Talk about refractory disease. I have to thank somebody. I can just come here. All right. These are my disclosures. Um, so for a long time we've been trying to figure out what to do after audio refractory, and to a great extent it just looks like we're gonna throw spaghetti at the wall and hope that something will stick. We've done this, uh. Not really a hypothesis we haven't really done the work that needs to be done to try to figure out what exactly it is that we're dealing with when somebody is progressing. We realize that this is a very difficult patient population. We have primary refractory disease. We have acquired resistance, uh, so this is, this has not been easy and it's not, uh, looking like unfortunately we're gonna be, um, uh, uh, making it any easier. There are certain elements here that we all recognize as being uh potentially problematic and could point to why patients would have progression of disease when they are being treated with a checkpoint inhibitor with or without chemo with or without CTLA4. There are, um, uh, technically issues that you can call primary reasons as to why someone might progress and or not respond, um, uh, for example, EGFR I was just suggested. Um, and there could be secondary mechanisms that actually developed. There could be host reasons, uh, there could be tumor related reasons. Um, I think the, the, the lesson that we're learning from all of these studies is that unfortunately there's not one or two mechanisms that are leading to IO refractory disease and therefore it is not a surprise that most of our studies that are just in all comers are failing to make any kind of progress in this stage. For the difficulty here is that to understand at the tumor microenvironment level what exactly is going on has not been easy. We don't have the technology, quite frankly, we're not smart enough in my view, to take a biopsy and within a few days to say Mrs. Jones' primary resistant mechanism is X, and that's what we're gonna do here, and Mr. Smith has Y as a mechanism of resistance and therefore that is the treatment we're gonna be giving. And until we can find that kind of a balance or answer, I think most of our studies are gonna be minimally positive or gonna fail. So you can categorize this into several different categories. This paper I kind of like it because it gives you six different categories tumor antigen presentation, tumor microenvironment, is it the blood vessel formations, and the genomics of the tumor that it happened. So one of the things that has emerged, and we've been a lot of interested, there's been a lot of interest in it, if this is this VEGF inhibition, so why would we be interested in it? Look at the reference on the, on the bottom there. That's 2014. That's technically a year before Novolumab was approved in the second line setting, which means that as, um, uh, basic scientists and tumor microenvironment researchers have been looking at VEGF inhibition as potentially one area where you can actually have immune modulation, and there were really old studies, a couple of them at ECOG, using vaccines with bevacizumab. David Carbone did one of those. Unfortunately it was negative, but I think it was because the vaccines were not really all that good. All the newer um vaccines that we have with the tumor specific or the mRNA based vaccines might be a different story, but the VEGF inhibition is in fact immunomodulatory. So perhaps if we can identify patients through the pre-post biopsies that have a mechanism of resistance that points to this, we could come up with studies that does the patient selection appropriately and perhaps we will be able to get that. But as it stands now, we have pra pragmatica again. I don't know why the the the format is um kind of messed up, but Pragmatica was sort of uh uh uh the eco the SWA study phase 3 randomized written the whole protocol was 11 pages, the consent was 4 pages. The whole goal was to try to figure out if the combination of a checkpoint and. Beta plus rami serumab can be superior to docetaxel plus ramiserumab, and the survival, which was the primary end of the study shown on the slide, was completely equal. So in a, in an all comer patient population we have several examples of it, including this phase 3 suggesting that this is not gonna succeed. But if you can select the tumors that could potentially have an immune modulatory impact with VEGF inhibition, maybe you can get there. This is another study that was just referred to with Ivan Neimab, so it was at the overall survival analysis negative. However, consistently, the PFS benefit with this drug has been shown again, is it possible that if there was appropriate patient selection, we could actually have a positive study based on overall survival in this patient population. The next mechanism is enhanced NK cell or T cell function. Now, we talked about some of these immunoregulatory issues. For example, the tigid antibodies have not quite been as successful, but I would like to argue that perhaps with the use of some of the more newer bi-specific antibodies we could have an impact even in the tigid world because I personally haven't given up on the tigid story in non-small cell lung cancer. Um, but is it possible that we can come up with by specific antibodies that would address these issues? Cancer vaccines can increase, increase tumor via vis visibility. So again, there are a couple of newer versions of the cancer vaccines that are being tested both in the adjuvant setting, a couple of them in a, in a locally advanced setting to see if we can change that tumor microenvironment. Again, the problem I have with all of these is that we are offering all of these very specific, very targeted therapies to everybody who comes in through the door. So again it's gonna be difficult to sort of have a positive trial as long as our approach is everybody's exactly the same. We know that everybody's tumor is not exactly the same so this is an example of a couple of uh other trials or other mechanisms whereby we could potentially have an impact on the tumor microenvironment. Uh, cytokines are gaining interest again because in the old days using cytokines by themselves were highly toxic. We were not getting anywhere with them, but newer generation of drugs specifically going after specific cytokine receptors could again alter the tumor microenvironment in the right patient population and have an impact. Why do I think my specifics are better? I think the structures are different. I think the binding capacities are a little bit different, and binding to one antigen can drastically alter the binding to another. Now I can tell you there is a little bit of a luck involved in getting the right antibody and binding to the right epitope. But in general I think the approach of using my specifics is gonna be a little bit more successful than using two different IGGs, uh, because you wanna hit two different targets because of the changes in the in the mech uh the, the mechanics of engagement of the targets with the two bi-specifics. So personally I think these are gonna be more effective now in the world of small cell we are using bio-specific T cell engagers and we're having really good success there. The problem in non-small cell lung cancer is the antigen selection, because if you trigger an immune activation, uh, to an antigen that's widely expressed, you, you know, it can be a disastrous sort of, uh, in terms of a side effect profile. So choosing the right antigen when it comes to non-small cell lung cancer for these biocystic T cell engaged is gonna be really, really important. And at the ESMO meeting there were a couple of, um, sort of abstracts suggesting that perhaps we can find such targets. So, uh, a whole bunch of different biospecific antibodies are being tested in various patient populations. This one is specifically an EGFR wild type adenocarcinoma. Again, we do have to deal with specific toxicities. The toxicities to me are a little different than what we get with antibody drug conjugates. After all, you get a lot of cytotoxic type of, uh, side effects with the antibody drug conjugates, but not as much with the by specific antibodies. These were updated that ASCO providing, um, uh, some clues as to whether again we are able to have a patient selection criteria for these or not. At this point, the only criteria that we're using is the old established PDL1 status. However, Um, I'm hoping that with the additional, uh, bio samples that are being collected as part of all of these studies, and this one is a bio-specific PD1 on IL2, we will be able to identify a patient population that we can enrich for and hope that at least for 20%, 30% of our patients some approach like this would be helpful, um. Other dual inhibitory antibodies, uh, that are becoming again more popular, uh, as presented at uh some of the recent meetings are shown here again the purpose here is not to go through every single one of those but to sort of, uh, show you, um, my bias towards choosing clinical trials that I wanna participate in with these dual inhibitory checkpoint by specific antibodies because again I think the toxicities are a little bit more manageable and I think the clinical efficacy can be better. I again I have to go back to this patient selection idea. Again, apologize for the um uh the uh the the the formatting here uh but the list here that you see on the on the right hand side is a partial list of all the specifics that are not under clinical investigation. Uh, the real question becomes, are these all going to make it to the clinic and are these going to really drastically change the clinical practice? I think the honest answer is that many of us in our careers are unlikely to see another revolutionary drug like the currently available checkpoint inhibitors unless we get really, really lucky, uh, you know that we can't rely on luck all the time. I think these by specifics are going to be helpful in specific patients, but I don't think we're gonna can we can't expect anything more than incremental improvements above and beyond what we're getting until we have a better understanding of what we're doing. Fecal fecal microbiome has received a lot of attention. Our European colleagues and also our colleagues in Canada are a little bit ahead of us in terms of, uh, studies that they have conducted in this. This is just the, um, latest published in Nature Medicine where a limited number of patients were treated with fecal transplant. Uh, these patients were audio refractory and after, um, uh, the intervention, as you can see on the spot. Plots and the swimmer plots there, many of them have responded very elegant biological samples were collected and examined as part of the study, and the bottom line again is patient selection seems to be the difficulty. And also interestingly, there are geographic variations in the microbiome as you can imagine dietary and uh other habits could have an impact here. So a study that's positive in North America. Might not be positive in South America or in Europe because of some of the dietary changes and if you notice a lot of the bacterias that have been, um, sort of checked, um, are different if you compare studies across the world. So as we're trying to get away from chemotherapy, we sort of find ourselves as thoracic oncologists going back to chemo, and that's the antibody drug conjugus, of course. They are effective. They do improve, uh, response rates and perhaps PFS, but they come at the cost of, um, um, some toxicities. Uh, Teliavi is the latest one for med over expressing tumors that has been approved. Um, we are testing everybody for med IHC, at least at Fox Chase at the time of initial. Diagnosis to try to identify these patients up front, but this is the latest drug that we now have in our, um, armamentarium for treatment of patients in the second line space. Now again to me this is an appropriate way of developing a drug. We have a defined patient population. You have a biomarker for it. The clinical efficacy has been shown, so the toxicity. And efficacy balance is in favor of using this drug so I think things like this are going to be more helpful. Sacetuzumab is another one that has undergone extensive evaluations and again ongoing trials are ongoing. We'll see what happens there. The way I think we would like to approach this is sort of have these correlative studies collected as part of any of the investigations we do. I realized that this is easier to do when you're doing an investigative initiated study, but there are plenty examples of this where patient populations can be identified who would benefit from specific treatments. Again, we can shorten the time interval between the biological marker and treatment. I think we can actually conduct clinical trials like this. So despite all the clinical trials that we've conducted. That we've not really been improving standard of care in patients in the second line and beyond. A lot of the phase 12 studies, um, are, uh, suggesting interesting findings, but we haven't been able to have the patient selection the way we wanted to. I certainly think that cancer vaccines, intratumoral injection of oncholytic viruses by specific antibodies, um, are probably going to be a lot more helpful than what we've been so far. Um, we'll look forward to the additional trials. Thank you.
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