What is neoadjuvant therapy? What is adjuvant therapy, and where do we go? I realized that we're speaking to a group of Patients and advocates and physicians who are well aware of what's happening in melanoma, but in every other solid tumor, when we have something that works in the metastatic study that helps patients do better, live longer, and have long term benefits, which means. Uh, no side effects, uh, living longer, and it shows durability. What happens is we bring it earlier. This is not a model that was built purely in melanoma. It's a model that's been built in other solid tumors, and I'll explain to you. Most of us know someone who has had a breast cancer who had the tumor taken out, like we have the almost taken out and then had the lymph nodes looked at. Like we do with melanoma for local disease and then there was no evidence of that disease having moved from one area to another, still remained in the original area that it had shown up. And therefore, yeah, they saw physicians and they said this is the risk of coming back. And drugs have been used for any cancers, but for breast cancer, there is chemotherapy and or oral therapy and or radiation therapy, not only to prevent recurrence but to allow patients earlier to reap the benefits. Of this therapy and not have metastatic disease here and that's what we've done with these drugs that were just discussed in the in the metastatic setting like anti CTLA4 therapy with ihalomab, otherwise known as Evo or anti1 therapy withruda um. Or avo, some may know it as pembrolizumab and Ebolaab. So what is Shown here in a basic cartoon is what we want, that we cannot tell if there are any cells that are circulating in your blood that belong to your initial uh tumor and therefore, if we give therapy, can we clean up what is there? And what is in that syringe at this point for melanoma is the therapies that have been approved in the metastatic setting. And this is a huge point to make that immunotherapy has begun to be approved. For melanoma all the way back to 2015, where the initialumumab. Studies showed a survival advantage and as I've moved forward, as you can see the block here, as they have moved forward, we have moved it on to other, uh, uh, other tumors like bladder cancer here, breast cancer or triple negative breast cancer, and then other solid tumors, kidney cancer now uh and esophageal and gastrointestinal cancers. So a lot to, uh. Develop and discuss as we move on. So, Here is an easy cartoon that helps me understand what we're talking about. Neoadjuvant therapy, which we'll get into later, is prior to surgery to activate the tumor. Uh, to attack by immune cells, then we surgically remove, finish out therapy. Adjuvant immunotherapy is that which we see most patients for where they have been diagnosed and surgically had their tumor taken out and their lymph nodes taken out by a world-class surgeon like Doctor Ferris, Fisher, uh, a surgeon in your vicinity. And then we risk classify and discuss adjuvant therapeutic options. It's a long talk and for me in my clinic with the patients that I'm here, it is a talk that can take time, multiple visits, uh, and possibly a second opinion consultation with another opinion leader. So where did this begin and what do we know? I will set the stage by saying that there are Clearly two therapeutics that are available in those melanoma patients who harbor the BRAF mutation that you've heard exists in about 50% of the cutaneous, those skin melanomas, targeting that mutation with a regimen that's been approved at this point, they're the drugs that target EAF and the drugs that target neck, the durafintramenib, as shown. The ability to to prevent relapse. Relapse means that the tumor has become back into your body and is now visible. So What we show here on the left, that it is the ability to give targeted agents orally to patients with high risk stage 3 melanoma. Stage 3 melanoma are those melanomas that had involvement of the lymph nodes in the body of the local area for only 1 year, and to show long term, if you can see here, this is months from randomization. A significant benefit in relapse. That Even after just 1 year of therapy persists out 8 to 9 years and further. We've shown the same. With anti-PD1 therapy, pembrolizumab and Evoliab, both have shown in comparison to uh standard therapies for the placebo, the ability to prevent Recurrence, which is relapse. So that is a standard for stage 3 melanomas when we discuss it and also now for patients who have an area of metastasis resected have no other evidence of disease by imaging, exam, uh. To benefit from this, that's the adjective. Adjuvant therapy is therapy when there is no. Clear evidence of tumor left in the body to prevent recurrence. And here again are two studies that show the ability for both PD1 inhibitors for, uh, many a time patients ask, are they different? And the answer is no, they both present the same kind. The desire for this therapy is based on our ability to prevent the tumors coming back and affecting your life, morbidity, or causing the end of life mortality. So The other question that comes up when we consultations is, well, you've shown that The PD one inhibitors here, uh, like nivolumab, on the top line. They prevent recurrence, but as we've looked at the data, When you look at overall survival, they haven't affected survival, and that's partly because of our ability to give some of these therapies once there is recurrence. Why do we not see that benefit? Well, I think it's more to do with having seen it at some time therapy, but remember, a recurrence is not an asymptomatic case. At times you may have disease that goes to bone, brain, other places that causes disability, and that's what we're trying to also avoid. The middle one looks, the middle trial is a trial that's going to help us. Uh That actually set the stage for, and that is it theloma in the time where there was nothing after anti CTLI4 therapy and compared to not giving anything, there was an overall survival incentive and that's what keeps us going. The the question will come when we look at Uh, the trials that randomize from early usage before recurrence to usage after recurrence and that trial has been done and is going to move forward, uh, and give us that answer in the future. So, What we usually say is because anti CTI4 therapy with ipilimumab, beat observation. And antiPD1 therapy. Uh, antita4 therapy, therefore using the transitive property. That NTPD one is better. Uh, then observation, uh, that's a little bit of a stretch that we're trying to prove. OK, what have we learned? So hot there, it's confusing, but it should only serve to Push patients and advocates to ask these questions. Should my melanoma receive this type of therapy? What is new? What trials are there? Because at a time when we had stage 3 melanoma patients getting this therapy, we knew that there were patients with stage 2. That is only locally where the melanoma has shown up. Only there and no nodal involvement. We knew that they had worse prognosis than some of the stage 3 melanomas. And so we did 2 trials that looked at comparison to Comparison to uh placebo. And both of them showed a benefit in what was a primary like relapse. That coming back, we're still waiting to find out about overall survival, and you can see here, both of them. Now, these um curves are hard to read, but you want to be on the on the curve that's on the top and on the green top lines, those are all the patients with stage 2 high risk melanoma that were treated with a PD1 and. Well, you can relapse locally, or you can relapse in a distant fashion. Yes that means in a metastatic fashion, and those are where we see. Of the morbidity and where we feel are directly related to mortality. And so at this point, we're seeing some initial evidence of that moving forward. OK, if you've heard about adjuvant therapy, the question then becomes what is neoadjuvant therapy? Why do we have it? Is it better? Should I get this? Should I get that? Where can we go? And that is the idea of earlier blockade. When you, uh, earlier checkpoint inhibition, earlier immunotherapy, when the tumor is in place, that sounds, uh, you know, contraoral, contraintelligent. Why is that? Well, this cartoon, uh, that was put forth by Carolina R in France, will give us some idea and I'll take you through it step by step. All right. Is is Uh, adjuvant immunotherapy and On the top, you see distant microscopic metastasis. That means cells that have gone elsewhere. In your body that you cannot see by imaging. So we say, hey, it's only in one area, let's take it out and then give the immunotherapy. Well, what we, what some may argue is there is only small amounts of tumor out there for the immunotherapy to react against. And therefore, there may not be as strong of a recognition from your immune system to make those T cells, those fighting white blood cells that recognize the tumor and all parts of the tumor. All right, well, now I slipped. I here? This is a. Here, I flipped a neoadject. Again, adjuvant, neoadjuvant, left eye, right eye, but The thought here is when the tumor is in place, there's a greater bulk of tumor and a greater ability of those T cells that recognize tumor. These are those colored circles in there to recognize not just the tumor, but recognize multiple different antigens or proteins that are specific for that tumor that create that immune response by saying, hey, This is not a normal cell. And then when you do the surgery after initial, you know, 6 to 9 weeks of Immunotherapy, then you have a more amped up prime immuno system. So, we've looked at this in clinical trials and as you can see here because it's written down, true, very convincing results in a perio-operative treatment frag. That's the neoadjuvant top part in blue before this was a trial done with 300 patients and reported by our friend Sapta Patel, who's now at the University of Rado and this was done to look at what happens if you get Your neoadjuvant therapy, then do the surgery and finish out your one year, adjuvant therapy, only one year of anti-PD1 therapy or cursus getting melanoma taken out and then receiving a full year of therapy. This was a randomized trial that was meant to decrease any bias. And when we looked at it in relapse pre survival, the blue line is where you wanna be, and that was the neoadjuvant paradigm. While we're still waiting to find out is what about your overall survival, where there was a trend to doing better, the numbers were not big enough to to show that, and we're waiting for this data to mature, to be older, to have more events, and to know what's going on. And that pushed us to say, wait, we have One drug. What if we gave two drugs early to get a better response? And this was a very straightforward trial done by Christian Plan, uh, in the Netherlands. I'll say that Doctor Arias was the only investigator, only state in the United States to be part of this, but it looked at, how about giving to and um I hate explaining these things. You just have to make it very easy. So they took stage 3 with big bulky nodes, you can tell it's stage 3. And you gave them either two courses of combination epillonevol the TD1 CTLA4 like you've been introduced to by doctor lawyers in the neoadjuvant fashion. Then you go see the surgeon, they do the full surgery, and then you finish out for the year. Or you do the surgery, and you just get your PD1 therapy for the year, and guess what? The primary endpoint of event free survival, that's relapse or mortality, etc. favoring the blue line. That's where you want to be higher on this graph, and that was the neoadjuvant approach. And when we updated it, this was the early presentation when we updated it. It continued to have the same benefit if you look many more months. And as I've said to you, distant metastasis free survival, that's what these letters, it going outside of the local area, it leaving Bronx and going to Manhattan and Brooklyn was. You had better protection with the neoadjuvant regiment. What we also learned here on these crazy colorful uh charts you saw here is that It needed to do the surgery to understand what the benefit was. When we did just imaging, just CTs before going to surgery, there was a concern that there was no clear response, clear benefit, taking that tissue out pathologically. And looking at it under a microscope, and then seeing how much viable disease, a path CR or a near path CR, that means when you look at it, everything is gone, the melanoma are dead or the lymph node. cleared. When we looked at it, those people who had a major response did better. Those people who had a major response, again, you've seen these before, these slides should now be very easy for ah. The green, the dark green. I want to be higher on these recurrence free survival curves. That means I haven't and those. Benefited those people who had a response when you're looking in, and a major response. And that was the same for distant metastases for survive. So, Not only did we see that, we found that 60% of those patients who were on the neoadjuvan arm had that major response that we were looking. Which means, possibly we could back off on further therapy, and there's trials that are looking at that right now. So we're understanding more and doing more. How do we really understand who benefits and doesn't? Through these neoadjuvant trials, what do we have? And these and what do we have? We have tumor in place that's been biopsied before, that's been treated and then has been taken out, so we can see the treatment. And treatment effect help us figure out the most important part is we're gonna make this more of a personalized paradigm. You know, we are not all the same. I wear a Extra large jacket, and somebody else may wear a medium jacket. We may need different things, so predictive biomarkers are now coming by looking at the blood and the tissue. Of these patients being treated neoadjuvantly with different regimens, uh, so we can figure out who does well and who will only need one who needs two drugs, who can't even benefit and move forward. So we look at while they're on therapy, what happens, and then after the surgery, what happens and whether they have A response or not helps us to understand how to move forward. So a lot is being done here, and this stuff will help not only in the adjuvant or the neoadjuvant, we're hopefully it'll help us to be able to turn this stuff around rapidly to choose the best first line therapy in the metastatic setting. And not just for skin melanoma, but also for mucosal melanomas and acro melanomas and ocular melanomas. And then behind those people in line are the other tumors waiting for us to navigate this and put down a roadmap on how this can help other tumors that require this type of therapy. All right, so a lot there. Well, what happens if you show up to my door? And then you've already had the surgery, then you say, what? I heard all about this neoadjuvant stuff. I didn't get it. How can I benefit in that way? Well, that's where this idea of a neo antigen comes into place. Remember, I used it all the way back when I talked about that cartoon. So Eo antigens are proteins uh that are expressed on the tumor that are novel or that's the neo novel. Proteins that are foreign to our immune system. OK. Oh, well. How can I utilize that? Well, this is where the Moderna MRNA vaccine comes in. And yes, it's similar to the Moderna vaccines that you've been uh exposed to in the Vaccines work in the way that they stimulate your immune system to recognize a foreign part of an invader. Similar to bloodhounds sniff the shoe of an escaped convict. So these neo antigens, if you have some tissue. Can be utilized to make a vaccine, and this is what this is. This is the neo antigen vaccine. It picks the 34 neoantiggens that are responsible for that tumor. If you have tissue sitting somewhere. On these protocols which are not standard yet. But Hopefully we'll be sued. Be and These vaccines are made based on the way that these neo antigens are are spliced and put forward onto your tumor. Right? And so you get. Vaccinate, and that primes the immune system, then to be boost. And what are you vaccinated against? Those Uh, those antigens that are specific for your tumors. So it is somewhere in between the top and the bottom. That you've had the surgery, but the tissue that's been taken out, the main immuno immunogenic portion is introduced into your body along with your immunotherapy. And this is the trial that has been done and been uh is ongoing virus melanomas stage 3. And it did show, we wanted relapse free survival advantage. Again, a significant relapse free survival advantage and oh. It continued as it further and further, and I've shown you. As we updated it, it still stayed, distant metastasis free survival benefits were there. And as I've shown you, step by step by step, we have built a paradigm of how to help patients before the surgery, after the surgery, stage 3 and stage 4 and stage 2. Hopefully, this in the future, you could take a very high risk stage 2 and make a vaccine against it and move forward. Uh, but overall survival, encouraging, we still need to see more events. But guess what? A 1200 patient randomized study has already been accrued and we look forward to data coming from it in the next year or so. As I can, I'll bring forth a couple of other. Ideas and that is just like uh in the metastatic setting, we have seen response. Happen even after one dose. Of these drugs. So there are multiple trials looking to decrease the time your adjuvant or neoadjuvant, whether it goes from what's standard now. 12 months of therapy to 6 months of therapy, and Europeans are looking at a trial grand slam that is randomizing patients, neoadjuvant or adjuvant to 6 months versus a full year. What about newer drugs, and this is Radaba Amaria MD Anderson's trial, don't need to know all the smuts. But it used neoadjuvant uh relalanivollimala 3 PD1 and still showed high benefit rate. Who will do well with one or the other is still left to be teased out. About how much surgery do you need? And uh the lovely and talented surgeons, the surgical oncologists led by Doctor Mark Ferris, who will be speaking shortly, have proposed a plan to look to see if you really need to take out a lot of lymph nodes in the neoadjuvant setting, or if you have a major response, you just take out all the affected nodes and monitor. Uh, that's coming up. What are we doing? We're showing the ability to affect long-term outcomes. By standard regimens that are viable in the metastatic setting, move it to the adjuvant setting with high risk stage 3 disease, move it to the stage 2 setting with high risk disease or to. Increase the responses and then decrease the amount of therapy you need from 1 year to 6 months less. Identify who does well with what and decrease the amount of surgery that you need. So I will just show this and say there are paradigms looking even to our patients with earlier and earlier stage one disease, and that's coming forward. What I like the most about this meeting is the ability to work, to talk and collaborate with colleagues. This is the aforementioned Doctor Blanc, who brought us the Nadina trial. And with that, I will stop sharing. And thank you for listening.
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