Chapters Transcript Video Intelligent Immunotherapy Innovations in Initial & Second Line Therapy Our first speaker is Justin Moyers, who's here, who has joined us, uh, over the last couple of years and worked to build our immunotherapeutic program, cellular, uh, cartil program. Uh, Doctor Moyers comes from a huge background of drug development. I look forward to hearing his thoughts and uh welcome and take the Thanks such things such. I mean, um, so, uh, I'm gonna talk about, um, kind of set the stage for all the other speakers. So I, I'm gonna call this our melanoma 101 talk. We're going to um review, uh. The initial, um, first line and second line treatments that patients with um metastatic melanoma may receive as part of their care. Um, so quick agenda, so. We'll talk about the current first line treatments, um, and we have some long-term updates that have come out over the last basically year on several of these, then talk about some selected second line options, um, in immunotherapy, targeted therapies and cell therapy. Um, if you attended any email with talk in the last several years, you'll see this awesome, um, uh, timeline of drugs that have been approved. Um, here's the most recent one with the update of uh lifiucil, the cell therapy last year. Um, and so, you know, we know that there were few approvals until 2011, um, and since then there's just been a number of approvals and immunotherapies and cardio therapies. Um, First up, there's the keynote 006 study. This was um the trial that established the Pembrolizumab as inhibitor that was um good efficacy metastatic melanoma, they compared embrulizumab, which is anti-PD1 to illuab, which is anti-la4 um. But this is the 10 year follow up. So you can see out at um 10 years now, we see that there's long-term survivors um of metastatic melanoma and that tail, um, really. Doesn't change much after 6 years. So people are surviving with melanoma on single agent checkpoint inhibitors for, you know, a decade. Um, the biggest trial or one of the biggest trials that changed everything was a checkpoint 067, where this is where we found out that dual checkpoint inhibitors work better than single a checkpoint inhibits for untreated melanoma, untreated metastatic melanoma, and so it was three arms, either we give nivolumab, also known as Optivo, or evolimab plus Iliumab, um or ipilimumab alone so it's 3 different arms of those +22 drugs and 3 different permutations. Um, and the initial trials, we saw that the progression of free survival, so the time it took from the cancer to um grow or not respond to the immunotherapy was longest in the double combination. Um, so these data have been ongoing, they've been following patients for now 10 years. So this is the last update, I just published a couple, couple months ago, um, for the 10 year outcomes of this data. And so what we see is that um after 5 years, not a significant change too much in people having recurrences or um a death after that time. But I think the interesting thing point out is that um if we look at the melanoma specific survival, um, When you're out at 10 years, people start to, you know, have other illnesses, you know, diabetes, heart disease, other cancers, they can, um, you know, affect their life spans and so. If you look at melanoma survival means people who died from melanoma specifically, um, there is not significant changes for any three of the arms in that 5 year and 10 years. So still over half the people are, you know, living with um. remissions for their melanoma at 10 years if they got the double checkpoint inhibitors. Very great stuff. Um, And one of the also interesting things is if you were without melanoma 3 years, so surviving and not having your melanoma progress or grow at 3 years. Few people had additional recurrences after that time period at 10 years. So most of the people if they're having recurrences are happening in that 1st 3 years. So that's an encouraging thing that we can tell our patients if you're doing really well at 3 years, you know, we, we think your melanoma is gonna be under very good control based on this data. Um, Other interesting part to kind of pull out of this fake data, this landmark trial is that Depending on how much the tumor is shrimp. On any of these three arms, that correlates with how well um. Uh, you will have remission from your melanoma. So the more shrinkage, the more likelihood that the melanoma will remain in control at 10 years even. Also interesting, one of the things we always point out is there are side effects with these immunotherapies, but we actually don't, we actually, it's not a horrible thing to see some side effects with the immunotherapies, as we see that if you have some side effects with immunotherapies, you're likely to have a better response than, um, if you don't have any side effects at all. So we see that people who have some side effects, their survival, their remission rates are much higher than If you had any, if you do not have side effects. Um, so moving on, The other combination is anti-PD1 which is nivolumab plus um latumab anti like 3. this is the relativity 047. This combination was proved within the last several years as well. Um, this trial looked at previously untreated metastatic melanomas that compared single agent V1 versus this dual checkpoint inhibition with LAG 3 and Evolumab. What they found out was that the progression free survival or time it took the melanoma to grow, um, if you are the combination was um longer than if you had just a single drug. So we found out that this drug combination seemed to be better than a single drug alone as well. correlated to people surviving with their melanoma longer as well, um, if they got the combination vol plus rela. So moving on, the other first line category to think about is first line target therapies. Um, you know, what are target therapies, so in melanomas or any cancer in general, there can be mutations that form to cause the cancer to have unregulated growth. 50% of melanomas of the skin have a BRAT mutation. Um, there's 3 different classes of BRAP mutations. The ones that we care the most about are these BRAF V600E. Um, you'll see this information on your sequencing, so the DNA testing of your tumor, um. Since we call this class one, they are the ones that are activated by this mutation and cause unregulated growth. These are the Mutations that are most responsive to the therapies that we have um right now approved. Um, so this landmark study compared to uh drugs that act on the B reputation, Debraffeim and remeini, um. In melanoma and they compared it to, um, it was a phase 3 trial, so a large trial with 700 patients. They compared the combination the braffeim and remeinnib versus the old first slide therapy for this, which was the marainib. What they saw was that people's tumors took longer to grow on the combination compared to the single agent BRAF inhibitor, um, and people live longer with this combination. Complete response, um, happened in 47% of complete shrinkage of the tumors, at least temporarily happened in nearly half the people of the combination BA inhibitors, whereas only 27, only about a quarter with the single agent BAF inhibitors. There's multiple trials that have been looked at this combination, they combined them to find out that at 2 years. With this combination, as the people were having were live in through melanoter control basically, um. And if we separate out those responses or what was the best tumor response you had. So if you had a complete response, meaning the tumor shrunk to nothing, or if you had a partial response or meaning the tumor shrunk a little bit, or if you had stable disease, meaning the tumors. Didn't grow, but they didn't shrink too much either. Um, the best response is the best, uh, Temporary tumor shrinkages happen in those who had complete response at the beginning. So we talked about the Debraffemb and remanab. There's actually two other sets of combinations basically made by different drug companies, Vobi, Nemeraffe Coib, and inrainib and bean. And they each have their own different set of side effects. So, um, the pink or the graph and reveib, the renish or the immigrasib, and the orange or the in raib. You can see that if you break it down side effects. Different ones have different side effects, so the tram doesn't have much of eye side effects, but it has uh more fever, um, and, uh, we tend to use, I think most of us interaction with Ben me it seems to be the best tolerated, but any of these three can have different side effects for the individual. Um, this moves on to, so we talked about therapies and target therapies, which one do we choose for first, because we can only get one first, um, and so they ran a trial called the Dream see trial to answer this question. Um, all the patients with melanomas, um, were randomized either to either get you know therapy first or get the target therapy first, and then once the cancer grew, they would switch over to the other treatment. Um, we found out that it does matter, we found out that giving the immunotherapy first allowed more people to have remissions and control their tumors compared to those who got the targeted therapy. Um, so this really settled the, the question. Um, we also see that, you know, about 46% of people, at least in this trial, um, had Tumor shrinkages um with the immunotherapy compared to only 43% of the targeted therapy and then importantly, in the second line, those who had the targeted therapy first, the immunotherapy just didn't respond as well. Whereas if you had the, you know, therapy first, the child therapy still responded. You know, nearly as well, um, in the second line setting. Um, Next question, which of those immunotherapy combinations should we pick? So we know now immunotherapy is the best to go forward first, which one do we pick? So this one, this um graph I really love shows. Great 3 for side effects or those serious side effects that can lead to treatment or hospitalization on the Y axis going up and down, and then on the X-axis going sideways, we see how long they work for and you can see that the Nivvo AP has the most um side effects but also works the best, whereasivvorela is pretty close. It it works nearly as good as the combination of you on a, but doesn't have really the amount of side effect. Like each of the single. Um, checkpoints have less side effects and also less um efficacy. So that naturally it's the next question. Why not use all three at the same time? It's not about you got Epi and Newvorela. Why not buy into the 3. So this is an interesting study. This is not yet standard, but I thought this I include this, um, our colleague Gilbery, um, this, um, presented the trial of Relativity 048 where they combined Nivvodlumab and latumab, and they see that. In this small group of, there's only 46 patients in this trial, but in the other ones we saw 100. Um, we see that people are getting remissions, having tumor shrinkage at a high rate with this combination. So hopefully more to come on this um combination. Um, after first line therapies, so what happens if the tumors still or start to grow after the first line therapies are given. This is our NTCN guidelines. We have a whole list of things that we can consider, um based on BA mutation or not. Most of these are immunotherapies. Um, we will go over a couple of them. Why do we think about immunotherapy combinations? So immunotherapy has allowed field of oncology to, you know, change. We have even durable cures like talked about. However, some people's tumors are cold, they don't respond to the immunotherapy. So these combinations, um, hopefully can resist checkpoint blockade due to several different modes by changing the cytokines, by um changing how the tumors present these antigens that allow the immune system to respond. And then also just causing Deaths of the T cells that are regulating um the immune response, um, and therefore, new therapies to try to overcome these obstacles that are hirances to immunal therapy is working well for all melanoma patients. These are some of the targets that we looked at. So, you know, PD1, we've talked about this, the timberliumab new Boumab, um CTLA4, that's um IPlumumab. And then what are the investigational ones, so they're not investigation, the newer ones luxury, um, we have uh the relalaab or on the right, um, there's trials going on in pretty much all the other ones that were listed here, we have seen trials and PTLA 4, 4041 BB. Um, so what are some combinations that we are in the guidelines or people use? One of the ones that I like the most is, um, it's it's not approved, but we have phase two evidence is the LEAP 004 study uses a drug called lymphatinib, brand name yema plus primrolizumab or Keytruda. Um, for melanoma after PD1 Drugs did not work. And how does this work? So, we already talked, we've talked a little bit about how Kerida works. It activates the T cells, try to fight your melanoma, um, how does lymphoma work? It's something called a multi-yrazina inhibitor. It blocks several different proteins, um, growing, so the thought is that it can disrupt blood vessels and allow for um the immune system to target the cancer. Um, this is a single arm study meaning that they didn't compare it to anything. Everybody got the same drugs. Um, this waterfall plot shows tumor growth if the bars are going up, shows tumor shrinkage if the bars are going down. So we see that, um, 65% of patients on this accommodation had some sort of shrinkage. There's an arbitrary, somewhat arbitrary threshold set at 30% shrinkage to call it verifiable shrinkage and about um 21% of patients got, so pretty good combination to keep things stable for many patients. Um, If it worked for patients, the duration it worked was about 8 months. Another Combination we sometimes use after PD1 therapies is something called TEC, um, TEC. I put the infographics here on the right. How it works is it's a virus, it's a modified herpes virus, um, that's injected into the tumor itself. It then allows the tumor as a host to grow and it releases these antigens, releases bits of itself, um, upon breakage, which is attracted to by the um immune cells called dendritic cells in this case, and forms a response to attack the tumor. So this is it. causes inflammation of the tumor, allows the immune system to attack the cancer. We call these alkalytic virus. Um, so this probably looked at um taking Tbe plus pembrolizumab or placebo plus premier map to see how well this combination worked in the church setting. Um, what we saw is that if you compare the two, first line Pembro versus Pembro plus the Tack, we saw a slight improvement in How many patients would have tumor shrinkage, but it did not reach statistical significance. So was it for certain without chance that this combination was better than the single agent. Um, nonetheless, it's something we consider in the second light therapy, especially if patients who have tumors we can seal and we can poke a needle and put that, um, uh, modified alkalytic virus. Um, That also brings us to this next phase, so the kind of the next generation, I mean, uh, is something called RP1. It's another herpes virus that's modified, um, works the same way. It's injected to tumor cells, causes the ration which activates these T cells. Uh, but the interesting thing about this is that unlike Tve where we've mostly seen the tumors cells that are injected shrinking, we're seeing tumors outside of that injected area shrink as well. And so this, we call this a spider plot, the line started to be middle, and then like legs of the spider, if they go down, that's shrinkage of tumor, if they go up, then that's growths of tumor. The red ones are the ones that tumors are injected, the blue ones are tumors elsewhere. And so you see not only the red injected tumors decreasing in size, but many of the blue non-injected tumors are shrinking in size as well. This is one patient's example that was presented by Dr. Wang and Asco, um, injected tumor, the forehead, but also having shrinkage in the liver tumor. Very cool stuff. So there's at ESO this last year, um, preliminary data for some of this was presented, um, we're seeing responses again and injected and non-injected lesions, um. There's ongoing trials to um further take this information uh this, this drug to, you know, for, for phase trials. That like penis. Um, next. Targeted therapy. So what's after Brax and me inhibitors, what else is there? Um, so one thing that's Uh, based on an older study in 2017 from The Lancet, if people have NRAS melanomas, there's targeted therapies with be. This was compared to chemotherapies. This was over a decade ago, and If you use theneedib that works better than chemotherapy for NRAS mutations. So still a drug that we can um we can consider if people have NRAS mutations and we don't have other better options for them. Um, we also look at the tumor, um, DNA to look if there's something called fusions. You see on the left, um, we call these translocations the other name for them, you see, uh, red and change and blue, um, chromosomes. They do some handshake and they switch parts and afterwards they have what's called the translocation. Few animals have this, um. I looked at this from ACRG has thousands of patient cases of NGS. Over 90% of melanomas do not have fusion. Fussions are really uncommon. Um, the most common ones are BRAT fusions, Ross REs, intre nowfusions. Why are these important? So these are the needle in the haystack cases, um, BRAF fusions, there's new drugs to be developed for these, um, and there's Right now I'm really only The single patient or small trial data, um, for one patient who had a gap 2 raft fusion, they got remeinib, had a response lasting months of tumor shrinkage in their livers. There's also what we call Tor agnostic approvals, meaning no matter what cancer type you have, if you have this mutation like a re fusion, you can get a drug that can shrink the cancer. So, um, in this trial of erretinib, which is a refusion drug, if you've had a tre fusion, most of the time your cancer shrunk. And if you look at this list of, you know, 30 odd patients or so, um, The green bars are, it's dark green bars are melano, so a couple of melanomas with tract fusions had significant shrinkage, one of which had complete shrink to the tumors if you have this rare mutation. Ross fusions, similarly, a patient withnoa um got crizotinib, uh on a case report and it took their melanoma to shrink it basically down to nothing, at least temporarily. At 2 years for this patient of, you know, complete tumor shrinkage. Um, another one, the last one that has a tumor and osteo approval is alceinib and reent positive cancers, um. Another uncommon mutation in melanoma, but something we look for in the standard NGS panel. Lastly, um, going to cellular therapies. Um, this is an infographic I created that kind of explained patients how this happens, so, um, patients will have a tumor. An excellent surgeon like Doctor Ferries will take it out. They will isolate the tills from the tumor tissue in the lab. They will expand or or or modify these, these, um, lymphocytes that are extracted from the tumor tissue, and they'll make this till product. This can take weeks to months, um, and then they'll come into the hospital or clinic, get 3 to 5 days of what we call lymphopleting chemotherapy to To decrease the amount of lymphocytes, which are part of the white blood cells in the patient's bloodstream, allowing room for the tills to be infused. The tills are then infused, and then we activate the immune system by using up to 6 doses of something called interleukin 2, which is a synthetic version of a cytokineary inflammatory protein in your bloodstream. Um, Well, how is this process developed or how, how is it proved so there's a landmark trial that um of till so tumor infantry lymphocyte therapy or using anti Cla for epilumumab done by the Dutch and advanced melanoma. They looked at comparing these two and second line therapy, they found out that um people had more remissions, live longer if they got the tills compared to if they got a lot in this trial. You can see on the right, I have had far more growth than the tills on the top. Um, the US approval was based on a, um, Composition of several trials um with the Ivan product known as lifiusil, um, overall response rate was 31% in these refractory patients who got till. This has led to the FDA approval of the first cellular therapy and solid tumors, um. And one of the side effects of this? And mostly relate to the lympha chemotherapy, having your blood counts be lowered, chills, anemia, more things that are causing your immune system to be responsive, um. Fatigue, um, and some other kind of immune related side. So this is just a game changer for us. Um, many trials going on in this, um. They're using tills in combination with other drugs such as checkpoint inhibitors, radiation, target therapies, scenes, and then also just modifying the tills in some manner. Um, This is the updated results of this, we see considerable tumor shrinkage from part of that IO advance trial. Um, this has led to a next step where they're trying to compare pembrolizumab alone versus the till plus Pembrolizumab, um, to see how much significant improvement we can get for, um, using tills in um the first line treatment. So will tills be a first line treatment? That's what this um trial is trying. And that ends kind of an overview of our melanoma 101 to um as it serve as a basis for everybody else to um expand upon. Created by Related Presenters Justin Moyers, MD Phase I & Experimental Program View full profile
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