Chapters Transcript Video Clinical Trial Options, New Data, Future Therapies OK, so this is probably one of the most uh challenging presentation there for, um, because there is so much going on, which is Not a bad thing overall because it does lead to improvement of overall care for our patients, getting them newer options, less toxic or toxic options, um, perhaps short treatment, uh, to improve their quality of life, letting them do the things they want to, but nonetheless. Number of um things that are going on, I'll try to summarize some of those. Um, first of all, let's look at the checkpoint 067 slide that you've seen uh from Doctor M at Time and Doctor Morris today. Um, look at, you know, not all of the melanomas. Are responding or at least cutaneous melanoma responding to up to 1 year more invo. Some melanomas, uh, their, uh, progression is early and the others later, and that key point is, uh, thought to be 6 months. But you know, 2/3 of the, the patients actually. And not to respond, only 1/3 of the most durable response. And out of those 2/3, uh, you'll see that, you know, some patients will, uh, their melanoma will fail much earlier. Uh, that's called the primary resistance, and that's number of reasons that's listed there why these patients, uh, their, their melanoma doesn't respond to A level and others fail at a later time, and that's called the second year resistance, and again, there are a number of reasons for that. Um, And uh that Katie Campbell, who's at UCLA, you know, I, I think she's done with her PhD or close to it that she was looking at some of this translational data from SWAG S1616 trial that looked at patients whose melanoma didn't improve on. On one drug, either navalimab or uh pembrilizumab, and then they were randomized to get either ipilimumabone or combination and we now know that the combination does a lot better than single agent ipilimumab, but what Doctor Campbell did was look at what are some of the markers in these melanomas that could tell us, uh, with some certainty that this patient's gonna do better on, on this treatment or, or, you know, uh, if they've had resistant disease or not. And one of the Key was having plasma cells or CD4 positive regulatory cells in the micro environment that was essentially pretending, uh, not very good prognosis amongst other things. So the next question is, can we change this microenvironment through a number of different mechanisms? Can we use more drugs? Can we use different drugs? Can we use activated cells, uh, to overcome this resistance? So that's what I'm gonna try to demonstrate. So this is something that Doctor Moore has already brought to you. Efficacy and safety of triplet, uh, nivalimab, Ratimabilimumab in advanced melanoma that hadn't been treated before. This is the relativity 048 study presented by Doctor Paolo Eerto, um. Last year at our American Society of Clinical Oncology meeting happening soon this year, and this showed that, you know, the exploratory endpoint overall survival was very good in these limited number of patients that were treated. Um, based on this, um, Dr. Webber's brainchild here, um. Uh, clinical trial NYUS 2200325, which is looking at the combination of these three drugs and combining with uh interleukin 6 receptor blocking antibody Cerulumab, the intention is to reduce the toxicity of it and perhaps improve overall outcomes and ongoing trial with some. Data being presented at ASCO this year, so stay tuned. Again, ongoing study now in a randomized fashion where a group of patients will be treated with 3 drugs directed against melanoma and the other group will be treated with 3 drugs against melanoma and the serriumab and comparing their outcomes, uh, as far as is. The other option is, so that was, you know, trying to use more drugs to kind of overcome that resistance. Can we capture those individuals whose melanoma may have not responded to two drugs? Can we give them 3 drugs? The other option is we know that epilimumab is very important in the immune function against melanoma, and that's demonstrated when we looked at, uh, iilimumab those of 1 mg per kilogram, 3 mg per kilogram, and 10 mg to look at. The toxicity goes up, and Doctor Moore is also showing you that when we see toxic events that in that is in itself an indication of response. Does it mean more toxicity, more response? We don't know that yet, but still, the, the, the data is shown that the higher dose of epilimumab. Potentially leads to better outcomes against melanoma at risk of toxicity. So the next question is, can we improve this CTLA4 blocking function? Can we design a drug that potentially give us the higher dose but not the toxicity benefit? And that was the attempt to buy bio Atlas, um, conditionally. Active CTLA or antibody which when moves into the tumor microenvironment, which is more acidic, it dissociated from a blocking counterpart and allows the CTLA 4 blocking mechanism to be active in tumor micro environment alone and not away from it, thus reducing toxicity and improving benefit and some of this data has been presented and we've seen. Benefit in the first line setting and potential benefit in the the second line setting, and ongoing study, and we'll see what how it develops. So, giving more than 2 drugs perhaps a way to overcome resistance or prevent resistance using a higher dose of ipilimumab to overcome resistance or prevent resistance. Um, again, the same slide showing, um, you know, the, the population of plasma cells and CD4 T cells, these immune cells, um, unfortunately, it's, it's not able to be done in a, in a usual, you know, pathology lab, specialty labs, and this data is still sort of in a research setting and not gone. Completely public yet, so, but still this is something that, that's developing and can we modify these, you know, reduce the number of the CD4 T regulatory cells to improve the, the immunotherapy that's already available, and that's the, the function of sort of the, the. Hope of this particular study by Georgia Mun using GIM 531 small molecule inhibitor that inhibits an AKT3 uh enzyme important for deregulatory cell maintenance and uh activation and by blocking that you're reducing the function of. for regulatory cells and not allowing them those regulatory cells to impede function of the important lymphocytes in control of melanoma. Ongoing trial open in multiple places along with Angelus's clinic and look forward to the benefit from or or uh uh the data from this study. How about uh acolytics and some of this we've talked about in ocular melanoma with R2, um, incutaneous melanoma with RP1, you know, these are the next generation, um, oncolytic viruses, TAC being the first, uh, generation, um, and the thought is that the, the composition of the. The family of modified HSV viruses is a lot different and it, uh, the GAV fusion protein allows additional function for immune stimul stimulization and uh and that's why you're seeing these benefits not only in the injection but also in the nonions. This is the data that um that Doctor Moyers have talked about, you know, RP one initial articus data uh showing the benefit in uh the patients with uh. With RP1 approach And actually this is another important study that is complete and we're waiting for the, the final results. Um, a while back when, you know, immune therapy combinations were still sort of, you know, in their early development, um, IDO inhibition was very important. We knew it was important, um, and initially it was attempted with the Catastat in combination with embrolizumab. Unfortunately, the, the late phase study. Didn't show the benefit, but that is making a comeback with IDL1 and PDL1 um sort of uh uh vaccine in combination with Pembro and it's shown, uh, initial results been very good, um, and we're waiting on phase 3 study, uh, results. As you can see that this is in the first line studying, um, published in Nature Medicine showing a lot of these waterfall plots with the bars pointing downwards rather than upwards showing you improvement in, uh, in melanoma metastases and combination with body bath. They showed 50% complete responses um at a median follow up of 45.3 months, uh, 25.5 months in median progression free survival, um, and overall, uh sorry, median overall survival has not been reached yet. Only 17% of the patients had SOS. CCD is significant enough to discontinue therapy, which is again a very good indicator. Uh, overall response rate in first line setting at 80%, probably the best response rate that we've seen so far. Again, this is in a limited number of population of patients and we're looking for the phase 3 data to show us more benefit. So this is uh a trial design of the phase 3 study that's completed and waiting for results. So one of the other ways that I talked about earlier was, you know, targeting particular antigen, um, uh, with, um, perhaps activated T cells or TCRT or TT receptor, T cell receptor uh targeting therapy. Um, Prem is, is, um, an antigen that very um strongly expressed a number of different melanomas, cutaneous being one of them, and here the patients are getting actually uh. Sort of engineered, um, a targeting T cells, um, and these are the patients who have seen a number of different, uh, treatment options before. I'm sorry, the slide's a bit blurry here, but it shows that on the spider plot, a lot of those legs are below the, the, uh, line, the arbitrary line where you see the response and showing ongoing response, uh, improved progressive speed survival. Improved the overall survival in these patients. Again, an option that, that is uh hopefully coming up very soon uh with the late phase data as well. So another way to sort of bring those active T cells to control melanoma is trafficking those cells from periphery into the tumor using uh impacts that we talked about uh in uveal melanoma talk and these. This particular impact is targeting brain, um, also important in cutaneous melanoma, uh, no muscle lung cancer, sperm cell lung cancer, and others ovarian ongoing data, um, this is a trial that actually. In, in multiple different solid tumors that's ongoing, but focusing on uh on uh renetaus or the pain targeting uh intact, uh, in melanoma showing its benefit in pain positive um with overall survival benefit. Um, and that led to the prismL 301 study, which is a first line study in cutaneous melanoma face the study comparing nivolumab in combination with Bernetaho to nivolumab and relatumab or nivalimab um alone, um, 325 patients and each on large study that'll hopefully, um, will give us another option to consider for our patients. So we've looked at combining multiple drugs, increasing dose of ipilimumab, uh, using next generation, um, immune stimulant, uh, viral products, um, then we talked about, uh, using cream target, um, and now. What about the, the tumor microenvironment that hosts these active T cells, but for some reason aren't active enough to control melanoma and that's already been introduced to you by Dr. Moyers with. With literally cells from Iiovan that's shown benefit in uh heavily pre-treated uh melanoma patients uh with benefit that has gone on to get FDA approval and second line study, um, and Doctor Thomas from Orlando actually shown the first line data showing, um, you know, previously untreated patients with a very good benefit with overall response rate of 65%, complete response of 30.4%. Uh, in, in metastatic melanoma and uh the confirmatory studies ongoing with comparing glyphilla cell with embolism after to pembrolizumab alone and we'll see um it's uh outcome in the future. How about, you know, using um engineered um tills, um, I think Doctor Ferris is gonna go into much more detail about this, but obsidian's product OBX 115 is an interleukin 2 sparing uh drug. We know that most, a lot of the toxicity for patients for tills coming in from interleukin 2 administration as well, and older thereic options, very good options in the past nonetheless, and these are the patients um that were, they've seen a multiple number of therapies before and uh. You know, showing its benefit, um, ongoing study for both non-spinal lung cancer and the metastatic melanoma, um, of cutaneous erosion. Again, the early phase data or a small subset of data uh was presented at ASCO um a year ago and Again, the basis of this ongoing study. Other ways to um sort of improve the tumor infiltrating lymphocytes is PD1 knockout, and that's the IOS's attempt at improving their till um the cell to the sort of maybe till 2.0 and we'll see what, what that data shows. It's an ongoing study available at multiple different sites. Um. Again, T cell receptor-based therapy is, is very interesting, um, because it recognizes greater number of intracellular tumors specific or associated antigen or new antigen, um, that cannot be targeted with either aminoglobulins, for example, your run of the mill aminotherapies or cars, um, and, uh, NK cells that do not express CCR. So there's no risk of mis pairing or risk of um off target toxicity. Um, again, a number of different trials that are looking at CAR-19 IL-15 NK cell therapies and uh lymphoid uh key malignancies with established uh uh benefit in small number of patients, um, durability of durability of response overall survival in single arms that he's been established. Um, number of different options that are in development, uh, that Doctor Ferries will see, uh, if you in it. Um, last slide here is, um, Um, you know, how about activating the NKSL population, uh, within the GMR microenvironment. This is an ongoing study, GV20 that data has been presented at numbers conferences. I think there's, uh, there is an abstract at ASCO this year that's updating, uh, all of these patients' data and showing us responses in a refractory melanoma patient. OK So you can tell that Doctor Memmi has been here for For 5 years, it picked up the traditional Hamid approach to many slides. Just switch the time. But it's just to prove that there's a lot of work ongoing here for our program, for our patients to move things forward. The push for uh patients at any stage, at any time to ask questions like you're doing here and to be evaluated for other therapy. Created by Related Presenters Inderjit Mehmi, MD Medical Oncology View full profile
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