Dr. Merrick Ross discusses immunotherapy as a modality to use prior to or in conjunction with surgery as a pathway to combat melanoma.
and now we would like to bring back dr ross for his second of believe, three presentations on non I'm sorry Neo Adjuvant therapy for advanced respectable melanoma America are you here? Ah see the fingers. So Merrick um we had several questions which we will forward to you but one of them which I would like for you to take a like one minute to answer is uh that sentinel node is good for staging but doesn't do anything for therapy. So if you would take a moment to address that and we'll go from there. Yeah, I saw the three questions and that clearly was the most complicated and I'm sorry if I caused some confusion so I understand that the M SLT one trial was to look at look at outcomes, regional disease control and also melanoma specific survival. And if I understand that in their trial, only 20% of the patients had positive notes. So To address the question for the note positive patients, you couldn't really answer that because only 20% of the patients it could actually benefit from from, from the therapy that you were actually testing. And but it was clear when you look at no positive versus you know, such a positive patients versus macroscopic positive patients that the there was improved um um melanoma specific survival for the patients who were treated for positive central notes. The confusing thing was that what role does completion lift node dissection have? So in reality all those patients had completion, no distractions if they had a positive central so that so that that trial did not ask that question. It just asked the question. Could treating lift no disease early be of some benefit? The question is how you treat That became the question. Since the vast majority of the patients who had a positive central only had the central lymph nodes involved removing the central No it was potentially therapeutic in those patients that only had central node involvement. So now it would now we go forward to the M. S. L. T. To trial. Those patients already have their positive center and lift nodes removed. So whatever therapeutic benefits they could achieve had already been achieved in both arms. So the question for that trial was what in addition could completion no dissection provide and it could only provide benefit in removing additional positive nodes which also represents about 15% of the patients. So again not powered to look at that but because the patients with additional positive nodes have such bad biology, whatever they're persecuted benefits are going to achieve surgically would have been already achieved by removing the sentinel node if that makes any sense. So the MSL t to trial showed that then in actuality the central lifting the procedure is not just a staging procedure but it's also therapeutic and that and that the that the completion lift of the section only provided additional staging information because additional positive nodes was important for prognosis. So if that clarifies things, I hope so because that was clearly the most positive when I was trying to figure out how to how to type that in a way that would be clear to the person who asked it. Is that okay anybody terry? Yeah. Yeah. No, that's good Merrick. Thank you. You're a muted for a while. I thought maybe you fell asleep, you know. Uh huh. All right. That was good merry. Go ahead. Okay. All right. So let's talk about neo adjuvant therapy for advanced stage melanoma. Are we ready? I will give you the surgical perspective. This is this actually is one of my major interest in not only clinical care of patients but also it's one of my major research interests actually. Um let's see here. I don't really have control yet. There you go. And same same disclosures. All right. So let's look at the patients who we would consider candidates for a neo adjuvant approach. And this is the the patients that have respectable metastatic melanoma. So, the most common scenarios patients with advanced regional nodal disease. So, these are the three Bs three C and three D patients clinically apparent lift nodes. Also respectable. Local satellite or in transit disease. Fall within that same regional disease category. Then there's a group of patients with distant what we call a legal metastatic and very small numbers of distant disease that could potentially be respectable and considered for neo adjuvant approach. So I think it's important to look at what we would consider standards of care for this group of patients upfront. And right now the standard of care is upfront surgery uh selective use of edge of it noted based on the radiation for the really advanced stage stage three patients and then systemic edge of in therapy for all essentially the respected stage three patients because they had clinical nodal involvement. So their risk of additional disease is really high. Um and the therapies that we have a single agent anti PD one G raff neck for the draft positive patients or a clinical trial And then for the resected stage four patients. Anti PD one is also a standard of care. Combination checkpoint blockade is being evaluated in clinical trials which is also available to patients. So if we look at the management goals for respectable advanced Stage three disease would be to provide durable local regional disease control which could translate into long term survival uh a paley ation and also try to minimize the morbidity and functional deficits, reduce the risk for future distant failure because that's why people dies from distant disease but also recognize and manage the toxicities of either agreement or neo adjuvant therapies. So it's important to recognize upfront that even though we have very effective edge of in therapy, the outcomes are still not great. And so the outcomes with respectable stage three melanoma remained poor even with the adjuvant therapy, particularly in those with macro metastases or clinical disease involvement. So it's also important to recognize that our edge of in therapy trials are biased towards the better biology groups, understand when patients undergo edge of imagine therapy trial, they have surgery, then there restaged The ones that don't have recurrences already can then be entered into the trial. But there's a fair number of patients that fail early with distant disease and that probably represents 15-25% of patients. So those are the bad biologic actors that never get entered into a gene therapy trials. So the ones that are left over are the ones that have better biology. So the overall, so the overall outcomes is actually better than what you were predicted by just kind of real time data are are real world data. So you can see here for the for the for the targeted therapies on the left and anti Pd one on the right, kind of very similar outcomes for adjuvant therapy overall, but we can still do better and there's obviously opportunities to do better. So the challenges are more efficacious therapeutics or combinations of effective agents. Maybe adding a novel agent that may have synergy with a single agent. I'm sorry for the format here. The biomarkers are to determine would be prognostic or predictive. And tissue is always the issue here, whether it's you or blood and finding biomarkers for for for for relapse. It would be nice to try to avoid large phase three randomized trials to get answers of additional therapy. So that provides some opportunities for a neo adjuvant approach where we can't therapy first observe responses have surgery and then a phase of additional the same therapy or maybe a different therapy in the adjuvant setting. After surgery provides an objective measure of patient's response to therapy. So we can better personalize their edges and faces a potential pathway for a new drug evaluation and potentially registration and more importantly, understanding the tumor biology. So we have the ability of acquisition of cereal bio specimens through the course of their therapy to provides insight into drug resistance and as as well as um drug response. Um there are potential benefits of a neo agile in approach, tumor shrinkage could result in into decrease surgical morbidity provide better regional disease control. And also potentially avoid the morbidity of engagement. Noto based on the radiation more effective treatment of distant micro micro metastatic disease with chemotherapeutic agents. That's an important biologic question or research question to ask is giving an immunotherapy in the context of intact tumor burden a relevant thing where there's these antigens that are available. Um that that could elicit a better response in the edge of an setting. Because if we think that that that that that that that that that T cell activation is like the is the important piece of information um for for response to immunotherapy that that excitement or our initiation of T cell activation can be better in the context of an established an established tumor burden or an established micro environment which may not be present in the adjuvant setting. Furthermore, there's no delay in the treatment of micro metastatic disease and hopefully prevent distant disease spread. So that last thing is really important. So, so is there a potential disadvantage of delay and surgical therapy therefore making the surgery more difficult? But I will tell you missing the window of opportunity for cure probably does not happen if there's a delay in surgery by leaving the tumor in place, potentially promoting metastatic spread or the concept of losing local, local disease control. We don't think anything is any of that is really relevant. What's more important is what about delaying the initiation of an effective systemic therapy or an effective adjunct therapy. And if you look at, So this is the B. Ref mech data, which is placebo vs. Combination be roughneck and patients who had resected nodal disease. And then we were randomized to therapy versus a placebo. So this is probably the most effective adjuvant therapy ever reported for any tumor whatsoever. You could drive a truck through these through these survival curves. The look at the p value, there are so many p values here, you can't even count them. The other interesting thing is that despite the fact that we've weeded out some of the really bad actors in the placebo arm. You've got a pretty significant drop off early on. So this concept of the laying systemic therapy may be very important. And we and we see a similar thing for the keynote 054 which is the average of unp embolism versus placebo. We see a similar thing, it takes a while for the therapies to actually work. But then again there are patients who drop off relatively early. And the same thing that with the checkmate 238 that compared to bloom a mob versus versus novel ahmad that led to the approval of NovoLOG mob as opposed to a problem a mob in the edge of the setting. So early initiation of systemic therapy may be very important. So which is more likely to have an impact on distant failure, delay in surgery or delaying effective systemic therapy. I will tell you it's probably the latter. So we started thinking about neo edge of and approaches for these patients have developed had developed really advanced borderline respectable disease. No, no disease. In the context of already having very good information in the stage four setting of the effectiveness of different different therapies, particularly be Ralf Mac or the or the combination checkpoint blocking agent. So this is a patient with really bulky disease in this particular nodal basin and you can see this is response to be Ralf Mech and while there appears to be some residual disease, the pathology report showed complete path a complete pathological response. There was no viable tumor, there was only only only only fibrosis. So this led us to think about neo adjuvant approaches in the in the in the clinical trial design setting. So these are the these are the contemporary neo edge of in candidate therapies that we've been looking at. So bereft Mac and the beer F mutated patients. Single agent checkpoint blockade some of the ankle Ilic immunotherapy is particularly to the vet. And I'll mention tomorrow and then combinations of the above. So a combination blockade like in Geneva there's a standard dozing and then there's a reverse dozing P. D. One plus on politics and the arts. Politics can be tyvek HF 10 T or nine coxsackie virus A 21. We'll talk about those tomorrow pd one or Pd L. One plus targeted therapy wheelchairs, a fair bit of toxicity. And more recently we have a very interesting trial with a combination of Pd one plus an anti lag three therapy which is a uh relentless math which is really interesting. T cell activator. So this was our initial uh combi neo trial which was the combination be raft mech in patients who had metastatic stage three disease or so. Um a local metastatic stage four. And you can see that the radiographic response is actually significantly underestimated the pathologic responses. So we had a 58% complete pathologic response rate in this trial the trial had to be and had to be closed soon because our very early because it was pretty clear in the patients that received neo gene therapy. We're doing much better than the patients who receive surgery up front and then achievement and the patients that had a complete pathologic response. We're doing amazing. Um Then we had our neo adjuvant checkpoint blocking trial which was a randomized trial of single agent P. D. One versus the combination of hippie Nevo. And this was the european evil kind of standard dusting of three of epi and uh one of NovoLOG mob. And um This was some interesting data as well that the single agent are a few patients actually had progression and the complete pathologic response rate was only 25% versus the combination checked by blocking of nearly 50% complete pathologic response rate and really no patients had clinical progression um on therapy and if and if you look at if you look at overall survival comparing patients, they had a complete pathologic response versus the ones that didn't have a complete pathologic response. The complete pathologic responses are doing much better. So therefore we think this is a really good surrogate for outcome. And this led to a really nice international neo adjuvant melanoma consortium of more than 80 institutions now that are participating. And uh we have published a white paper with agreed principles for neo adjuvant trials and doing multiple trials in terms of the populations at risk duration of therapy. How do we evaluate bio specimens and and also the endpoints. So there are several ongoing neo edge of in trials looking at this particular platform and this was like the prototype um uh the prototype for for for for this drug development where you had intact respectable disease, you had biases up front to get certain biologic markers. Um and then the patients receive therapy anywhere between six and 12 weeks, then they had surgery but they had biopsies during therapy and then we had the whole tumor present to do a bunch of clinical a bunch of translation of resource to look at clinical uh correlates for for the type of response and also also for resistance. So this is a nice pool of analysis that was published about a year and a half ago That was established through this through this consortium of 184 patients that underwent a variety of different Neo Ajman trials, either immunotherapy based or targeted therapy based. So overall there was a 31% complete complete pathologic response rate and you can see the overall outcome in terms of relapse free survival for the complete pathologic responders versus the patients that didn't have a complete pathologic response. Understand that the neo adjuvant therapy approaches an interesting because it includes all the actors, Even the bad biologic actors because they get therapy up front. So you don't know who the bad actors are as we would see in an edge of in therapy trials where they have surgery first, some may recur and never get to go on to a management therapy trial because they got restaged and they already had relapses. So this this includes all all the patients good back to good actors as well as well as the bad actors. Now, if you look at relapse free survival by drug. So the immuno the if you look at immunotherapy in terms of relapse free survival versus targeted therapy, these are not direct comparisons understand that because these are not these are not randomized trials comparing immunotherapy versus targeted therapy. But if you look at relapse free survival by pathologic response and drug. The interesting thing is edit for targeted therapy. If you don't get a complete pathologic response, you don't do very well. You can even have a partial response with immunotherapy and still have a good outcome with a nice plateau. And you can see so far there are no patients have had a recurrence if they have a complete pathologic response if they underwent a if they underwent immunotherapy as part of their neo adjuvant approach, A lot of data is emerging that are that that sometimes real logic response can be good predictors of a pathologic response. Here's someone that had some residual disease and a 79% decrease by resist in terms of radiographic response, but especially had a complete pathologic response. And here's a patient that had minimal response and you can see that patient had a ton of viable tumor um at the time of surgical resection, here's another patient this patient received the neo edge of an empty Nevo. And this is their this is their pet scan kind of upfront. This is disease in the groin and here's a personal response re geographically and that patient actually had a complete pathologic response. So again, radiographic response is underestimating the pathologic response. And this is a kind of a pooled analysis that also shows that many times the radiographic response underestimates the complete pathologic response. This is probably the most interesting neo edge even trial that was done in europe through the Neo Adjuvant consortium that that I actually had talked about. And this was a three armed randomization scheme of the of the standard hippie Nevo. So three migs of P. V. P. And and two I'm sorry one of novel Ahmad versus the reverse dozing. Which has less toxicity of two doses of up front, one mg epi and three mg in novella man. And then a sequential arm of upfront hippie followed by followed by uh sequential novella man. And this is the results of that trial which is really interesting. So these are the radiographic responses. So let's focus on the center portion which is the reverse of the reverse dozing of hippie Nevo. And look let's look at the complete responders. Radio graphically. So just 3 10% complete response clinical response radiographic well 57% complete pathologic response. So a significant underestimation of dizzy of the of disease response. The other thing that's important if you look at the three arms that the reverse the reverse toasting of hip uneven not only was less toxic than the standard dose, it looked like it had a better complete pathologic response rate. So that became like the next standard or the next trial to look at to specifically look at that particular regimen and study that more carefully. So it begs the question. Since upfront surgery followed by adjuvant is really the current standard is comparing the sequence of therapy and important questions. So do we really need to prove that a neo adjuvant approaches either superior or not inferior to an adjuvant approach? I actually don't think so but if we're going to do that it has to be the same systemic therapy in each arm and one that is approved in the edge of and setting. So right now The only approved a German therapy in terms of immunotherapy is just single agent PT one and it has to be a direct prospective randomization designed with intent to treat randomization has to occur prior to either surgery or or in in or in in or in the same the same. The same systemic therapy. I have to have to search. So this is a current ongoing randomised phase two trial that's done through the inner group. Um um mechanism within the U. S. And this is for respectable stage three and four melanoma. The randomized upfront to either receive Pemberley Samad for three doses which is an anti PD one drug then surgery, then pemberley Sin mob or surgery up front followed by adjuvant pemberley Samantha. So all the actors are randomized upfront. So the good and bad actors are involved in both of these arms. So we can tell how many early recurrences we have in the upfront surgery on. So this is an ongoing trial. It will be interesting to prove that the neo adjuvant therapy is not worse and I would imagine it's probably better although pemberley cement may not be the best approach in the neo adjuvant setting as I showed in our particular small um phase two trials. So but there's also some interesting surgical questions. We always try to lower or minimize the morbidity of all of our treatment approaches was whether it's systemic therapy or surgery. So what about the extent of surgery based on presentation or based on response to therapy? Are we able to do less surgery without compromising outcomes? If we based our surgery based on response maybe just respect maybe just respect what remains if we're going to do that we have to place what's called the fiduciary marker. And we've been using MAg seeds as a traditional market because we have a magnetic probe that can localize the MAg seed prior to the therapy. Um So we can place these traditional markers prior to therapy. So they can identify the index side of disease after treatment and then you can potentially consider no surgery if there is a complete or major response. So that's kind of an ongoing question. So again, we'll get back to the morbidity of a form of lymph that next to me. And while I think it's overplayed somewhat because like I mentioned before, nexus sections and actually the sections are really really kind of uh tolerated very well. It's mostly the groin that has most of the morbidity related to a form of the section. And so this is an ongoing trial which is a follow up of the of the three armed trial that I told you now that we identified a very effective well tolerated kind of combination checkpoint blocking neo adjuvant approach. This is a really interesting trial where patients get randomized two up front surgery versus two courses of this reverse dozing hippie Nevo and then re section of the of the index node And that if there is a complete pathologic response or a major or a major response where there's less than 10% viable tumor, the patient does not go on to a completion lymph node dissection. But if there isn't a major pathologic response and the patient does have a completion surgery and then you will have an alternative adjuvant approach, particularly if the patient has a baby reputation because we have other options for those patients. So this is a proposed trial through the neo adjuvant consortium that I mentioned and this is the next kind of concept where we're looking at maybe even reducing the extent of surgery for these patients? So there may be a neo edge of a paradigm shift or neo adjuvant strategies for advanced, respectable notice disease. I think our rational, there's no delay in the systemic therapy, complete pathologic response, maybe a nice surrogate for outcome. And we may be able to do needle biopsies or core biopsies to determine if they've had a complete pathologic response. Combination strategies will be employed to increase the complete pathologic response rate and that will be one of the major goals of the neologism consortium. And it also provides the ability to really test biomarkers for um for for predictive response as well as resistance of therapies. It also facilitates the study of a selective approach to lift node dissection and we talked about the fiduciary marker placement as part of that period part of that paradigm. So a few final comments, I do not think we need to wait for the neo right through the results of the Neo adjuvant versus a german trial results. I think we can try to enter all these patients onto neo edge of in trials and I would consider a neo edge of in trial as the new standard of care for patients with clinical nodal disease that's potentially respectable with, with importantly answering the following questions of can we identify more efficacious regiments? Can we minimize toxicity of all of our therapies? What are the best imaging modalities to a sense response? One of the biomarkers for a complete pathologic response? And can we start doing less surgery and I'll stop there and thank you for your kind attention? Thank you, Derek! If you have questions for dr ross, please send them to me and we'll make sure they all get answered.