so i’m gonna i’m going to start this session and I’m a medical oncologist and what I thought would be important to do is to review the systemic therapy that has been available and that is available for mesothelioma we have very distinguished investigates now that we’ll talk after me that perhaps will address more of the newer things that are on the horizon because we have quite a mixed audience in their patients in the gathering I’m going to talk a lot about the statistics and about clinical tribulations that have been done and what I want people to keep in mind that a lot of these statistics don’t apply to individual patients they got applied to groups of populations but whoever is here is certainly is an outlier and please don’t you know centre in the future and don’t look at the numbers and get baffled so a prior to 2003 there was no standardized rehabilitation that was acceptable for mesothelioma there was a meta-analysis of 119 ordeals that demonstrated that combination chemotherapy with sis platinum stipulated better response than sis platinum alone in 2003 there were two international contests that were done that demonstrated that the combining chemotherapy with two anti Foley dopes pemetrexed or and relative trackside increased survival compared against single bureaux platinum both tests proved a significant improvement in response proportion and no deleterious impact on the quality of life pemetrexed is a somewhat brand-new dose not so much better new anymore but existing mechanisms of action is that it intrudes it’s an anti folate that restraint pure and synthesis and it inhibits key enzymes that are important in the formation of purines and pyrimidines the key enzyme of course is the thymidylate synthase and it has the greatest effect on thymidylate synthase nonetheless it inhibits dihydrofolate reductase and a garbed enzyme as well since platinum of course is an old friend and admonish to nuclear DNA and encroaches with regular transcription where reference is intercalate sit ego between the DNA locates so the visitation that was done in 2003 was pemetrexed and cisplatin versus cisplatin alone in cases with mesothelioma this was a randomized inquiry 456 patients were randomized all of them had unresectable disease and they were treated was his platinum and payment trackside every three weeks versus this platinum alone and what the test demonstrated that there was a longer overall survival in time to progression and patients that were treated by the combination there was a statistically significant difference in response rate time to progression an overall existence and the study proved the combination of cisplatin and pemetrexed on every three week three weeks as the brand-new standard of care in 2003 and was a plenary presentation at ASCO and same decisions were achieved in a european trial that used rowlett tracks it so the current recommendation is to of course administer at least four the curriculum of pemetrexed and sis platinum nonetheless if delayed response is realise or if patients are responding well we can go up to six trends and when pemetrexed is worked folic battery-acid and b12 supplementation is required to decrease hematologic toxicity so various questions have been raised about the purpose of applying pemetrexed and “theyre using” at the use of carbon magnum instead of cisplatin’ um so this question was asked and reacted and it was evaluated in the international extended access planned this was a multicenter non randomized open-label trial in chemotherapy naive patients who received/ lured and since platinum and pemetrexed and carbo platinum and mostly the overall response proportion the time to progression and other existence were equivalent so even though this platinum remains the standard of care substituting carbo platinum is certainly an acceptable pick the next question was addressed is that can pemetrexed be reused in can patients be retreated with pemetrexed at advance and again another phase two trial was conducted in cases with progressive canker that were randomized to best caring upkeep or two single worker pemetrexed and in fact there was significant better response proportion and longer time to progression in parties that were retreated with pemetrexed and finally this is a question that is borrowed from lung cancer is there a upkeep persona of a pemetrexed and can we use that and there is an ongoing CL gb trial that is multicenter randomized tribulation that is looking at the question where the pemetrexed maintenance is useful and the girl is to determine what the maintenance therapy improves progression-free survival in of that overall survival the ordeal is ongoing and due to close in 2005 where after four cycles/seconds of platinum and pemetrexed patients are randomized to receive pemetrexed upkeep or vest supportive care so the question that everybody questions is that not everybody responds to our standard therapy and are there any biomarkers that are available that we can use to predict clinical response and can we identify the patients that will respond so several biomarkers have been evaluated there is a biomarker for pemetrexed and by grocery versus platinum the middle-of-the-road at synthase again as the enzyme that is inhibited by pemetrexed and excision amend cross complementation group one or ercc1 is the DNA damage repair gene that removes substratum generated DNA adducts and has been evaluated to look at cisplatin resistance so there was an Italian retrospective study that was done looking at patients that have been to previously dealt with in pemetrexed and platinum or single negotiator platinum and levels of thymidylate synthase in ercc1 were assessed by both pcr and by immunohistochemistry and if you look at this graphs the gold line represents patients that had low-pitched thymidylate synthase levels and off-color position represents the patient’s was high semi Tillotson taste levels and what they were able to show that in patients that were treated bathymetric grain and low-pitched epoch rustic Santa’s protein grades that was predictive of improved time to progression and longer overall existence nonetheless the Adam Edelen synthase evaluates had no prognostic appraises in patients that were not treated with pemetrexed this lumber was shown with ercc1 cases with a high ercc1 level had a longer medial survival that patients but lower ercc1 degrees regardless of chemotherapy regimen that was filled and there was no correlation in mesothelioma between ercc1 ranks in response to cisplatin amor carboplatin as has been shown in some other cancers so other chemotherapy workers in addition to pemetrexed the other agent that has been used as gemcitabine gemcitabine as a nuclear analog of deoxycytidine in which to fluorine atoms have been utilized inserted into deoxyribose reverberate gemcitabine participates for the inclusion into DNA thereby hindering DNA synthesis and prior to introduction of Pam lures agent gemcitabine and cisplatin have been used as the first medicine and Misty leoma with response charges arraying between 12 to 48 percentage as we have heard about in the previous talks there is significant the patients with me the philly mesothelioma have significantly the high levels of the vascular endothelial emergence causes and in fact these levels are much higher than another solid malignancies like colon cancer lung cancer so phase two tribulation of anti-vegf antibody bevacizumab has been evaluated when it was added to cisplatin amande gemcitabine and this was used as a first-line therapy this was a terribly this was a phase two trial that the results of which were waited uneasily and cases were randomized to receive gemcitabine cisplatin inand bevacizumab on every three week basis for six cycles/seconds and the other group received gemcitabine cisplatin and placebo on every three week basis the patients is dealt with for six cycles/seconds and if no illnes advance was noted they were used the maintenance regiman but this is a map on every 21 daytime basis was used as to report to placebo and regrettably the results has been extremely disheartened disappointing there was no difference in progression-free survival or an overall existence with the addition of Bevis is a man nonetheless what was quite interesting is that there was a difference in overall existence if patient who are stratified by baseline but really rank in cases with higher baseline but Jeff ranks had much worse progression-free survival and overall existence and what was also somewhat frustrating is that veg of elevations were not different between responders and nonresponders and so there was no difference with the addition of bevacizumab nonetheless at the beginning of the inquiry pemetrexed was still not available and now there was information about the negative interaction between gemcitabine and bevacizumab so the next logical inquiry that was done is the addition of bevacizumab to standard chemotherapy which is climate rx8 and cisplatin and this is a Maps trial which is a multicenter randomized stage 3 trial where patients are randomized and then analyse for pemetrexed and sis platinum with a without bevacizumab for six repetitions and then if there is no progressive disease they’re given bevacizumab on every 21 eras the results that preliminary results were presented at the emic find in boston this year they have this as a French contest where 280 cases have been enrolled so far the goal is to recruit 445 patients and there is an absolute difference in survival that is seen at this early analysis so we’re quite we’re very excited for the results of this test the end of their cruel is expected in September of 2013 and biomarker analysis of tissue specimens is ongoing so unfortunately again there was no approved or accepted second-line treatment for ms athili oma that has demonstrated a survival advantage countless agents just like countless chemotherapy operators have been investigated in the past now numerous brand-new or biologic negotiator are being investigated with quite disappointing develops so they’re anti-angiogenic agents that are in development tyrosine kinase inhibitors have also such as of a different kind have been looked at histone deacetylase inhibitors have been previously been evaluated in a large contest immunotherapy is on the horizon as well I is not relating to the anti-missile Thielen negotiators because they will be extensively examined in the next talk so the oldest anti-angiogenesis agent is the lid amide and a lot of hope I was given to the lid amide that could be used in upkeep therapy so this was evaluated in a large period 3 trouble where cases that accomplished four cycles of standard chemotherapy were randomized to thalidomide 200 milligrams a day versus placebo or encouraging care and regrettably there was no difference in time to progression or survival and is not merely that more adverse events were reported in this the lid amide group several other workers ought to have tried up Sarathy nib is a potent inhibitor of the wrath fury and mac a pathway a pathway that is activated in multiple malignancies it also targets veggie afore scepter and recognize adolescents a period 2 test phase 2 trial was performed in cases in second-line chemotherapy the response rate was pretty low-grade I was simply sixty-six percent however fifty 4 percent of individual patients had stable illness and two different experiments were done and one of them had a longer time to progression of 5.1 months however the overall survival was similar in the two contests sunitinib has been tried another anti-angiogenic inhibit of multiple tyrosine kinases another second cable stage 2 study of occasional blasphemy internet 53 cases outcomes were similar to the serotonin trial with medium time to progression of 3.5 months in overall survival of six station seven months sadira nib is another anti-angiogenic tyrosine kinase two different ordeals were done again but moderately disappointing reactions would even lower time to progression and unfortunately with this trial there was significant grade three to four adverse events such as pulmonary embolism angioedema and reversible posterior leukoencephalopathy so this drug is no longer being looked at dasatinib this inquiry I met very interesting not only because it was done at the University of Minnesota but too because it was a CL GB trial where cases were already treated with chemotherapy the South nibud 70 milligrams daily was used with a primary endpoint of progression-free survival but but was very interesting about this trial is that they had an thorough biomarker analysis they looked at the vascular endothelial raise cause at the platelet-derived growth factor in that the colony provoking influence or csf-1 and in this contest what they were able to show is that survival was markedly longer in the patients with lower pretreatment CSF level and in patients who CSF level decreased during the therapy so currently there is an antibody that is available to the CSF one and from anecdotal suffer from collaborators patients have had sturdy replies from this CSF antibody and stable infection the one trial that had a lot of people waiting for was the with histone deacetylase inhibitors merely to remind you to carry out gene looks the cell must control the coiling and uncoiling of the DNA and this is accomplished by enzymes that are called that are called acidities ass it’ll asus so when DNA is in a quiescent position it is it is looped and it is in a tight verification wrap around the histone a nuclear protein it is uncoiled by an enzyme called acetyl transferase and when DNA becomes uncoiled it becomes the chromatin is more likely and more suggestible so to speak to a transcription so histone deacetylases represent a role in the malignant changeover of mesothelioma and hijack inhibitors or inhibitors or or treats that inhibit histone deacetylases ought to have looked at and evaluated to see if they would play a role so very large trial announced Vantage 014 was a multi period time 3 test 660 patients that was previously treated with different rehabilitations were randomized to receive a varenna stat a drug that is available in the treatment of lymphoma versus watching alone and they looked at at primary progression outcomes with progression-free survival and secondary outcome was overall survival and unfortunately again the results of the study were disappointing there was no change in progression-free survival overall existence and even if they are figures were statistically significant for progression-free survival six point three weeks versus 6.5 one weeks are not clinically significant evaluates so so far the workers that we have looked at are either cytotoxic chemotherapy workers or targeted rehabilitation the problem that we’ve had with me the steely oma is in order to have an active targeted care you need to have a viable target and we have had difficulties identifying that so tending has been turned to immunotherapy as another approach and there has been a very long-standing interest in harnessing or turning on the immune method to treat cancer and immune response to yank answer of course is the body’s natural mechanism of Defense and the clinical testing of immune arousing cytokines led to low frequency of responses but the responses that were seen were cute responses in obstruction and interleukins are immune inducing cytokines that have activity and several cancers that are we’re immune system is active such as melanoma and renal cell carcinoma so simply be remembered that dendritic cells are antigen representing cadres and they they pose this is the tumor cells so the antigen is presented to the dendritic cell dendritic cell manages the antigen and existing it to the T cell and the T cells are the main effectors of the immune methods antitumor response and this is what happens at between this is the interaction between the dendritic cell and the t-cell the t-cell recognizes the antigen that is presented to it by the dendritic cell vs T cell receptor it’s recollects it in combination son was self of the major histocompatibility complex complex so this is the first type part of the immune response the second part is this part right here the T cells generate the immune response by binding of the cd28 and imogen to the b7 antigen and that dendritic cell and in this way the immune structure is activated which results in increased production processes the T cells that secrete interleukin 2 and likewise cytotoxic T cells that instantly can destroy and target tumor cadres to avoid the over activating of the immune system there is an increased speech of ctla-4 which is a transmembrane protein the ctla-4 is expressed about 48 hours after the immune organisation is activated and what it does is that it competitively covers to be to the b7 cells and it essentially outcompetes the cd28 so the immune response is turned away and this is the dominant negative said restraints the immune response so I antibody to ctla-4 has been prepared and that forecloses the their relationships with the b7 and removes the down-regulation of the immune plan so essentially it takes the break off from the siege that is provided by the ctla-4 and the siege of this checkpoint rendered the first evidence of improvement in overall survival in patients with metastatic melanoma so ctla-4 obstruction with monoclonal antibodies again blocks inhibitory signal there by sustaining the activation and proliferation of the active T cells to workers that are currently available both of them are human Monaco no antibodies if a luma mAb was approved by FDA in march of 2011 for the care of metastatic melanoma and trauma luma mab is currently in clinical trials Tremmel uma mab is a full of humanized anti ctla4 monoclonal antibody with a half-life of about 20 eras it blocks the inhibitory signal it enhances the t cell activating and proliferation and by itself it’s felt to have enhanced antitumor undertaking it is has been used as a single negotiator in nine different clinical troubles and different tumors and because there is a component of immune mediation that is felt to be coming from the asbestos and mesothelioma this agent is approaching the immune organization and it may have significant pleasure so we are very excited about this agent some preliminary results from ctla-4 have been presented at the 14 th lung cancer meeting they have had patients that has been have been heavily pretreated with boosted me that still feel yoma the agent was found to be safe 22 patients were treated two of them achieved part response and four of them achieved stable sicknes what was interesting about these is that all almost all of these responses were quite sturdy all of them were lasting more than six months and three were lasting longer than nine months that is significantly better than anything that “were having” seen with chemotherapy so we and some of our other colleagues that are here in the public are opening a clinical experiment that is a randomized double-blind study that is going to compare tremmel uma map to placebo in second or third word management in patients with mesothelioma the study is planning globally to enroll about 180 themes and parties would be randomized to the one to get either Tramel uma map or placebo the primary objective is overall survival secondary Objectivist progression-free survival we’re certainly going to look a sturdy accomplish response and this is where we’re hoping we’ll accompany a difference the authorities concerned will also be looking at validating quality of life questionnaires and we will also do a biomarker analysis which is going to be key in their association for the call aluminum medication individual patients will be assessed with examines every three months as well as questionnaires so in conclusion there have been some important changes in the management of mesothelioma chemotherapy regimens are available but clearly this is not the answer much more needs to be done we have briefly talked about during the previous session that mesothelioma is most likely in reality of sarcoma and should be treated as such certainly when there is sarcomatoid histology this is a very different disease than epithelioid mesothelioma the role of veg f and first-line treatment is being investigated and we’re waiting the results from the from the large trial terms used in combination with this platinum and pemetrexed what is more important is that the molecular and biological pathways are being used to work and they genuinely need to focus on further treatments and persona of immunotherapy and reining the immune plan is very promising and we’re very excited about opening the tremolo mmmm trial now and I would like likewise accept my colleagues and the UCLA mesothelioma program thank you
Olga Olevsky, MD: New Results in Systemic Treatment of Mesothelioma
