weekly and completed depletes the arginine supply so arginine deficient cancer cells are effected because they cannot not get arginine anymore and rural cells are not effected because they have the internal pathway polatris trial atomic trial two trial it is an ongoing phase two trial where our primary objective is overall survival it's hopefully going to progress into Phase III trial so these are the treatments and patients that have been tested for arginine synthetase usually they are biphasic histology and the ASS 1 deficiency is determined by a central lab so they are randomized and force filed and again they are going to pemetrexed so go on now we're going to shift gears again and we will talk about the new images processed and greatest film presents the image into the T cell T cells recognized antigen has presented response to the critics don't see the businesses to the activated aware to herself our helper t-cell cytotoxic T cells are produced so in order from the immune system not to go out of fans there was a great of their new system and in 48 hours after the t cell activation protein of the t cell surface called CTLA-4 and CTLA-4 essentially competitive divine CD 28 so the first have been you know therapy and has been developed is ctla-4 antibody and this is the antibody that binds to ctla-4 and essentially does not allow the break that normally goes on to happen and blockaded this checkpoint provided the first evidence of improvement in overall survival in improvement in patients with metastatic melanoma and this was done in 2008 another pathway that is very important and that is all or most of the immunotherapy trials and agents are is the PD-1 pathway and again PD-1 stands for programmed cell death there is another receptor on the e on the t cell surface that is PD-1 this is the more specific receptor and against it's also used to shut down the immune system so normal circumstances after the immune response has been so calm has been going on and needs to be shut down the PD-1 receptor is expressed in advance to PDL ligand that is present on the dendritic cell and this acts to shut down the immune response a tumor squab as pathway because they can express a PDL ligand on the tumor surface and again this the presence of this ligand binds to PD-1 and shuts down the immune response that is generated by the T cells what is this PDL of one expression means of their several settings that rootedness the first item is on my handsome clinic and study is to benefit absolutely our lab from the group so so yeah multiple agents are development trying to correct this problem so this is a PembrolizumabTremelimumab CTL 4 antibodies there PD-1 antibodies nivolumab of course in pembrolizumab have been approved for lung cancer but these are the pd-1 antibodies and these are the new PDL one antibodies that are currently being looked at and Avelumab has been FDA approved in urothelial cancer so the first agent that was evaluated that I showed you is the ctla-4 antibody tremelimumab AB this was the preliminary this was the first study that was done in 2012 it was the first author and the person who developed these trials is Dr

Calabro from Italy so his results were initially very exciting he had 29 patients he treated them from May of 2009 to January 2012 and what was exciting is that even though only two patients had durable partial responses one response lasted six months another one lasted 18 months and he showed that he had thirty one percent disease control in second line setting with an overall survival of about ten point seven months so this there was a large phase 3 trial we participated in that trial and actually recruited quite a few patients so this trial took place from May of 2014 to December of 2014 and in that short period of time 571 patients were recruited which is very impressive for any trial but especially for mesothelioma and those patients there were patients that could have had up to two lines of treatment primary endpoint was overall survival they were treated with tremelimumab q four weeks for seven doses and then every 12 weeks versus placebo and unfortunately there was no statistical difference and overall survival which was very disappointing but that seemed to be not completely a new thing in this disease and trauma looma mab patients had Ida's type or in autoimmune side effects or adverse events such as disney diarrhea and colitis and this was again presented at ASCO in 2016 so what so the group Dr Calabro took this to a different level and now they presented at ASCO again they're going to open a nibud meso study where they're going to combine the ctla4 pathway with a PD one pathway so again they're going to enroll first a second lion patients plural of peritoneal mesothelioma and they're going to give them tremelimumab at a much smaller dose together with an anti pd-1 agent durvalimumab and the primary objective is going to be immune mediated objective response rate secondary objectives are going to be overall survival and Disease Control rate as well as safety so running through very quickly the immunotherapy trials this was the first one this was the keynote trial pt1 inhibitors in mesothelioma keynotes keynote trials were the trials with pembrolizumab in different diseases there was a meso mesothelioma cohort that had 84 patients those patients were PDL positive and they received amber lose about 10 milligrams per kilo q two weeks for up to two years a primary endpoint for safety tolerability and they was an overall response rate was about twenty four percent of a disease control rate of seventy six percent and importantly there were no new safety signals with this regimen so this again was presented and ASCO 2016 avelumab part of the javelin solid tumor trials he had 53 patients that progressed after platinum and pemetrexed those patients were unselected for the PDL one status and they received a volum AB every two weeks until disease progression and again a very similar overall response data stable disease disease control rate of fifty-six percent with the progression free survival of 17 weeks this is the compound that is called atezolizumab it is a anti PDL one compound so this is a compound that is against PDL one that is located on the tumor cell and on the dendritic cell so it inhibits PDL one and this is a swag trial and this group of trials is a little bit different this is neoadjuvant patient so this these are patients that are potentially resectable so resectable me this mesothelioma patients chemo naive they get neoadjuvant treatment with cisplatin pemetrexed a trackside if there is no progression they go on to surgery and then they get maintenance therapy with a atezolizumab for a one year so the plan is if this particular trial of the part 1 of this trial goes well they're going to move on to the next phase of this trial where they're neoadjuvant treatment is going to be chemotherapy bagbone plus a atezolizumab and again if there is no progression they're going to go on maintenance and a body therapy for a year so and what would be very interesting they're going to have translational correlates and this is an MD Anderson trial that is leading this in the swag group I'm going to just introduce the idea of vaccines this is the WTI vaccine that Poe studied at Memorial sloan-kettering SLS 001 as I mentioned earlier wt1 is a transcription factor that is expressed on mesothelioma cell surface and immunohistochemistry is used in diagnosis so at Memorial they developed a multivalent vaccine using the WTI peptide sequences to stimulate the cd4 and cd8 t-cell responses and they had a trial they presented this in ASCO in 2016 they had about 40 patients that were randomized so patients were randomized to receive the adjuvant the gm-csf and the sls 001 vaccine and the other group received the adjuvant the gm-csf and placebo they did not receive the specific wt1 vaccine so they the patient's they and I have to mention they completed their multi modality therapy so they completed surgery they completed radiation and they've already had chemo so this was a good group of patients and they had the word wt1 positive by immunohistochemistry so again these are the median overall survival was twenty one point four percent in the vaccine group and it was sixteen point six in the nonspecific vaccine group the patients that had r0 resection had a 393 overall months overall survival verses twenty four point eight months which again probably speaks more for surgical technique as we've heard before but maybe there is a signal here with the vaccine as well so in conclusion they're important changes in the management of mesothelioma in the last few years the role of a vgs vegf has been elucidated and probably we found the correct bagbone since the previous trials with gemcitabine and sis platinum didn't work of course we need to focus our research on biomarkers and the pathway the role of immunotherapy is more and more promising and I'm very much looking forward to hearing today about the vaccine therapies thank you

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Update from Recent Mesothelioma Clinical Trials: Olga Olevsky, MD

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