Janice Mehnert, MD, reviews recent developments in Melanoma treatments, specifically Adjuvant and Neoadjuvant landscapes. Dr. Mehnert identifies a selection of targeted therapys versus immunotherapy, and also describes the management of brain metastases.
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our next speaker this morning is Dr Janice Maynard. Dr. Maynard is the associate director for clinical research at the Perlmutter Cancer Center and is the director of melanoma and cutaneous medical oncology. Dr. Maynard is a nationally recognized expert and early phase therapeutics. And for the treatment of skin malignancies, she will be speaking to us this morning on the evolving paradigm of melanoma treatment. If you have questions for Dr Maynard, please use the ask a question chat function, and we will collate questions for the panel discussion at the end of our speakers this morning. Please, everyone welcome Dr Janice Meinert. Thank you, everyone, for the invitation to speak today and for your attention, we're going to take sort of a world when tore through the evolving paradigm of melanoma treatment and hit some of the high points of recent developments in the past years. My name is Dr Janice Manner. I'm the associate director for clinical research and the director of melanoma and cutaneous medical oncology at the promoter Cancer Center of N. Y. U lingo. These are my disclosures. So to start looking at the landscape of melanoma therapy, I've divided this talk into three parts looking at a given and neo adjuvant landscape, looking at the selection of targeted therapy versus immunotherapy for a Stage four patient and finally, the management of brain metastases. So let's start with a case we've got. A 56 year old female who presents with the bleeding pigmented lesion on her left thigh. She has a wide local excision, which is a 4.3 millimeter ulcerated melanoma, and I suddenly with no biopsy that shows the note is positive for disease she presents in your office for Medical Oncology Consultation. You advise treatment with interfere on treatment with combined people Um, Ahmad bin Abdullah mob treatment with single agent, anti PD one therapy or beer off mutation analysis of the tissue and follow up consultation to review the results. And so do the answer. This question, as I've written it, is deep so prior to 2017, we really didn't have too much in the space for patients with respected melanoma. We had multiple clinical trials of a given high dose interfere on, none of which showed an overall survival benefit. Consistently, we did see a relapse free survival benefit, but this was accompanied by significant toxicity fast forward. Several years later, we were able to study through our help with our E R T C colleagues at the limb a mob in the adjuvant setting, and what we found here was the RFs and OS benefit we were looking for. But 42% of patients experienced grade 3 to 4 taxes today. And I think when you're considering that most patients with respected melanoma will never recur, even without therapy, these are odds that are sometimes a little steep for patients to consider. Luckily, we've had multiple advancements since then. I always called 2017, the year the world turned upside down. That was, of course, before 2020 in a pandemic. Nonetheless, new paradigms in the treatment of locally advanced no positive disease came about with the publication of M S L T to, uh, in the New England Journal of Medicine. And with this large randomized surgical trial, we have a paradigm shift that we now no longer perform completion lymphedema Chinese boy in every patient that has a positive sentinel node because it did not change melanoma specific survival. So that's important to note because at the same time we had no less than three large randomized adjuvant trials published in the following year that actually utilized the old surgical patterns. And so what we're faced with is integrating our new surgical techniques new surgical approaches with the medical therapies that have since been approved. What these three papers showed was that we can have advances in both targeted therapy and immunotherapy approaches that can change relapse free survival for patients with respected disease. So this slide captures the keynote 50 for trial, which, compared Pebble is a map versus placebo and the checkmate to 38 trial, which compared, uh, anti PD one therapy with Novela Mab versus diploma map. The populations for the two trials were slightly different. Checkpoint 2 38 treated patients with Stage three and above disease, while Keynote 54 included patients with Stage three, a disease. But what you'll see is is that we see the similar slope of the curves and a similar, uh, relapse free survival benefit between the two arms of these patients, indicating that anti PD one is a very significant component of adjuvant therapy for patients with respected melanoma. What's also very important to note is between these two trials um, we do not necessarily see a breakdown or benefit or a difference and benefit as compared by Barack status of the patients were treated. What we see here is that the top panel is our checkmate. 2 38 patients in the bottom metal bottom panel is curves from our keynote 54 trial, and what we see again is is fairly similar differences in recurrence free survival, regardless of patients. Whether patients had us that had to be reputation or not, immunotherapy can be a very important component of treatment for patients with the raft positive or negative disease. So this slide is taken from a presented by my partner, Dr Jeffrey Weber. Uh, in this year's Is Mo showing that we haven't yet quite seen that overall survival difference. We're looking for between the two curves for checkmate to 38 we are still following events, and so those data are forthcoming. But what we do know is that late toxicity follow up from either of these. Child did not show necessarily new safety concerns. I think it's a generally accepted consensus that patients who are treated with single agent anti PD one therapy often tolerate the treatment. Well, yes, there are side effects. Yes, there can be great three side effects. But in comparison with an agent like people in a map, that rate is much more, uh, much more permissible in the 14 to 15% range. Early discontinuation of treatment often also happens far less frequently in patients treated with anti PD one therapy versus anti tilt for therapy. And I think that this is a re ensuring an important piece of information as we make decisions with our patients about adjuvant treatment. Yeah, so our next turn in the road is can be a D. And that's where our large randomized Phase three trial comparing, uh, debriefing of intermittent combined map K inhibition therapy versus placebo in the treatment of patients with stage three and above the Raffi 600 mutation. Positive, respected disease. And what we see in that trial again, you've seen these curves before. Most likely, we have our relapse free and overall survival curves. So what's different about this study is we do actually see an OS benefit between the two arms, um, also indicating that this is a very important and reasonable approach to consider in patients that have had melanoma completely removed by surgery. Mhm to also look at the safety profile of this approach. We see that there's certainly, it seems, compared to anti PD one therapy. A larger proportion of patients that have a s leading to treatment discontinuation, fatal eighties related to the study drug were at zero in both groups is captured on this trial. I think the take home point here is that anyone who has given these drugs knows that that some of the side effects that we've captured as even as low as Grade One in our clinical trials can actually be quite bothersome to patients, namely Pyrex, CIA chills and fatigue treatment breaks have usually been an important component of giving therapy to these patients. Nonetheless, despite this, we see relapse free and overall survival benefits, and I agree that this represents an important treatment choice for patients who have respected melanoma. Yes, the map K therapy has shown a sustained overall survival benefit over time. This is a snapshot presented from last year's ASCO 2020 and I think what's important, even though the cross child comparison here is inherently flawed, because these approaches have never been compared head to head. It's important to note that you have disease free survival between Kino 54 which is AARP embolism and versus placebo trial and can be a d, which is our map K targeted trial that's similar in our beer off mutated patients. So for me, this says that it is important when patients have the option to experience both treatment strategies to have an informed discussion about each of these and their accompanying side effects. So how do we make this choice? Well, if we were to stack, the survival curves back to back, which again is, as we've just admitted, an inherently flawed across trial comparison. We can see that the top diagram, which shows are anti PD one therapy versus the bottom diagram, which is our targeted therapy map. K directed therapy appears to have the most pronounced benefit over the first year and increased evidence of relapse after completion of therapy where immunotherapy might have less differences in the first year. More sustained benefit over time. Finally, we can't forget that the biology of disease at presentation may dictate the use of neo adjuvant approaches, which is an entirely different topic altogether. So when we're making this choice with our patients. I think it's important to take all of these factors into consideration for those of you who might think, Why not just reach for the immunotherapy? It certainly seems to achieve a Gold Star standard of standard of even cure in our stage four patients. I'll bring to your attention Some data from a trial conducted several years ago called the Brim eight study, which looked at single agent them. You're offended and stages to see 23 c and what this trial had done in its design was allowed for a pre specified hierarchical testing such that the patients in the Stage three C group who were analyzed separately because their disease is more aggressive. This cohort has to be positive for the entire trial to be considered a success. And what they did see, in fact, with the hazard ratio of 0.8, is that the trial failed to meet criterion for analysis of the entire study because of failure to improve relapse free survival on the Stage three C group. However, if you take a look at this stage to see 23 b group with a hazard ratio point by four. We see a difference that we might want to see in an earlier lower risk of a group of patients. And and so to me that that's an interesting hypothesis to to consider that the raft therapy might perhaps work better even on our earlier stage. Patients who need adjuvant therapy. Yeah, So in terms of our patient centered considerations, we obviously always think about cost of therapy and whether insurance covers and approach schedule and convenience of administration patients specifically or trying to hold down a job and tied to their schedules. May may find it quite inconvenient to come in for anti PD one infusions and prefer oral therapy. The side effect profiles autoimmune side effects conferred by anti PD one therapy are often manageable but can be permanent. And this can be very important, especially invite in light of life circumstances of different patients, including whether or not they're starting a family. Fertility can be profoundly affected by the end of monopolies that associate in a company. Auto immune therapy complement and medical conditions and safety considerations are obviously quite important as well. I'll say just a few brief words about new achievement trials this is where we have the least amount of data in comparison to the large studies have just presented. But I do think that the product, uh, study deserves mentions. I discussed this trial at a school last year is a personalized, response driven adjuvant therapy approach. Using a flip dose, it GOLIMUMAB and Ebola mob regiments, followed by reception of a pre specified index node. Patients that enjoyed a path CR or near passed CR did not have further surgery or medical therapy. Patients who had no response had both surgery and medical therapy, and patients in the middle had surgery and with an option of medical therapy. And what we saw was a major path response in this treatment group with the and about 99 patients in the 60% range. So when we compare that to other neo agin studies that have been conducted, which are admittedly much smaller, this is a higher response rate than, for instance, the roughneck therapy, which showed a response rate of a 45% major path CR rate and the paper of single agent anti PD one therapy, which showed a 30% rate of of of major pathologic response so I think these are important numbers to consider. This is a space to watch, but we need to have more data before we start making any kind of proclamations about about what the right approaches at this point in time. So in conclusion, immunotherapy improves relapse free survival in both the RAF wild type and mutant patients. Patients with the least amount of disease may be the best group to treat with your APP. Targeted therapy without a head to head comparison, there is not a right answer, and our new accident strategies are promising and require. Further validation will be an arch, the choice of therapy that really involves patient consideration, their co morbid conditions in the biologic behavior of their primary tumor. So let's switch gears now and talk about the stage for patient. A 45 year old male presents with scattered bilateral lung modules, his usual state of health. He has biopsy proven melanoma that is metastatic to his lung. That is be rough mutation positive with a normal ldh. So what is the best treatment options? Okay, so do we use targeted therapy or immunotherapy are both through these patients well again, looking at the patient in front of us. The factors that predict aggressive disease obviously usually drive our clinical choices. This includes the height of the ldh, the tumor burden or need for a rapid response. Whether or not the B Ralf result is available immediately. Will it take weeks to come back, as it sometimes does again? Insurance and prescription constraints and co morbid conditions all else considered when when patients require a truly rapid response, targeted therapy is often a very good choice. Those of us that use these drugs know that we can see responses in as little as 5 to 7 days. Immunotherapy can also induce responses, but it sometimes takes more time. Um, we're still trying to figure out the right timing of this, but practically speaking, that is often where we start. That being said, let's take a moment to review the seminal data that have brought us here. This is a progression free survival diagram from the seminal study that examined Nivola mob enabling a mob versus Nicola mob versus at the Lemon Mob. And what we see from this trial is that the both Ebola mob containing arms patients have far superior outcomes, something I think is very important. I bring this up when we talk about our selection of targeted immunotherapy to remind you, um, what the data showed when we looked at PFS by tumor pd l one expression and certainly while pd l one expression seemed to enrich for response, particularly in patients treated with just single agent anti PD one therapy patients who there were there were PDO one negative patients who enjoyed very clinically significant responses, especially when treated with combination therapy. I do not use PD l one as a factor in whether to consider single agent or combination immunotherapy or targeted therapy. I do not test for it regularly, and I believe that the majority of my colleagues who are key opinion leaders in melanoma feel the same way. Um, so I put the slide up because it's important to remember the trial that I just discussed was not powered to show difference in outcomes between patients on both novel a mob treated arms. However, I think that this, uh, this diagram looking at five years to follow up five year, uh, survival follow up rates deserves some mention. While the child was not tired, power to show a difference. I think that seeing the difference in this overall survival for me is something I make a mental note of. When I am discussing these data with patients, we do see that patients treat with combination immunotherapy have typically enjoyed higher overall progression free survival rates and a five year follow up series. Um, certainly I use doublet immunotherapy in patients to have a luminous disease and brain metastases. The rest of these patients. We discuss choices in light of the increased toxicity that is achieved with combination therapy as well as data such as this. Okay, it's important to remember looking at data from the comedy trial, which looked at the bracket of tremendous versus, uh, policy vs the bracketed and placebo to remember that patients who have good prognostic factors tend to do better no matter what therapy we give them. I think that's important to remember, because, uh, well, again, a lot of times we might still reach for the immunotherapy first, because we can ultimately stop immunotherapy as opposed to targeted therapy. Uh, I think a lot of times we forget that patients who for whatever reason, might only have targeted therapy. We might have started with targeted therapy can also enjoy very good long term outcomes when they start from a place of good prognosis e things like a normal ldh, or low volume disease. To begin with, these red boxes sort of call out the difference again and progression free and overall survival, adding the underscoring the benefit of the Mecca him bitter in these in this patient population. So, which be rapper MC inhibitor Do I choose? Well, I think we have a variety of good choices, which is always a good place to be. But I will call out that I see differences in the anchor after having been the magnet combination. There's a numeric difference there in the number in the number of months measured for me no overall survival. And also this is a child that can bear that actually compared to be rough inhibitors, head to head and looking at Ankara University from your opponent. In this prospective study, we see a difference, um, as well, with the Ankara from it being superior. Uh, I think that this is a more potent agent, and I think that it's something that deserves consideration when we're selecting a combination to use. So so when, If ever, do we use triplet therapy? Well, we've had a number of trials that look at integrating B Rafique therapy with immunotherapy. At this point, this is the only combination that is currently approved. It's a child looking at Tesla's, um, ab Kobe Met nip, And then you're offended versus the Kobe met in it, and the more often a combination alone and the primary endpoint was investigator assessed progression free survival, which was significant. I think it's important to note that when the same PFS was assessed independently, it was not a significant result, and I think these data deserve further follow up. Nonetheless, it was enough to lead to approval of this regimen. My personal opinion is, I've I've often not use this regimen because I do not necessarily think that the difference in progression free survival, um, justifies the increased toxicity, and I don't think we yet know the answer of whether just using the agent sequentially instead instead of integrated is going to be just as good. So we're hopefully while on our way to understanding that, but to underscore a little more on the way, let's take a look at some of the other triplet trials that have been done. So I've just discussed the inspire study with with 500 patients a sizable study. But if we look at the the keynote 22 trial, which looked at Pebble is, um Abdal graphic of traumatic versus, uh, just d t alone If we look at the September study, which was an investigator initiated study that looked at various combinations of PTO in therapy alone or combined with targeted therapy, and then finally the combi I study, which started out as a phase one trial but recently had faced three data release. What we see is in general differences in PFS between the arms, but, um, and that also, there might be some differences in duration of response. Um, nonetheless, I'm not sure that we're necessarily seeing differences in overall responsibly or complete response. At the end of the day, I think understanding whether these outcomes, um, actually add life to quality of life to the patient's life is really the most important thing. Um, but I think at this point in time, we are many of us are sort of employee, either more pure, targeted for pure immunotherapy approaches. Um, given these, given these results. So this child, through our through the group, is actually looking at the proper sequence of giving immunotherapy and targeted therapy. If you have it open, I encourage you to keep enrolling. We've almost reached a conclusion, and this will be an important study to give us an answer of which therapy to do first and when. So in conclusion, triplet approaches have not shown improved efficacy or toxicity profiles. Let me know therapy confers durable benefit with the eventual ability to stop therapy. Targeted immunotherapy can achieve long term disease control and good apartment Asus patients regardless. So finally, we'll close with a few slides on CNS disease, a 45 year old male patients the same patient before presents with lung metastases. But this time we get a brain MRI, and it shows two lesions, each less than one centimeter. He's asymptomatic. What do we do next? So some historical perspective brain metastases in melanoma are an Achilles heel. Many patients have them a diagnosis half will develop it during treatment. Up to 80% have them at the time of death, And our biggest factors are how many brain lesions we need to deal with. How aggressive is extra cranial disease behaving? Whether or not the patient is symptomatic and whether or not the left um, and injuries are involved, this is obviously a treatment where we have a multidisciplinary team and we've really always done that. Historically, it's been mostly surgery and radiation. Um, I will say that surgery can potentially curative in patients with solitary or few brain lesions as a stereotype. Active radiosurgery In general, whole brain is often strictly a palliative approach and and is often very poorly infected. Unfortunately, the key limitation of these to date had been lack of impact on us outside of the brain. And that's why these trials, which have looked at the integration of immunotherapy and targeted therapy into our mainstay of treatment for CNS disease, have been just so important. So if the limb, um ab this is a small study done by my colleague Dr Kim Margolin, which showed that if the limb a mob in a Phase two trial had about a, uh response rate, mirroring what we see an extra cranial disease, Pastoralism ab also response rate in the brain of about 22% so so lower than what we see with extra cranial disease. Um, this is in a again a smaller study with both melanoma and lung patients. Uh, included in the cohort, um, following on the heels of these publications, the checkmate two or four study was released. This trial looked at combination full dose of polonium Abbott three mics per kig with novel, um, at one big per kig, followed by maintenance Nicola map and And this looked typically at patients who were who are not symptomatic to start, um, and had specific criteria for, um uh enrolling with respect to the amount of brain disease that they had. Nonetheless, the results of this study were striking in terms of looking at that both intracranial extra cranial and global response. Um, we see the global response in in, uh, nearly half the patients and similarly intracranial response just over half extra cranial just under half, um, with a 55% rate of grade 3 to 4 toxicities which are quite honestly acceptable in light of the fact that this is usually quite serious disease. Um, so this has become a mainstay of therapy for patients who present with intracranial disease. We also have our targeted that is, targeted therapy studies which have been performed. Um, this trial looked at multiple cohorts of symptomatic or asymptomatic patients with varying, be raft mutations. Either directly the Route V 600 e or D, K or R, And look at the combination of the brand debriefing have been traumatic and what we saw across cohorts. So the cohort B that was asymptomatic with prior local therapy stuck out a little bit in terms of having a slightly longer progression free survival. When we look at the intracranial response, it's very similar across all four cohorts. What this says to me is that targeted therapy is a very meaningful way to control disease in symptomatic or asymptomatic patients. Um, and I think that this is important because it's important. It's an important weapon we can use. Uh, if patients have both, uh, the raft mutation, uh, status and or a candidate for immunotherapy. I generally will start with the immunotherapy just for the chance. Adorable control. But it's nice to know that this is also an effective weapon. Should I need it? So so are emerging. Clinical issues include, um, whether patients are symptomatic or on steroids. Um, we are looking at the Those patients are admittedly harder to treat. We are looking at novel combinations which increase efficacy and decreased toxicity, including combining immunotherapy with Jeff inhibition, um, looking at integrated strategies and looking at new brain penetrate agents. And finally, the ideal incorporation of stereotype Actiq Radiotherapy is still the subject of ongoing study. So in conclusion, um, I think we can safely say we have both safety and intracranial efficacy of target therapy and immunotherapy. Immunotherapy induces durable intracranial responses. We've got novel combos on the way, and I think that for the first time ever, we've got a second line. Uh, CNS disease population, Which is nice to see. Um, but certainly at the end of the day, multidisciplinary decision making as important as error forever for for treating this very difficult problem. So with that, I'll conclude, Thank you so much for your time and attention. And I appreciate the invitation to talk
