I am very pleased to present to you our second line of MesoTV MesoTV is a program that was created by the Mesothelioma Applied Research Foundation. In response to the need to cancel our International Symposium on Malignant Mesothelioma, We recognized that countless were seeking information about treatment. The science behind malevolent mesothelioma word of local communities and information about the workings of the mesothelioma exerted investigate foot. This platform has been become possible by our generous supporters and sponsors. Thank you so much better. It is so important for us to be able to raising all this pertinent information to the community that we dish Dr Raghav. Thank you so much better for participating us today on this newest episode of MesooTV Happy to join. Thank you. Thank you. So you’ve created quite a challenge. For me, The discussion we’re going to have today is about probably the two hardest pharmaceuticals to declare in the following areas of mesothelioma. I know it’s, a mix of therapies, it’s bevacuzimab and atezolizumab, or so. If you would correct my inflection and then we can start in Yeah, the figures do deter getting more and more complicated as the years pass, but yeah the the first compounding medicine is bevacizumab and atezolizumab and then of course you know the next one is easier to Pronounce MCY m1 1, but we can call it m1 1 for short, Perfect. Okay, enormous, So I understand that this trial is strictly for patients with peritoneal mesothelioma. Am I compensate, or is it for all solid tumors? Yes, so this trial? You know when we designed this study Mary. You know we’ve found that there is a very big knowledge gap in understanding efficacy of drugs in patients who have peritoneal mesothelioma, and you know clearly, I don’t need to educate the target audience here. We know that peritoneal, mesothelioma and pleural mesothelioma are two definite diseases from an epidemiology view from the clinical challenges and presentations that these patients have down to surgical policies and approaches that we take towards these patients. The only thing that has been lacking in the field so far has been the coming towards systemic therapies. Where “weve been”, you know, acquiring from plural mesothelioma studies. You know, partly because of the scarcity, partly because of you know where these cancers are housed. But you know here at MD Anderson, we have a big GI center, where we have a dedicated multidisciplinary team towards care of peritoneal mesotheliomas and our pleural mesothelioma is housed in Thoracic Medical Oncology. So you know recognizing our “patients “, their unique needs and the fact that these sickness could be different even at a molecular stage. You know We are big-hearted proponents of doing dedicated investigate in rare and, in this case, an ultra rare tumor. So this study was alone designed for peritoneal mesothelioma. There was another cohort of pleural mesothelioma on this study, but it was a separate cohort than the peritoneal mesothelioma cohort So now for our patients with peritoneal mesothelioma. For this study, are you taking oil histology, epithelioid, biphasic and sarcomatoid? Yes, so there was no exclusion for any of these. You know we wanted to evaluate this in all our patients. Now, of course, you know, the experiment does manifest the dispensation of what we see with regards to these histologies in specific populations, And this trial was designed for patients who are either not candidates for surgery or following a surgical. Relapse. Yes, so unquestionably not candidate. For a curative meaning, surgery and about 60 of our patients have had some sort of cytoreductive surgery and HIPEC previously, which is consistent with what we check out in the community. And you know there were some cases that presented de novo with ailment. That was never a candidate for surgical resection. So is there the reporting requirements for these patients to have had the standard therapy of Alimta cisplatinum, or can cases enroll directly into this trial , not having had a platinum Right? So this was a second line study Mary, so cases had to have progression or antipathy to a platinum, pemetrexed based treatment, so both the pharmaceuticals Now Avastin was not mandated, but it was also not an exclusion criteria or bevacizumab was not mandated or was not an exclusion Criteria – Okay, good, so that’s important to know. So such is two relatively recent treats and I’m not sure that the patients that will be listening to this series are familiar with the mechanism of war and the type of drugs, because these are quite different from chemotherapy. So would you like to talk a little bit about the bevacizumab first and then we can go into the other drug Sure utterly And if you’re okay with it. Maybe I’ll really try to explain both those mechanisms sort of together. So bevacizumab is a very common drug. It’s an older dope. You know this is a drug that hinders the vascular, epidermal expansion factor pathway. So you know this is the pathway that should contribute to angiogenesis or blood vessel constitutions that that assist cancer swelling. So this narcotic restrains those new blood vessel formation that helps cancer growth, and this is a drug that has been approved in numerous tumor sorts: lung cancer, colon cancer amongst other, and it has been demonstrated good activity in combination with chemo. Now there is no evidence where this dope is used by itself. You know the rationale for using this dope in malevolent peritoneal mesotheliomas is. We know that these are vascular and VEGF high-pitched tumors. You know there has been a a number of studies that have been done for mesotheliomas with VEGF agents , not exclusively bevacizumab, but other negotiators that have not shown any promising incremental advantage in general. You know there was a study of bevacizumab here in the us that didn’t show any better activity than chemo. There was a French study, the MAPS study which actually use bevacizumab in pleural mesotheliomas in firstly route treatment with carbo Alimta. It did demo some improvement in progression, free existence and overall survival, but clearly that study was specific for pleural mesotheliomas. Too that study did have a maintenance bevacizumab arm, so you know you got chemo with bev and then you still got some treatment versus you had nothing. So you know there were certain aspects of this study, so even though there is a VEGF signature in mesotheliomas, let me introduced it this way: VEGF cares by themselves are not uber effective in this disease, So they need something else to work with Now. Atezolizumab is a newer drug and this is the same class of drugs as immunotherapy, the so called immunotherapy doses And precisely to give people an idea of what exactly these immunotherapy dopes are. So you are familiar with, recollect: cancers are foreign to the body, so the immune arrangement always wants to destroy them, but there are multiple methods in which the cancer shuns the immune structure and one of those spaces is called the pd1 pdl1 pathway. So, basically, what the cancer cells do is they express this molecule called pdl1, which is called programmed fatality ligand and on the immune cells? There is a receptor for these, which is called the pd1 and naturally the reason for having that on the immune cells. Is you know whenever you get infected your immune system revs up, but you need a mechanism to decrease that immune organization. Otherwise, after every illnes, you’ll start developing infections, which are called autoimmunity cancers, in which you know the immune system starts attacking your own body. So the body has developed this mechanism of this pd1 molecule where a revved up immune organization gets checked, But cancers exploit this mechanism by suppressing the immune method uncommonly and that’s why they can proliferate. So you know a lot of drugs like pembrolizumab or nivolumab or atezolizumab in such cases target this pd1 mechanism right, so what they do is they uh bind to these ligands and they don’t allow that pd1 to be activated. So, in a way, you’re taking the break off the immune system and allowing that immune plan to assault the cancers. Now the rationale for combining these two cares is in mesothelioma per se. We have tried just like bevacizumab, “weve tried”. You know single negotiator, immune cares and the response paces are there. There are some patients who benefit, but they’re very suboptimal, sub 15 response rates in the majority studies and in peritoneal mesothelioma per se. The data is extremely limited because most of the studies have been done for pleural mesothelioma, So the reason why we wanted to combine these two stimulants is because bevacizumab can modify the tumor micro environment and remained unchanged from immune suppressive environment to a immune, feelings environment. So what it does is bevacizumab has been shown to increase these foreign antigen introductions on cancer cells and when cancer cells present these antigens, and now you bring in a drug that can take the breakings of the immune plan. Now it’s a perfect mechanism. You have lots of bad antigen, and then you have these immune cadres that are now triggered and they can collide together to create responses. So that’s the principles of the combining – and this combination is already FDA, approved in treatment of liver cancer or hepatocellular cancer. So in liver cancer, same tale, VEGF stimulants have some undertaking immune inhibitors like pd1 or pdl1. Drugs have some undertaking, but when you combine them together, there’s a synergistic effect, so that’s, that was a potent combination in liver cancer and that’s. Why we chose to do this in peritoneal mesotheliomas, Which was lucky for the peritoneal mesothelioma patients. As well because the toxicity and dosing had already been worked out, so you sort of had a clean slate to produce now into the clinic. So how are these stimulants dispensed Are these IV or are they by a pill model? How do you give these doses? So these are IV stimulants. They’re, sacrificed once every three weeks about an hour infusion each And how long does this study continue? How long will you get the two medications, So the study was designed to continue the treatment till either toxicities arise that are unacceptable or intolerable in individual patients or till the time you progress. So there was no definite period of this care and you are familiar with, as “youre seeing”, from the results which you know we’ll be discussing, which were presented at ASCO this year. Some patients have been on study for about two years, two and a half years. Pretty much the duration of the study so far That’s great When they initiate this ordeal. So you start the treats you can you have the one cycle, two cycles/seconds? Is it after the second or the third cycle that you are able to scan to take a look to see whether this medicine is working for them Yeah? So after three cycles, so every nine weeks the checks are every nine weeks? Okay, great And you do a regular CT scan to assess for response Yeah. Absolutely all the responses were according to the standard, RECIST criteria, which is the standard radiographic criteria we use for any other malady, largely Okay, and then I approximates my next question would be what kind of toxicities are you mentioned and individual patients should be aware of Right. So we treated about 20 patients of peritoneal mesotheliomas on the study Mary, but you know at the same time, we had also launched this rare cancer program, so there were other rare cancers that were treated with the same combination, so in totality we had about 120 cases That we treated with this combination and irrespective of this ailment feature, the safety signals were very similar and overall, the study was very well accepted, at least for our mesothelioma patients. Most toxicities were pointed one gradation two, The more common grade. Three toxicities were hypertension, which forms part of the bevacizumab medication and some anemia, but they were seen in about 40 percent and 10 cases respectively and in most cases they were managed very easily. The anemia was not a major fus for therapy continuation and neither was hypertension because you could administer it actively by antihypertensive remedies About two cases of studies and research did have an immune, interceded harmful occurrence. So you know like we were talking about you once you rev up the immune organization. It can have autoimmune effects, so those two cases did develop immune mediated side effects for which we had to stop the treatment, but otherwise for 18 cases. Treatment was continued without any problems. Wonderful, So what is your next design with this trial? So, of course, I suppose the first step is to make this data out and available to everyone, and you know, peritoneal mesothelioma is a very rare tumor. I strongly believe that we need collaborative scientists to do larger tests in this disease, but for now this is one of the best available evidence. You know that we have with regards to activity of IO, immunotherapy or combination of IO immunotherapy in peritoneal mesotheliomas. There are some patients that get treated with other immune checkpoint inhibitors, as has been you know, done for pleural mesotheliomas. I think that atezo and bevacizumab they were perhaps better stood. You know, of course you can’t. You can’t compare two different troubles, but if you look at it overall, I think this treatment was very well abode compared to other combinations of IOs immunotherapies that have been done in mesotheliomas and, of course, our our efficacy develops seem to be significantly better than What we’ve seen with other IO combinings or IOs, so I strongly would consider use of this medicine as a part of continuum of charge. Now that doesn’t mean the work is done because you know our results established tumor, established, tumor responses in about 40 patients and some tumor response in about 50 of individual patients. So there’s still a long way to go, so all newer trials and more rational combinings are needed, but for those that are not able to participate on clinical troubles, I think this represents a awfully viable and safe standard of care. We have been discussing this with the NCCN guidelines body to try to actually you are familiar with. There is no good guidelines for peritoneal mesothelioma, either ways discussing with them about about including you are familiar with, guidelines for peritoneal mesotheliomas, so that you patients can get the most appropriate care. That’s available out there And of course we are trying to see if we can move that is something that a greater trial or even earlier word of adjusting. Because, frankly, the outcomes in the study were much better than what we would have even expected. Out of. First line chemo Right, so I guess you know that’s always their own problems with a uncommon sicknes, and you know now we have a super subset of a rare disease with peritoneal, so you are familiar with getting the numbers that they’ll be statistically significant to move. This into you know an FDA approval process is going to take some exertion and, as “youve said”, it’s going to make quite a bit of collaboration. So you are familiar with, I be understood that as the role of the Foundation to sort of insert ourselves in the middle of this and try to get everybody to the table, and you know advancing the regimen and actually trying to get more collaboration. More collaborative events among you are familiar with those medical oncologists that are interested in peritoneal meso, because you really are a handful. You know, and I don’t mean a handful difficult but a handful There’s so few of you that you know it seems that you know if we could get everybody to the table together again and start to discuss what needs to be done in This disease, we can, as you said, get some standardization which has been lacking for the 20 plus years. I’ve been in this disease that we need to move forward Great. So thank you for doing this trial. I know with something with a small disease like this: it’s hard to get those figures that you need. So congratulations. I’m sure it was quite an effort. So thanks for coming . .