Faculty from Penn Medicine’s Melanoma Disease team discuss clinical trials and the impact of COVID-19 on delivery of care. The discussion focuses on the latest updates in melanoma treatment, including complete lymph node dissection vs. observation, indications for sentinel lymph node biopsy, treatment of metastatic melanoma, and a case study presentation. A Q and A with the faculty is included.
Management of Low-Risk Thyroid Cancer Penn Orthopaedic Oncology During COVID: Provider Q&A Twitter @PennMDForum Dr. Schuchter’s physician profile Dr. Cohen’s physician profile Dr. Miller’s physician profile Dr. Mitchell’s physician profile Dr. Miura’s physician profile and I'm going to push the live button. Now, then. Good evening. My name is Dr Lin Schecter, and I'm so thrilled that you are joining us tonight. I have the honor of welcoming tonight's session. This is going to be updates in melanoma. And, uh, tonight, representing on behalf of the Pen Abramson Cancer Center and Penn Medicine on Defy could have the next slide, please. We have a great panel to discuss really current topics in melanoma. Um, I'm the director of the Tara Miller Melanoma Center and I'm a medical oncologist. Um, and we're joined tonight with Tara Mitchell. She's an associate professor and a medical oncologist in the Abramson Cancer Center. Dr. Chris Miller is going to serve as, ah moderator with me, and he is an associate professor of dermatology and director of the Pen Dermatology Oncology Center. Dr. John Muir. A joined us about a year or two ago from Moffitt, and he is an assistant professor of surgery focusing on melanoma surgery, And Justin Cohen is a clinical assistant professor, also a medical oncologist. On what we like to share with you tonight is a briefcase presentation to put some of our new information in perspective. Dr. Mural will take us through an update on the role of surgery focused on nodal surgery. Farrah will introduce some new information on adjuvant therapy of melanoma. Justin Cohen will focus on metastatic melanoma. And then I'd like to just go through an update on current recommendations. Current recommendations for vaccine with covert vaccine in our cancer patients. A very timely talk. Next slide, please. So our target audience is you, and we're so thrilled to have you join us tonight. The learning objectives are summarized here and on the next slide. Um, this shows you important disclosures in terms of financial relationships, but also, this is a CMI event. And a week after this conference, you will receive an instruction to get the credits for your CMI. So we have hope a really educational our to present some of this latest information. And then our plan was to take questions and answer at the end of the session. So again, welcome and enjoy. And I'm going to turn it over to Dr Chris Miller, who's going to take us through a really interesting patient presentation. Thanks, Chris. Thank you, Lynne. Appreciate. Thanks to all the registrants for joining us tonight. Our next slide, please, Kara eso. This patient represents the kind of multidisciplinary care that high risk melanoma patients could get it. 10 things is a 56 year old man with a history of seven melanomas who presented with this new growth on his scalp. Based on his history of melanomas, he would have at least a 31% risk of developing another one within five years. Next slide. We did a biopsy to confirm melanoma. You can see that this is an A melon. Ah, tick. Melanoma. And the biopsy showed at least a 6.5 millimeter Breslow depth with no ulceration, which is an a J C C. Stage t four A. That gives him a 10% chance of death in five years and a 17% chance of death in 10 years. Next line imaging work up with C t of the chest Marie of the head and ultrasound of the next showed no evidence of metastases X slide, and based on his t four a status, he would have a 33% risk of a positive sentinel lymph node biopsy next sign. So this patient enrolled in one of pens clinical trials that where our principal investigator is Dr Weir's colleague, Giorgos Carrick Asus and this trial asked the question. Does neo adjuvant Kimbrel is a mob? Reduce the rate of positive Sentinel lymph node biopsy for stage to be and stage to see melanomas next slide. So this our patient had a single dose of temporal is a map. Three weeks later, he had a sentinel lymph node biopsy, followed by a wide margin. Most surgery of the primary site Sentinel Lymph node was negative. Margins air clear, and now he's undergoing. Temporal is a map he's receiving. Temporal is a map every three weeks for the next year. Next slide. This clinical trial is available only a pen, and it's Dr Carrick. Asus and his colleagues and our medical oncologists are initiating exciting trials that are changing the way that we're treating melanomas. And the Tara Miller Melanoma Center represented here in this Web page, is committed thio improving outcomes for patients. Next line. I'm excited to be here tonight with our world class medical oncology and surgical oncology team. They taught me a lot over the years, and I'm excited for all of us to learn from them. Our next speaker will be Dr John were, uh, our surgical oncologists to talk about surgical therapy of melanoma. Thanks so much, Chris. Good evening, everyone. Tonight I'm gonna be talking to you about current updates in the management of localized melanoma specifically discussing indications for central info biopsy along with the changing treatment paradigm with respect to the management of micro metastatic disease of the regional lymph node basin. Next slide. Please have no disclosures. Next flood. Now, In recent years, a lot of attention has been placed on advanced stage melanoma. So stage three and stage four cases. But my hope tonight at the end of my presentation, it's really convinced the group that we can't forget about our earlier stage melanoma patients because in fact, they make up the bulk of new cases being diagnosed annually here in the United States. When we look at the most recent a CS statistics, we see that within 2021 there's an estimated 106,000 new cases that will be diagnosed by the end of this year next slide, and of those 106,000 cases, 85% of these patients, so the vast majority will present with clinical stage one and stage to disease. So they'll present with localized melanoma. And as a result, they will require some type of local therapy, which typically involves wide excision with or without central lymph node biopsy, depending upon the primary tumor features next slide. But with respect to the primary site, not much has changed with regards to the optimal management for the primary melanoma. Current guidelines have been influenced by six large randomized control trials that has spanned multiple decades. All the trials have really highlighted the importance that Lo are pathologic. Negative margin is most is key in order to decrease local recurrence rates and not affect long term outcomes. But current recommended clinical margins that we try to achieve our reflect on the right side of the screen for any melanoma greater than two millimeters in depth. We try to achieve a two centimeter margin. Melanomas, one millimeter or less. One centimeter margin has tried Thio. We try to achieve that and anything that falls between 122 millimeter Martin death 1 to 2 centimeter margins are more than adequate. Currently ongoing is the Mel Mart trial, which is an international randomized controlled trial, which is asking the questions whether or not to centimeter margins is too much and whether one centimeter margins are more than adequate. It's currently enrolling patients, and we won't have results for several years Next slide. But the primary site not only provides us an idea about the risk stratification in terms of how do we what type of margins we try to achieve but also gives us an idea of what's the likelihood that the melanoma would spread to the regional lymph node basin. So the risk for lymph node metastases, and so depending upon that primary tumor feature may may result in whether or not we offer central lymph node biopsy. And so what is sentimental biopsy? It's really a minimally invasive, low risk staging procedure. At Penn. We typically use a dual tracer approach, which consists of a radio label colonnade called Technetium 99 along with us so self and blue dye next Slud. But Senator Lymph Node biopsy was not the standard of care until 2014, following the introduction or following the publication of the multi center selective limped out in ectomy. Try our M SLT one for short. It was a trial that randomized patients toe either undergo observation or sentinel lymph node biopsy with immediate completion Lymph node dissection if patients were found to have a positive sentinel lymph node to be enrolled, you have to have a clinical stage one to melanoma and a Breslow thickness of one millimeter or greater. Study and points are seen on the right side of the screen, with primary melanoma specific survival being the primary outcome, they looked at. Secondary outcomes included disease free survival. They also compared the survival between those that had a positive versus negative center lymph nodes and finally, the incidents of Santa lymph node metastases. Roughly 2000 patients were enrolled Next next line. What the study was able to demonstrate was that there was really no difference in survival outcomes between those that had a sentimental biopsy versus observation in the overall study cohort. And this held true for both intermediate thickness melanomas, which they defined is 1.2 millimeters to 3.5 millimeters, or thick melanomas, where melanomas anything greater than 3.5 millimeters next slide. But what this trial also demonstrated was that sentimental biopsy was prognostic patients that had a positive settlement note experience a 10 year survival of 62% as compared to 88% for those that had a negative sentiment note. In sub group analysis. There was also some discussion of whether or not settling toe box. It was also therapeutic when we looked at the intermediate thickness subgroup, what we found was that those that had a positive sentiment that had a 10 year survival of 62%. But for those that under one observation, but then Rickard within the nodal basin, their 10 year survival was only 41%. And this would suggest that perhaps early intervention of the regional nodal basin may be therapeutic next line. So where does sentinel lymph node biopsy currently stand in? 2021? Well, I think if anyone has the risk for developing micro metastases and that risk is greater than 5% sentinel lymph node biopsy should be offered. And so for even the thin melanomas those between 50.8 millimeters toe one millimeter, this group has a roughly 8% chance of having a positive central lymph node. But for those patients that are less than 0.8 millimeters. I still believe that settlement. The biopsy can be selectively considered in this low risk group. When we reviewed our own pen experience, we identified certain high risk features that may increase your risk for developing a having a positive and a lymph node. Those included a positive deep margin high My toes is especially in younger patients or the presence of Linfield Vascular invasion. Next slide, please. But for those that had a positive sentinel lymph node, as of recent a completion lymph node dissection was the standard of care, and the rationale for that was for was that we felt that early regional disease control would translate into improve survival. But major arguments of this approach was that we really had no good prospective evidence that supported this treatment sequence through the M SLT one trial. Additionally, what we observe is that the vast majority of patients did not have additional disease in the completion lymph nodes specimens. So the non central lymph notes. In fact, only 20% of patients in the memo salty. One trial had additional disease that were found at the time of lymph node dissection. So the majority of patients are having their micro metastatic disease removed by the sentinel lymph node. And from a patient perspective, if you have a sense or if you have a completion lymph node dissection, up to 25% of patients may develop lymphedema, which could be permanent next line. So that's what led to the design of two large randomized controlled trials the de Kock trial and the MSL T to trial that both asked the question on whether its completion lymph node dissection improves survival for patients with simple little metastases. The de Kock trial was a multi center trial out of Europe and the M S. O. T. To trial was a randomized control trial here in the United States, and the trial design was simple. If you had a positive center lymph node patients were then randomized toe either observation of the regional lymph node basin or completion lymph node dissection. The observation consisted of ultrasounds every three months in the de Kock trial or four months in the MSL T to trial next one to go over the results of the decode trial first, which is reflected on the left side of the screen in total, roughly 470 patients were in road and median follow up was just shy of three years. But what the trial demonstrated was that there was no difference in three year overall survival for those patients that underwent observation as compared to those that had a complete lymph node dissection. Criticisms of this particular trial was a small study cohort, along with a short follow up. One year later, MSL t two was published in the New England Journal of Medicine, and this study was a lot more robust in the sense that enrolled to four times the number of patients is D cog, and the median follow up was about 3.5 years. But this trial as well demonstrated similar findings with three year melanoma. Specific survival was similar between the observation arm versus the dissection arm. So both trials came to the conclusion that immediate completion lymph node dissection does not improve survival and then observation alone is just a Z effective or equal or equivalent as those that undergo a completion lymph node dissection. Next slide, please. So where does the management of micro metastatic currently stand in 2021? Well, if we refer to the most recent NCC and islands. We see that for patients with a positive sentinel lymph node, current recommendations are for nodal Basin ultrasound, and this is the preferred approach at this time, but that. But keeping that in mind if close observation by nodal based on ultrasound cannot be performed at your institution thing completion Lymph node dissection should still be offered next slide, please. So what I hope I was able to show you is the dramatic evolution and how we currently manage regional lymph nodes for localized melanoma. Early on, when melanoma was originally being diagnosed and treated, patients were having routine therapeutic lymph node dissections. But over the years that management has trained drastically changed drastically toe one where we're just a million invasive surgery and now observing patients that have positive microscopic disease found in their sentinel lymph node biopsy. So perhaps less is more next slide, please. But I certainly think that there is unresolved questions now that we're practicing in accordance to findings based on the M S. O. T two and de Kock trials. Whether or not we'll see that same level of effectiveness with a German immuno therapies is unknown because, as we know for enrollment in the adjuvant immunotherapy trials, patients needed to have a completion. Lymph node dissection and tumor deposits had to be greater than one millimeter within the lymph node in the M S. A. T to trial. The median tumor deposit within the Sentinel lymph node was roughly 0.6 millimeters. And secondly, can we safely observed patients with high risk micro metastatic disease? And who are those patients? Those patients were largely underrepresented in both the MSL T two and de Kock trials and those patients with greater than three positive central lymph nodes. Hi central if no tumor burden or the presence of extra capsule extension next slide. So in closing what I hope I was able to show tonight was that sentinel lymph node biopsy remains an invaluable tool for the management off localized primary melanoma. It not only is prognostic, but it is able to rigorously risk stratify patients, especially allowing us to understand the status of the regional lymph node basin so that patients can be considered for judgment immunotherapy, which has proven to be effective. Second, who should be getting similar to biopsies? I believe that any melanoma of 0.8 millimeters thickness or greater should be offered to settle until biopsy. I certainly think that we can selectively offer several biopsy for patients with thinner melanomas, especially among younger patients with my Toasties Limpele Vascular invasion or a positive deep margin on the initial biopsy, we have now good data from the MLS 82 trials. Well, it's a de Kock trials that support the role for observation in lieu of completion lymph node dissection and that demonstrated no difference in survival and from a patient perspective by admitting a completion lymph node dissection were also sparing them the potential mobility from surgery. I'll be happy to answer questions at the end, but we'll move on. Thio doctor Thora Mitchell's Talk, which is titled Achievement and New, Adding Therapy and Melanoma. Thanks, everyone. Thank you, John, for that excellent introduction and talk on a judgment on surgical management of melanoma, and I'll focus on the next stage in which we observe patients for recurrence and try to minimize risk by offering agin therapy options as well as new engine therapy clinical trials. So our standard current approach to patients with melanoma is to offer curative intent resection first surgical resection followed by a systemic adjuvant therapy in order to try thio, reduce the risk of recurrence and improve survival, followed by a period of observation with, UH, routine history and physical examination, as well as cross sectional image ing in our highest risk patients. However, unfortunately, several of our patients still have a high risk of recurrence, despite the standard A judgment therapy options and curative intent surgery. The current standard of care agin therapy options which are approved, all of which have a recurrence free survival benefit in melanoma are debriefing him. Instrumented. A combination of a B. Raffin, a mechanism bitter in patients who have the raft mutant melanoma or P D. One blockade for up to a year with either Nivola map or Pemper Eliza map in patients with either Be Raph Mutant or be Raph normal melanoma. All of these studies have shown similar activity, with significant improvement in recurrence free survival in patients with high risk stage three melanoma. I'll show you an example of one of these agents. Pemberley is a mob in the next slide, so here you can see in the randomized prospective Phase three study of temporal is a map compared toa placebo P embolism AB in blue. If you look at 36 months or the three year follow up, 63% of patients remain cancer free, compared to 44% of those who were randomized to placebo. So you can see there's a clear, significant and clinically meaningful advantage in recurrence. Free survival in patients who receive PD one blockade and the results were very similar in the studies of Naval A Mob and in the studies of Deborah often have been tremendously been be Raph mutant patients. So all three options will remain active and effective. Therapies toe offer patients with high risk, respected Stage three disease. However, I would say that these studies were all conducted in the era of a J. C. C. Seven staging. If we look at the updated A. J. C. C eighth edition melanoma staging, which Onley included patients in the modern era of sentinel lymph node biopsy, we see that patients with Stage three, a disease in shown in the Green Line here, have an excellent melanoma specific survival, with a five year survival of 93% and a 10 year survival of 88% meaning in patients with Stage three a melanoma. Less than 12% of patients are recurring in the era prior to any effective therapies from which these data led to the A D. C CS eighth edition. Therefore, I would strongly suggest that we consider the individual patient risk. When we see patients with Stage three melanoma, we try to talk more specifically about their risk of recurrence, according to the A J. C C eighth edition staging shown here and the decision making to talk about the risk of recurrence and way that, in the context of potential benefit from a given therapy with the agents I've shown you before and we therefore have the option. Thio offer therapy if we feel that the risk benefit ratio warrants that or to have patients choose observation alone if they feel that the risk of their melanoma is acceptable to them and to the physician, or if the risk of therapy is unacceptable observation. So it's really a two way discussion, especially in light of the fact that none of these agents have shown survival benefit, meaning long term follow up data is not available or not available for any of these agents to suggest that there's a clear survival advantage. So in the absence of a survival advantage, but with clear recordings free survival advantage, it's reasonable to offer and discuss the therapy potential, benefit and risk with patients in light of their specific risk of melanoma. So instead of our standard adieu an approach which I've shown you on the left, I'll now talk about on the right. What we can see here is what we consider a neo adjuvant approach. So in a neo adjuvant approach, instead of using surgery first, we consider systemic therapy. First. These are patients who have a very high risk of recurrence, and so a new adjuvant therapy approaches the systemic therapy first, followed by surgery. This gives us an opportunity to assess at the time of reception, the pathologic response to systemic therapy, and there's potential to personalized care according to that pathologic response, and ultimately with the goal of improving outcomes and survival in patients with melanoma. So recently I participated in two consortiums, one of which was called the I N M C. The International Neo Graduate Melanoma Consortium, and another, which was a collaboration with the melanoma Research Alliance and the FDA. Both of these were highly collaborative meetings in which we proposed and published guidelines for clinical trials of neo adjuvant therapy. In general, the consensus based on clinical trial data, some of which I'll show you in the next slide, is that the systemic therapy in new adjuvant therapy trials for melanoma should be a short duration. And in specific, it should be less than 6 to 8 weeks of new adjuvant therapy, followed by surgery. And the guidance here is that that the surgical approach should follow standard procedure, meaning it should be the total lymph node dissection of the nodal bed. Given that the patients would have had a clinical note on goes where the patients in whom neo adjuvant therapy is considered reasonable to consider for clinical trials. Patients with clinical or bulky nodes Stage three. Respectable disease. The path response is assessed after adjuvant asked after new adjuvant therapy, and I'll show you some guidelines of how we assess the pathologic response to therapy. And the guidance is that patients still complete a year of adjuvant therapy to complete neo adjuvant and agile totaling a year of systemic therapy, according to the standard of care for adjuvant therapy that are approved now on. All of these guidance is there are currently clinical trials that are addressing even shorter durations of neo adjuvant therapy. There are clinical trials that are adjust that are addressing a more limited surgical approach in patients who do have an excellent or complete pathologic response. And there are studies that are addressing a shorter duration of active in therapy in patients who have an excellent or a complete pathologic response, The question is that they still need to complete a year of systemic therapy. So in assessing the pathologic response, Thio neo adjuvant therapy in clinical trials at the time of surgery after the new adjuvant systemic therapy has given been given. We're really looking in collaboration with our pathologist who are trained in melanoma for Is there has there been a complete pathologic response, meaning no viable tumor in the treated bed, so there will still be a nodal dissection and that tissue will go to pathology. But instead of tumor, the tissue is replaced by fibra attic or a necrotic material. With the absence of any viable cells, there also seems to be great value and I'll show you in our clinical trial data of a major pathologic response or a near complete response, meaning that the remaining tumor is less than 10% of the tumor bed, with the majority of the tumor bed again being just necrotic or fiber optic material. Less responses would be a partial response or a non response in which the majority of the respected tumor remains viable. Tumor. So I'll end by reviewing some of the clinical trials of new adjuvant therapy at Penn. I'll start by emphasizing a clinical trial that Dr Miller shared in the introduction, and the next slide shows that trial design. So this is the clinical trial that Dr Miller mentioned in the beginning for Stage two patients. So patients with high risk Stage two B or C, including any tumors greater than four millimeters or patients with 2 to 4 millimeters and ulcerated melanomas. Thes patients are eligible for our new achievements stage to clinical trial, which offers a up to a year of adjuvant therapy as well for the patients with the highest risk. Stage two, for which adjuvant therapies currently not approved but available view of clinical trials in this study that patients who have Stage two B and C disease received a dose of Pemberley is a mob prior to their wide excision of the Sentinel lymph node biopsy, followed by the wide excision and sentinel lymph node biopsy. Three weeks later, after just one dose of neo argument, Kimbrel is a mob, and then the patient's Congar O on to receive adjuvant Kimbrel is a map for up to a year on the clinical trial, which again is not currently approved for patients with Stage two. But we know that patients with Stage two B and C have a very high risk of recurrence and so may stand to benefit from a judgment pt one blockade. I'll emphasize one of our completed adieu neo adjuvant clinical Trials, which we published in Nature Medicine, in which we also gave a single dose of PD one blockade, and that I'll show you the outcomes that we were able to publish in melanoma in our patients. So in our study, you could see again following this graphic of new adjuvant therapy we gave one dose of Pemberley is a mob that patients underwent the standard completion surgical resection three weeks later and again. These were patients with bulky or clinical stage three respectable disease, so they underwent a nodal dissection because it was clinical Stage three disease At the time of the complete resection, we assess their pathologic response in accordance with the guidance that I showed and then patients were able to complete, ah, year of achievement embolism per the standard of care. What we saw was that 30% of patients in our study at the time of surgery after just a single dose of Pemberley is a mob had either a complete or a near complete pathologic response, meaning either no tumor was remaining at the time of surgery or less than 10% of the tumor still involved viable tumor cells. More importantly, what we noticed was in the blue line. Those patients who had no remaining tumor or limited remaining tumor remained on three year follow up completely cancer free and free of recurrence. On the other hand, patients who had ah high amount of viable tumor at the time of surgery had a higher recurrence rate Maurin line of what we had seen historically with bulky stage three BNC disease. And so it was very clear from our data that this pathologic response in new age of in therapy after just one dose was prognostic of recurrence free survival in melanoma. We went on to confirm our data in a pooled analysis in which we combined our data with colleagues both in the United States and internationally in Europe and in Australia. And these exciting results were just published yesterday in nature medicine. And you can see very consistent, that patients with the top line straight across who had either a complete or a near complete response just as we saw in our pen study remained cancer free, whereas those who had less than a complete response to add neo active in immunotherapy had a higher risk of recurrence. So the question is, how can we improve outcomes in patients with the poor pathologic response to new age of in therapy? So we currently have a new investigator initiated Stage three neo agreement trial enrolling at Penn, in which patients still received a single new achievement dose of Nivola Map PD one blockade. However, now, based on what we've learned from our data and from our pooled analysis published yesterday, patients with a poor pathologic response can now be randomized. Thio Intensify therapy to dual checkpoint blockade with dilemma Mob low dose of penal, um Ahmad and Ebola mob to complete the remainder of their adjuvant therapy. And so all patients with clinical stage three respectable melanoma patients are eligible for this clinical trial that's currently enrolling at Penn. So to summarize adjuvant therapy with PD one blockade or would be rapid mech therapy clearly improves recurrence free survival in melanoma. However, neo adjuvant therapy may allow for mawr individualized care and improved outcomes in melanoma, and we would highly recommend neo argument Clinical trial enrolment for any patients with high risk stage two or stage three melanoma. Thank you. I'd like to introduce Dr Justine Cohen, who will give us an update on treatment for metastatic melanoma. Thank you so much. Terror Eso I'm going to talk to you about some some background of what we've seen in metastatic melanoma and then in some brief updates. So I love this picture. This is a man riding a bull as he's about to get bucked off the bull. And to me, this is a metaphor for the conceptualization of coping strategies that we use an oncology and actually in all of medicine with this goal of moving with challenges and not moving against them, not running away from them are running towards them. And on oncology, as you can see from everybody's, um, talk so far that it's it's an ever changing field with new trials, new approvals, new combinations. And so our goal should always be to move with both the science and our patients. On this journey, we really came from an era of futility from 1975 to 2000 and five. I mean, we gave chemotherapy, and we gave I'll to with modest responses. And as the survival curb shows this, this plot really emphasizes that there were few treatments available for these patients, and the line determines the survival of patients over years. And you can see that the that the numbers are just not that high. Yeah, The past decade, however, has been this amazing time of advancement in the field of both metastatic melanoma and in the age of in setting, as Dr Mitchell just so articulately described, um, and so here we see several options for both immunotherapy and targeted therapy approaches for the treatment of metastatic melanoma. So some of these therapies are older and with more toxicities and lower response rates such as I'll to you and interfere on. And so these have largely been replaced by newer therapies such as anti PD one and anti C T like four and then combinations, which we're going to discuss in a few minutes. It's also worth mentioning T back here, which is an Uncle Igic virus therapy, which uses genetically modified herpes virus injected directly into the tumor. And this therapy is designed to replicate inside melanoma cells and to kill those cells. It's, you know, typically used for locally advanced melanoma, which cannot be respected, which is why I included it on this slide. And then at the bottom, you can see that a test Eliza map in combination with Kobe Met nib and demure Affin IB is our newest approved triplet therapy, which will discuss a little bit further and then on the right side of the slide that targeted therapies. There's three bereft inhibitors and three mech inhibitors, all approved in combinations that will go over as well. So it's important to remember how we got to all of these approvals. Andi really. During that era of futility that we looked at, there were two fundamental and translational discoveries made. And those discoveries ultimately, is what improved the way we treat melanoma patients today. And actually the way we treat so many cancers, um, that these scientific advances air now applied thio. So the first discovery on the left was that T cell activation is a highly regulated process, and T cell activation had previously been shown to require two steps a T cell receptor recognition of the anti gin and co stimulation through the interaction of antigen presenting cells with T cells. The discovery was what so called immune checkpoints are and immune Checkpoints carry this regulated process and exist at both the level of the T cell activation, as in the case with C T L a. Four, as well as the level of tissue tumor micro environment such as that PD L one and PD. One interaction that we talk about so frequently. But perhaps the most important of all of this discovery was that weaken therapeutically target these immune checkpoint inhibitors using monoclonal antibodies or immune checkpoint inhibitors, and they that is associated with clinical benefit. The second discovery on the right was the identification that melanoma is a genetic disease, and it's often characterized by driver mutations, the most prevalent mutations that we see RB, Ralf and Wrasse and N F one and these. These are each associated with increased signaling through the map kindness pathway, which is demonstrated here. So translating this discovery into the clinic is really what stimulated trials through both be Raph and Neck and the combination of bereft mech inhibition for a rapid reduction in melanoma tumor growth. So just a timeline of the approvals of immunotherapy so that you see them here. It's just so impressive how many approvals we've had over the last decade, ending with this 2000 and 20 most recent approval of both targeted therapy and immunotherapy. Combination patients have the option to be treated with mono therapy, one checkpoint inhibitor or the combination of two checkpoint inhibitors. So for those patients treated with one checkpoint inhibitor, we have fallen away from using just a pill Um, Ahmad by itself, anti c t. L. A. Four. Because of the toxicity and the lower overall survival, which has been demonstrated in multiple studies, including the one on the left here, we now use either Nivola map, ORP embolism app. As mono therapy and five year overall survival data for Pebble is, a map shows the 38% of patients who receive it are alive at five years. Patients who receive appeal. Um, Ahmad and Naval a mob At the five year mark, 52% of those patients are alive. Just an important caveat to know about these clinical trials is that they're not all designed to look at the five year data point. So some of our some of what we talk about is a post hoc analyses. And, um, they're also not all accrued at the same point in time. So some of them are from 2016. Some of them are from 2018, and so it's hard to compare them, even though that's what we dio. But the idea is to show that just how far we've come and how dramatically better we have we have, like our tools are much better to treat melanoma. Important to remember that immune checkpoint inhibitors are not without significant toxicities, and this slide just illustrates that nearly any organ or gland in the body can become inflamed with immune checkpoint inhibitors. Thes are what we call immune related adverse effects or i r. A E s. And there's been a lot of research dedicated to learning more about Ira es, for example, learning about the timing of when they occur in the course of therapy, how fast they come on once they're treated, which we usually treat them by holding therapy and starting immuno suppression. Do they recur after we stop immuno suppression? Do they overlap with one another? For example, we know that my oocytes and myocarditis air to immune related adverse effects that do overlap and create a very complex toxicity. We're also learning how to treat refractory cases. And as a result of all of this research that we've been doing on immune related adverse effects, we're learning about who gets these toxicities and how it affects their clinical outcomes. But there's still a lot of unknowns. What we do know is that the combination of epilepsy, map and naval a map has a high rate of toxicities. In fact, more than 50% of patients will develop a grade three or four toxicity. On the other hand, monotherapy with anti PD one will only have about a 15% chance of a toxicity of a great 34 toxicity. And if the lemon mob has has more toxicities than anti PD one mono therapy lesson, it believable again. We don't give it a much so we were focusing on the combo and anti PD one mono therapy. But the most important thing that we've learned is that early recognition and early intervention with immune related adverse effects is critical. So this is the timeline of approval of targeted therapies just showing that we had the approval of Dubrovnik plus traumatic up in 2014, then Kobe Metta plus venue Rafinha and then Uncle Ralf in it. Plus Binney, Matt Nip. And we know that these targeted therapies will have a will allow a rapid reduction in tumor burden once they start therapy once the patient starts therapy so they can be very effective for patients with symptomatic disease. They do have toxicities, including, um, significant fevers in in some of these combinations photo sensitivities, rashes that are dermatologists are very familiar with, um, there's also some chances of acute kidney injury, cardiac toxicity and ocular toxicities. Almost all of which resolve rapidly when the drug is held. So the newest triple therapy that it the newest therapy that's approved is a triple therapy that combines immunotherapy and targeted therapy. So the combination is of a test Eliza mob and then the be Raph Mac inhibitor combination of demographic. Him and Kobe met nib and rationale for this triple therapy came from patients who were being treated with Mech and be Raph inhibitor combinations. And they had biopsies early on in their therapy, and it showed in influx of T cells in their biopsy. So melanoma oncologists and scientists thought toe leverage that finding by adding in immune checkpoint inhibitor into the mix. So the idea was that they would create a much more long lasting or durable response that we get from immunotherapy in addition to the rapid reduction of tumor burden with targeted therapy. So basically the goal of administering all three drugs in combination again to reduce the tumor regression of tumors immediately, but then also with a long term response. So it really was a synergistic way of combining these two. These two classes of therapies and two studies looked at the triple combination. One was with the tassel is, um, emblem with chip embolism, both of which showed a prolonged PFS when added to targeted therapy. Again, we look at multiple toxicities, as you can imagine when you combine immunotherapy and targeted therapies and it starts to get kind of complex. And so these therapies are not easy to manage or to tolerate. So we're still learning the best way to utilize this regimen and which patients we might consider to be the optimal patients for the regimen. And finally, the last two slides air from our colleague Georgina Long in Australia, and what she's done here is she's overlapped, the progression free survival and the overall survival curves of the treatment regimens from several pivotal trials. Here we see the trials of Deborah Fun Image, Matt Nib Debian, Ivo Nevo alone and Pebble is a mob alone, and you can see that the curves air fairly close at the one year mark. But then his patients are living longer. Those who received the combination of Ebola Mob novel, a mob versus the mono therapy of Nivola map AARP embolism app will have a longer PFS even than those who received target therapy. And if you advance the slide, you could just see that the numbers there show that in the next slide. Similarly, this is again overlapping, pivotal trials so overlapping the curves from pivotal trials focused on just the overall survival curves. And even at the one year mark, you can see here that bottom line is it dilemma mob. And so those patients who received a pill, um, a mob The overall survival is far inferior to the other options, which is why we don't use it as much as monotherapy. The overall survival of the combination and you can advance the next numbers at five years was 52% in the combination of appeal Um, Ahmad. But Naval Ahmad versus 42% of those who received anti PD one therapy. And, as I said before, 34% Those receive targeted therapy. And this is that the five year mark. So in summary, how do we know how to treat our patients? Well, we know that immunotherapy can take a little bit longer to be effective, but the responses air often durable, and we have to watch for immune related adverse effects. The raft targeted therapy a beer after targeted therapy and mech unhip bitters have rapid reduction in the disease related symptoms, but the responses air not as durable. So ultimately, we make the decision of how to treat patients based on clinical factors, how much disease there is, what the performance status of the patient is. What's the spectrum of their cancer, For example, our their brain metastases, visceral involvement? Is the patient really symptomatic? And we take all that data that we know from the clinical trials and the ad hoc analyses, and we look at the patient in front of us, and we discuss these cases as a group in our melanoma tumor board. This is how we all became very close and we help each other because these cases are complex and the decisions of which therapies to use for these patients can be very difficult. Hopefully, in the future, we're gonna learn Maura about clinically useful biomarkers that can predict who will respond to certain therapies, the sequencing of therapies if we can adjust doses to minimize toxicities and maintain efficacy and so forth. But we still have a lot to learn, despite the incredible progress we've made in metastatic melanoma. So the next speaker is Lynch Hector, who is our amazing division chief and the head of the Tara Miller Center for Melanoma. And she's going to talk to us about the Covad vaccination in our cancer patients. Thank you so much, Justine. Um, it's unusual for me to be in a melanoma session, and I'm not speaking on melanoma. Um, eso and I hope that you can see me. Eso what I'd like to share with you before we open it up for questions is we've been working hard at Abramson Cancer Center to provide really the very safest environment for our patients to be receiving care during this time of cove it and also to protect all of us in the delivery of that care. So I'd like Thio touch on those topics tonight and then We've recently been reviewing the guidelines around covert vaccination for patients with cancer and sort of like to share that with you tonight next slide. So we're all have been in this together now, actually, a year. That is really hard to imagine, and our overall guiding principles of care during this time has been to deliver timely and high quality care to our cancer patients. And I know that the timely part of it has been really hard for a lot of dermatology practices and that you were, you know, had had to close for some of this time. So, um, this has been really challenging, and we recognize that the hardships that many of you have had in your in your own practice obviously we want to protect patients from a cove in 19 infection. So we're really creating safe environments as we deliver care. Um and then importantly, we know that patients with cancer who develop a cove in 19 infection do have increased risk of complications, morbidity and mortality, and so very focused on early recognition of potential Cove in 19 infection. And then again, to protect all of us as we're trying to care for patients next life. So I really want to focus my comments tonight on the rollout of the covert vaccine. Andi. Obviously, the goal is to vaccinate as many patients as quickly as possible on bond. People on the call tonight and on this meeting are in different states, and you're in different counties. And so this has been really challenging about the rollout of the current Thio Emergency use authorization vaccines, which has been the Pfizer vaccine in the Modern, which are the Marna, Covad, 19 vaccines. And so, as we've been implementing this, too, all of us to get vaccinated and as we think about our patients now, obviously we have to follow federal, state, county and city prioritization guidelines about who are the patients that are able to come in first to get a vaccine. This vaccine distribution and availability is really hard, and I know your patients are calling and they're registering and multiple sites, um, in order to get the vaccine, which is really hard. And then, you know, the current vaccines, especially the Pfizer, requires very specific storage requirements with minus 70 freezer. And so that really makes the distribution at some sites really challenging. And then the way we've been staffing this and again across counties and states is is a lot of volunteers, um, Thio staff these stations, and it's all staff people who can do registration pharmacists who can administer the vaccines. People are going to get the consent. People are involved with monitoring, so it certainly is an all hands on deck initiative, you know, across the states and counties. Next slide. So, at least for Pennsylvania and New Jersey, what we know is that for the phase one, and it's one B or one c dependent again about the county. But cancer has been identified in virtually every guideline as, ah group of patients that should be considered for covert 19, um, vaccination, because this tends to be ah higher risk group of patients again about complications from Cove in and then also those patients who are immuno compromised, either because of solid organ transplant, prior other kinds of transplants or being on medications. And many of you have patients who are on high dose steroids for other German geologic conditions or treatment. And these patients are increased risk for complications of covert and may be eligible for a vaccine next line and then in Philadelphia. Their guidelines have also been very specific about cancer, and again, each county and different states have different age requirements, but cancer and we've also identified sickle cell patients because their hypo splenic function are also at high risk for complications of covert. And so we've been able as we attempt to vaccinate patients in Philadelphia, patients who have sickle cell disease. Air also, um, qualified for vaccine for with Philadelphia and the Health Department, Um, and then staff, of course, that we've been trying to vaccinate all our staff who are encountering patients next line. So it's a lot to say that somebody with cancer has that. I mean that if you use that as the denominator, that's a very large number. And so some patients kind of cancer 10 or 20 years ago, some patients may have a very low risk cancer. Some patients may have basal cell or squamous cell skin cancer, so we have, uh, so just to say, cancer at a certain age, that is a large number of patients. So we have tried to come up with guidelines about who are really the highest risk patients that we should get in, and we should recommend the cove in 19 vaccines. And so we really focus on, well, who are the group of patients who are most at risk for complications of cove it and so that is, the older patient who has cancer is at higher risk for complications. And again, when I say complications, I'm often I'm referring to needing hospitalization oxygen, I see you care and then increased mortality in some cases. So what has been shown in a series of studies now over the past year is that patients who are receiving active therapy, whether that's chemotherapy, immunotherapy or targeted therapy seem to have increased complications from Cove A patients with advanced cancer. So that's metastatic cancer and, in general, patients with he mythological Eligon sees, regardless of whether they're on active therapy, Um, and regardless of their stage, this is a group of patients that seem to be at higher risk, particularly patients with lymphoma myeloma. And this is because of B cell dysfunction. And then patients with lung cancer have been identified in a Siris of papers that may have higher risk of complications that may be related to underlying pulmonary conditions, not clear and other therapies that may be receiving. But patients with lung cancer have been identified as higher risk. So as we've tried to stratify, we've really tried to focus first on this group of patients who are highest risk and that we would prioritize in a cancer population vaccines next life. So what we've recently put together and is on our website is an f A Q. About information for our patients. For providers. Um and so we are. Abramson Cancer Center is, um, consistent with other national international guidelines, including N c C N. Is that we have a very strong recommendation that our patients should receive Cove in 19 vaccine, um, and that the cove in 19 vaccine is safe and, as I mentioned, should be given to all cancer patients. But prioritizing first, those patients who aren't active therapy. Now the big question is what is the efficacy of the vaccine in patients who are receiving active therapy? Eso well, how robust is the immune system and patients who are on chemotherapy? So we obviously don't have data. None of the clinical trials of the currently, um, emergency use authorization vaccines enrolled patients who are on active therapy. Um, but if we extrapolated from other scenarios, so we've done actually hear a pen a number of studies in patients receiving a flu vaccine and looking at patients immune response on flu vaccine when there are active therapy, and in general we see a robust immune response, it may not be as great as somebody who has a fully intact immune system and is not on therapy therapy. But the consensus is that whatever immune response you would have, that it's certainly better than no immune, no immunization against Cove. It so we don't know, Um, data that one will have a robust response. But it's predicted, based upon other vaccine studies, that patients should mount a good immune response. Um, and then it should be safe as well. So again, we give flu vaccine and a lot of other vaccines to patients who were on concurrent therapy on DSO. Um, there is a recommendation while on active therapy to receive the vaccine, and they're really at this point, there are no guidance about timing off the administration of the vaccine to treatment. So we give sometimes the vaccine same days treatment, but depending upon again the availability. It could be a day 15 and a particular cycle. So on active therapy, including radiation therapy, chemotherapy, immunotherapy, etcetera Um, there are no data to suggest that timing matters. There are few exclusions related thio severe immunosuppression, like a bone marrow transplant patient. Also patients who've had a prior cove in 19 infection. The recommendation from the C. D. C. Is that those patients should wait 90 days before receiving the vaccine, and the idea is that they, like, likely have, um, I've developed an immune response and are safe for that period. And so idea also related thio the limited availability. But general recommendation is to wait 90 days from an act of Kobe 19 infection. And then there is also guidance, um, that if someone is having a large major surgery, that the vaccine should be two weeks post op and that may be related to the side effects of the vaccine next line. So you are aware of the vaccines because many of you have received your vaccine and you especially know that after the second dose of vaccine fever was a is a very common side effect. So the side effects of the vaccine fever rigors, muscle aches, flu like symptoms. This could be very confusing in our cancer patient population, where fever is often a very alarming symptoms, so again, very limited data. But this is guidance Aziz. We reviewed the data and from N, C, C. N, and other organizations that it seems it's reasonable to give the patients the vaccine even in the setting of neutropenia. Um, but of course this has to be individualized. And in a patient who, um, is neutral Penick, you might delay it, because again, the concern about fever in the Senate of neutropenia, that patient may need to come in for an evaluation to make sure that there is no bacterial infection. And in general, the volume of the vaccine is so low that patients with a low platelet count is likely to be a safe situation. It isn't. I am shot, but the volume is very low. We don't hold anti coagulation for this vaccine or for flu vaccine. And then the side effects, as I mentioned, just could be really significant. And I know some of the Panelists had temperatures of 102 after the after the vaccine and in sickle cell, which I won't go into tonight. But there could be some specific issues. And so again, patients with other conditions. This is a careful conversation with their provider next slide. So again we've worked Thio how to prioritize patients, and we worked with Pete Gabriel, and this is just a really interesting program where we can put in the risk factors for particular patient and then identify that group of patients who we want to invite in for vaccine. So what? We're currently using a similar strategy on using the Charleston morbidity scale and that identifies patients who at high risk. So I'm speaking about cancer tonight. But of course, patients with diabetes, obesity, chronic renal failure, underlying lung disease, thes air, high risk patients that are were now offering vaccine in Philadelphia at our Perlman Center, hoping that we're gonna be able to offer vaccine in our suburban sites on Ben. Many of you are also giving vaccine at your hospitals. I know mainline health and, you know, other health systems also working hard to get vaccine for their patients next life. So just thio end with a couple of more comments, which is that this has been a really hard year, and there are emerging data on the emotional toll of delivering care during this time of cove it and just for us to continue to be really mindful of the burnout for all of our staff, as we're trying to negotiate lots of complicated issues of working from home school schedules and just, you know, being at risk as you're providing care. This issue unknown impact of the covert variants, you know, as we move into this next phase. But just again for us to pause and recognize how hard this has been and as we continue to care for each other as we go through this and my final slide next slide is we've gone through this evolution of how we're delivering care during Cove it. And it's a very onset, just like in many of your practices. We were just shutting down and we were stopping. Screenings were postponing surveillance scans. We were modifying treatment regimens to make them or outpatient or to be have less toxicity so we would avoid hospitalizations. But we know that there is going to be a reckoning about the lack off survey, not so much surveillance but cancer screening for our patients. And Thean C. I. And Asko and other groups are really calling the alarm about what is going to have happened because of all the delay in screening. And I think in our own community we're worried about screening for patients with melanoma, and it feels like we're seeing higher risk patients lately with thicker primary melanomas. I think we're entering into this. I don't know if it's coated stable. We certainly have seen a decrease in the number of Covic positive patients, which has been great. There's been this huge shift to telemedicine, which has been, I think, one of the major silver linings and has been a fantastic way for us to deliver care. We're getting back to cancer screening programs, and this is really important. We're now vaccinating our patients, which is going to make such a difference, and then we'll enter into this future state where we have a better understanding of the impact off the modifications that we made at the onset. Um, you know, the effect that it's taking on the workforce, So I think we're in a reasonable state right now where we're all learning how to do this. But I think much to learn for the future. So I'll end there and I will turn it back over to Chris. Thank you, everyone for listening and joining. And again, it's just so for me, delightful that having my colleagues Justin Cohen and Tara Mitchell present on melanoma, and so that was really fun for me. So, Chris, turn it over to you Thank you. Thanks. Then I think Why don't we have all the speakers get their videos back up? As there were questions for everybody. And then since you just talked about covert Steve has asked the question if you have any more concerns about co vid vaccinations with the recent reports about onset or exacerbation of I t p. I didn't I didn't I saw that one case report I did did see that. So I'm actually not as up to date on, you know, mawr cases of that. But that certainly was a concern. And the timing of patient with I t p I don't know that one can predict it. So, um, if more patients have been identified than that would be added Teoh a consent form, certainly. But I don't think any issue off in patients with a history of I t. P causing a recurrence of I to be the patients that I'm aware of. The single the first index case was new onset. Great. Thank you, John. You had a question from Emily Chew. I think she was trying to highlight that there's a big difference in the complication rates between completion lymph node dissection which is no longer routine therapy versus sentinel lymph node biopsy. Can you comment about complications from sentinel lymph node biopsy? Absolutely. The major fear. You know the reason. One of the major impetus behind seeing whether or not we can forego completion Lymph node dissection was the dreaded fear of developing permanent lymphedema, which in the lymph node dissection trials was up to 20%. Whereas in Santa Little Biopsy it's an extremely safe procedure where we're not seeing clinically relevant lymphedema that remains permanent. Probably it's on or 1%. In fact, the more common complication that we see is the development of a Ciroma. And that's probably on the order of 5% in our patients that is actually relevant. So I would say, Take home is that it's extremely safe. It doesn't result in any long term complications, specifically, lymphedema, that is life altering. Great. Thank you. So those complications air local and surely not a deterrence to using this procedure? Absolutely. Um uh, sorry. You had a question from Dr Kaufman about whether you're using biomarkers to help determine which patients would enroll in neo A human trials. It's a great question. We're not using bio markers to determine enrollment, so enrollment is purely based on their clinical stage of stage, higher Stage two and stage three respectable. However, it's incredibly important in all of the new regimen trials that we collect blood and tissue data for biomarker analysis in an exploratory analysis, eso that we can, you know, learn Maura about which patients may be benefiting from therapy. So that's certainly part of the trials, but not part of the determination about eligibility. And Chris, can I follow up on the patient you presented? So I'm taking care of him and and first, the way we should get a picture of the after surgery because he's healed up so beautifully and the site looks really good. But he is such a good example of why the identifying patients who are at high risk stage to that we could get them on a clinical trial because, as you just all described, patients with high risk states, you melanoma, we cannot get them adjuvant therapy so FDA is not approved. Member lose a member novel amount for patients with stage two melanoma, so he had incredibly high risk melanoma for recurrence higher than stage three, so it is strange and are staging system that some patients with stage to have a worse outcome. The patients with stage three. So he was really eager to enroll his sentinel node did turn out to be negative, and so he we would not be able to have him on a German therapy. So I would, you know, for our Durham colleagues were on the call identifying patients with thick primaries that we could see them, You know, prior to sentinel note. I just think this is such a great clinical trial option for them because otherwise we don't have therapy for them. They're such high risk we can't. Insurance companies are not covering agreement therapy for stage two. Yeah, I'll follow up to emphasize for the dermatologists in the group to make sure they know which patients qualify for this. If the patient has a melanoma between two and four millimeters and is ulcerated or any melanoma greater than four millimeters, your patient could be enrolled in this new achievements clinical trial. Again. It's on Lee here at Penn, and no matter which of us you refer, the patients who were all looking thio improve outcomes for these patients so we will all get them Thio the oncology team to make sure they get treated. Um, Justine, there was a question for you. About what? What you think are some of the newer treatments in the pipeline that you and I are both highlighted. Some Maybe you wanna highlight one that you think is that you're really excited about s. So I think that the changing landscape and and the new combinations of immunotherapy and targeted therapies raise really practical considerations for MAWR clinical trials. And so this is really what continues to drive future research efforts. So if you ask me what's in the pipeline, I just always say enrolling patients on clinical trials is the best way to move this field forward. So specifically, a pen we and and Dr Mitchell and Dr Structure can chime in. But we have a couple of really amazing trials. So the neo adjuvant trial Dr Mitchell already explained, And then we also have a trial for patients who have the raft mutated melanoma in the metastatic setting. So we know, like I said, that patients who are on Barack mec in him bitter combinations, their responses are short lived and they almost all go on to develop resistance to drugs and experience disease progression. So we have a trial that combines hydroxy claure queen with Barack inhibitors to enhance the target. It did enhance the effects of targeted therapy and hydroxy Clara Queen blocks atop a G. The a Takaji pathway, which is really being studied by Dr Ammirati. And it's really an amazing pathway that cancer, like sort of cancer cells can recycle their building blocks and fuel growth. And so blocking that pathway along with the RAF inhibitors has a synergistic effect. We also have another clinical trial that combines the combination of appealabama, but Nivola map with radiation. So again, I think that combinations are are going to be really important and and enrolling patients in clinical trials. And so I would encourage everybody if you're if you're not sure, and even other oncologists in the community. If you're not sure if we have a trial and you have a patient with metastatic disease, always feel free to reach out. We can talk about them in tumor board, and we can hopefully enrolled patients because I do think that's the wave of the future. Yeah, you guys it's It's always fun to listen, Thio. Your whole team is because you're developing new trials and you have so many options available now. Tumor board. It's fun to see you decide whether which, which, which direction you're gonna send patients. And that communication makes a big difference. Um, John, this might be a good question for you. I know we discussed it frequently. I wish Emily Chew were on the call because I know she has great expertise in gene expression. Profiling. Um, I've talked with one of your colleagues, Gianvito from Oregon, who is using genetic expression profiling to decide which patients might you qualify for. Sentinel lymph node biopsy. How are you? What are your thoughts about genetic expression? Profiling. How are you using it right now? And where do you think it might be headed? Yeah, that's certainly a hot topic right now, especially for early stage melanoma. I think it's really an emerging, you know, adjunct. That is probably gonna provide a lot of valuable information in the future. I still think that it has not been rigorously tested in a prospective manner where we can abandoned center lymph node biopsy or use that as a way to identify when to perform sentimental biopsy because you know, one area that it has underperformed is in our thin melanoma patients where I think that's especially the group where we're trying to determine, Can we omit sentinel lymph node biopsy? But certainly I think it's an important adjunct that I don't commonly use that within my practice currently. And I don't think my partner, Dr Carrick uses does either. But certainly I think it does provide a lot of important information, especially for counseling and surveillance, and follow up for patients. But I know that there was some interest in now applying those results for who may undergo sent a local biopsy versus those that could admit it. Great, Lynn, you look like you wanted to say something. Were you going to say something about this? Well, the question was about indeterminant, but I would just say that in from melanoma really looking at whether tumor mutation all burden is a useful biomarker for predicting predicting response to immunotherapy, Um, and, uh, just lots of different markers that might be helpful in predicting response. So in melanoma, we don't look at PD l one expression to make a decision about treatment with immuno therapies. But we're hoping that some combination off in the future of PD l one expression Now there's PD l to to our mutation burden. Other things may help us select what is going to be the appropriate treatment. And I just Yeah, our Durham path colleagues certainly developing a lot of interesting essays, too. Both predict risk of recurrence and then predict response to treatment. Yeah, I think the question also highlights one of the strengths with the way the melanoma team here handles uncertain new treatments. For example, these clinical trials were done in a fashion where, when we introduce a new treatment, we're finding the evidence to determine whether it truly makes a difference. And that's something that you had, you know, the expression profiling lacks. Right now, um, it's we only have about a minute or two. So then I thought maybe you might wanna close up with Cem. Final comments for the group, Sure. I mean, I miss seeing people on dso. I really thrilled that you joined us tonight, and we I think this is the second we've done during this period and we love your feedback on doff their other topics that you like us to cover. We have our melanoma patient conference that is gonna be virtual this year. That's going to be in May. And so we'll get the word out to you. We're planning a larger melanoma conference in October. But I just think that I really enjoyed hearing my colleagues. I learned from them tonight and I just thank everybody for participating. And please send us your feedback and your questions. Thanks so much. SZ joining Good night, everybody.