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CME / ABIM MOC

A New Era of Progress for Melanoma: Leveling-Up With Immunotherapy

  • Authors: Michael A. Davies, MD, PhD; Charlotte E. Ariyan, MD, PhD; Kelly Nelson, MD
  • CME / ABIM MOC Released: 11/29/2022
  • Valid for credit through: 11/29/2023
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Target Audience and Goal Statement

This activity is intended for oncologists, including surgical oncologists, dermatologists, pathologists, surgeons, and other members of the multidisciplinary care team.

The goal of this activity is for learners to be better able to recognize treatment strategies involving immunotherapy being evaluated across the spectrum of melanoma and how they impact the multidisciplinary management of these patients.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Key clinical trial data evaluating immunotherapy-containing regimens for the management of patients with melanoma
  • Have greater competence related to
    • Individualizing care for patients receiving immunotherapy-containing regimens for the management of melanoma
  • Demonstrate greater confidence in their ability to
    • Coordinate with the multidisciplinary team in order to optimize care for patients with melanoma


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Faculty

  • Michael A. Davies, MD, PhD

    Professor and Chair
    Department of Melanoma Medical Oncology
    The University of Texas
    MD Anderson Cancer Center
    Houston, Texas

    Disclosures

    Michael A. Davies, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: ABM Therapeutics; Apexigen; Array; Bristol Myers Squibb; Eisai; Iovance; Novartis; Pfizer; Roche/Genentech; Vaccinex
    Research funding from: ABM Therapeutics; LEAD Pharm
    Contracted researcher for: Pfizer

  • Charlotte E. Ariyan, MD, PhD

    Associate Attending and Oncology
    Surgeon, Melanoma and Sarcoma
    Memorial Sloan Kettering Cancer Center
    New York, New York

    Disclosures

    Charlotte E. Ariyan, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Iovance; Merck
    Owns stock (publicly traded) in: Pfizer

  • Kelly Nelson, MD

    Professor
    Department of Dermatology
    The University of Texas
    MD Anderson Cancer Center
    Houston, Texas

    Disclosures

    Kelly Nelson, MD, has no relevant financial relationships.

Editors

  • Deborah Middleton, MS

    Senior Medical Education Director, Medscape, LLC

    Disclosures

    Deborah Middleton, MS, has no relevant financial relationships.

  • Yoji Yamaguchi, MA, ELS

    Scientific Content Manager, Medscape, LLC

    Disclosures

    Yoji Yamaguchi, MA, ELS, has no relevant financial relationships.

Compliance Reviewer

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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Developed through a partnership between Medscape and Society for Melanoma Research.



In support of improving patient care, Medscape, LLC is jointly accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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CME / ABIM MOC

A New Era of Progress for Melanoma: Leveling-Up With Immunotherapy

Authors: Michael A. Davies, MD, PhD; Charlotte E. Ariyan, MD, PhD; Kelly Nelson, MDFaculty and Disclosures

CME / ABIM MOC Released: 11/29/2022

Valid for credit through: 11/29/2023

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Activity Transcript

Chapter 1: Adjuvant and Neoadjuvant Melanoma Strategies

Michael A. Davies, MD, PhD: Welcome to "A New Era of Progress for Melanoma: Leveling-Up With Immunotherapy," segment 1: "Adjuvant and Neoadjuvant Melanoma Strategies." My name is Dr Michael Davies. I am professor and chair of the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, and I'm joined today by Dr Charlotte Ariyan, associate attending and oncology surgeon, melanoma and sarcoma, at Memorial Sloan Kettering Cancer Center. Thank you so much for joining me today, Dr Ariyan.

Charlotte E. Ariyan, MD, PhD: Oh, it's a pleasure to be here. An exciting time.

Dr Davies: So as you said, it is an exciting time because after many years of progress in patients with stage IV metastatic disease, over the last few years we've seen many of those advances now translate to patients with earlier stage disease. For patients with stage III melanoma, we now have 3 FDA-approved adjuvant therapies. Nivolumab, approved in 2017; dabrafenib and trametinib in 2018; and pembrolizumab in 2019. And then most recently in December of 2021, we saw the approval of pembrolizumab for patients with stage IIB and IIC disease. Now, as you recently discussed in an excellent way at ASCO® this year, the real question about each of these treatments is who are they really right for and when do we need to use them? So that's what we'll spend about the next 10 minutes talking about.

So let's start first with talking about stage IIB and IIC melanoma and the benefits and risks of adjuvant pembrolizumab. And so here are the graphs showing the impact of pembrolizumab on both relapse-free survival and distant metastasis-free survival. Dr Ariyan, what is your impression of the results from the trial?

Dr Ariyan: Well, I think it's a remarkable trial because it does definitely show an improvement, a statistically significant improvement, in both recurrence-free survival and distant metastasis-free survival, as you can see on the graphs. And although that benefit is statistically significant, the magnitude is about 8%. So I think we need to put this in a framework of where these patients are in stage II disease. And what we're really faced with or blessed with is when to use these drugs because they are effective not only in stage II disease, and but also in stage III and stage IV disease.

So if we were to put this in a framework of what we know about patients with stage II disease, we know about 40% of these patients will relapse. And the most common site for relapse is actually the lung. And again, the absolute benefit here is about 8% of giving adjuvant immunotherapy, but unfortunately it's associated with a toxicity rate about 17%.

And so that risk:benefit ratio is important to consider personally for the patients. And of course it could be worse for some patients than others depending on how severe the toxicity is. And one question to think about in the future is whether giving that PD-1 in the adjuvant setting, which may not have a benefit to the patient, but may preclude first further use of an immunotherapy in the future if there was some severe toxicity like myocarditis or something that would make everybody nervous about using immunotherapy in the future. And of course there is the financial toxicity to 1 year of treatment. And lastly, we don't know whether this is really going to benefit patient survival yet, because fortunately with melanoma we do know that we can treat at the time of more advanced stage of disease and still have the opportunity to cure. And this is different than other types of cancers.

Dr Davies: That's a really great overview. And the really interesting thing is that this usually ends up being a pretty long conversation with our patients because again, we can talk about what we do know, but have to acknowledge what we don't know. And this begins, then, joint decision making between the patient and the physician about what they value the most.Certainly think it's not a situation where we automatically treat all patients, but we have a detailed discussion about both the potential benefits and the potential risks in this context. And I think that also holds true when we talk about adjuvant therapy for patients with stage III melanoma.

So again, here we have 3 agents that are approved for adjuvant therapy for stage III melanoma, and as we look across those trials, there are some common themes. So particularly in those trials that have a placebo group, what we've seen now is that in each of those trials that about 40 - 45% of the patients on the placebo arm have not recurred after 3 to 4 years. These are patients we can only hurt with adjuvant therapy. We can't actually improve their recurrence-free survival more than not recurring. And we do know there's also the challenge that we still have in this stage III population somewhere around 30 - 40% of patients that are recurring on our current therapies. And so there's still this relatively narrow window of those patients who may benefit from this treatment. And so Dr Ariyan, when you have patients who have stage III disease and they ask you, "Should I get adjuvant therapy?", what type of information do you discuss with them in response to that question?

Dr Ariyan: Well, I think it's still the same framework, which is understanding what their risk is, which does vary across the spectrum for more advanced stage III disease and earlier disease; what our absolute risk reduction is, which is better in stage III disease. And then the toxicities, and lastly the salvage. And I think that's really important because often in stage III disease the recurrences are regional and can be salvaged through surgery of additional systemic treatments. So there is a salvage options often for these patients. And so it's very much a long discussion, but I think in general, and with broad strokes, the earlier stage III patients are led more towards active surveillance, and the more advanced stage III disease patients enter into some sort of treatment.

Dr Davies: And just to reinforce too, similar to when we talk about adjuvant therapy for stage II, at this point, we still don't have clear definitive evidence that giving adjuvant therapy for stage III improves overall survival, which is ultimately one of the goals of our treatment. So certainly again, there's the challenge of picking out who needs the therapy, but I think one of the other things that we've tried to address is how can we make adjuvant therapy more effective, because we know that our current therapies are still failing in a high number of patients.

We've seen in our field now with the development of systemic therapies that are much more effective than what we had in the past, starting to really investigate the use of neoadjuvant approaches and particularly neoadjuvant immunotherapy. And this is an area that both you and I have been participating in research. So maybe could you talk a little bit about why we think neoadjuvant immunotherapy may be beneficial for patients with high-risk stage III disease?

Dr Ariyan: Well, I think that this is an area that's really, really important, especially in the field of immunotherapy, because what we're hypothesizing with immunotherapy is taking the breaks off the immune system. If you have a tumor that has some cells around it that just are not effective enough to kill the tumor, maybe you want those cells there at the time that you give your therapy. And so with neoadjuvant therapy, when you are giving the treatment those cells are there to be released and unleashed by checkpoint blockade. And then once that happens and you have a nice immune response, then you're taking out the tumor. Whereas in adjuvant therapy, you're actually removing that tumor and maybe some of those important tumor infiltrating lymphocytes or other things that are there, then you're giving a systemic treatment. And so you're relying on there still being some immune cells around that can be unleashed to recognize the tumor. So theoretically it really makes sense to give the neoadjuvant therapy, but more perhaps importantly, is that this window of response after neoadjuvant is becoming such a powerful predictor of how people are doing. And I think we're finding safer ways to take these nodes out and have that very, very important piece of information.

Dr Davies: Yeah, I think it's a really critical distinction because when we do surgery and give adjuvant therapy, there's no way for us to measure whether the treatment's working. We can just see whether the cancer comes back or not. But it's been demonstrated very clearly in pooled analyses across multiple neoadjuvant trials that seeing evidence of a pathologic response to neoadjuvant immunotherapy is correlating with much better long-term outcomes. Now, one of the most exciting trials that's been conducted recently was the SWOG 1801 study that was recently reported at European Society for Medical Oncology (ESMO) meeting, which compared the clinical benefit of neoadjuvant plus adjuvant therapy vs adjuvant therapy alone. Do you want to discuss the findings and significance of this trial?

Dr Ariyan: Yeah, I think this is really remarkable. This was designed in the time where we were giving a single agent, so anti PD-1 blockade in either 3 doses before surgery followed by adjuvant therapy, or surgery first and then just adjuvant therapy. And so a great trial, although today some people might want to give a different combination in the neoadjuvant setting. But the bottom line is that there is a remarkable difference in event-free survival between patients who got the neoadjuvant vs the adjuvant anti-PD1. And this was a well-balanced trial with over a hundred patients in each group, and it was a 12 month 72% event free survival vs 49% event free survival favoring neoadjuvant therapy. And that's really remarkable.

And the overall survival is obviously not as impressive, but it's still trending in the right direction. And again, I think a lot of people want to wait for the overall survival to be significant, but I think understanding that neoadjuvant is safe and it's giving you a window into what's going on with the patient. So it's giving you more information than just treating adjuvant for a year blindly, if you will, and seeing such a strong signal of event-free survival that I think it really is changing the way we're thinking about this disease in stage III patients.

Dr Davies: Yeah, so I think it's, again, remarkable progress in a short period of time. Lots of new therapeutic options, but also lots of new questions. And I think, again, neoadjuvant therapy is an exciting new approach for patients with high risk regional disease. So thank you very much Dr Ariyan for this discussion today.

Dr Ariyan: No, thank you.

Chapter 2: Metastatic Melanoma: Long-Term Outcomes and Future Prospects

Michael A. Davies, MD, PhD: Welcome to "A New Era of Progress for Melanoma: Leveling-Up With Immunotherapy." This is segment 2, "Metastatic Melanoma: Long-Term Outcomes and Future Prospects." My name is Michael Davies and I'm joined again by Dr Charlotte Ariyan from Memorial Sloan Kettering Cancer Center.

Charlotte E. Ariyan, MD, PhD: Nice to see you. This is a very exciting time in the treatment of stage IV disease, and we've come so far from a survival that was so poor and a treatment that was really only surgery. So how are you prioritizing treatment today in patients with stage IV melanoma?

Dr Davies: It's a great question. And again, I remember the days when we had these very long and complicated conversations, trying to figure out how we were going to mix together ineffective therapies, to now a time when we still have long conversations, but it's because we have so many therapies to pick between. And so yeah, it's my pleasure to talk about how we pick between them.

And so just in terms of where we are, I still think the CheckMate 067 study, which took treatment naive stage IV metastatic melanoma patients and compared single agent ipilimumab, which was our first checkpoint inhibitor, to single agent anti-PD-1 with nivolumab, or combination immunotherapy with ipilimumab and nivolumab.

We saw follow-up that demonstrated that we really had about 50% long-term survival rate with ipi/nivo, which was, again, unprecedented in this disease. The median survival's difference between ipi/nivo and nivo was really only about 7%. So both of these treatments achieve long-term survival in many patients, balanced by the fact that where a single agent PD-1 is very safe and very well tolerated, whereas ipi/nivo has a lot of long-term side effects. So we still try to think about who are those patients who need that most aggressive treatment with ipi/nivo combination therapy. I think the clearest indication at this point are patients with brain metastases. Response rates for ipi/nivo in the 50 to 60% range are maintained in patients with asymptomatic brain mets, whereas for single agent PD-1, the activity's down into the 20% range. So that's a very clear indication for using the combination.

We actually now have the interesting question of a new player in the field. Which is to have the new combination of nivolumab and relatlimab that was approved earlier this year, based on the RELATIVITY-047 trial, which showed that it had superior response rates and progression-free survival versus nivolumab alone, with a very similar toxicity profile. So not the high degree of side effects that we see with the ipi/nivo combination. Now we don't yet have any trials that have compared the 2 combinations head-to-head, so we really don't have definitive evidence to guide us on how to pick between those. I will say for patients with brain metastases, we don't have any data yet for the nivo/rela combination.

And certainly, one of the other questions that is often frequently asked is for our BRAF-mutant patients, who can receive targeted therapy, is should they received immunotherapy or targeted therapy in the front-line setting. And that really again got a pretty definitive answer from the DREAMseq phase 3 trial. This took stage IV treatment-naive BRAF-mutant patients, and half of them got treated with the ipi/nivo combination, and half with dabrafenib/trametinib. If and when the patients progressed, they switched over to the other treatment.

In this trial, pretty remarkably, we saw a very significant difference in overall survival. At 2 years, the overall survival rate in patients who started with ipi/nivo was 72% and for those who started with dabrafenib and trametinib it was 52%, an absolute difference of 20%. And so with that, and although the trial didn't look at single agent PD-1, I think we really now have data to support the upfront use of immunotherapy in the majority of our patients with BRAF mutations.

We do have one other treatment option, which is triplet therapy with vemurafenib, cobimetinib, and atezolizumab, our first targeted therapy immunotherapy combination, which was approved in 2020. However, because the trial that led to its approval didn't have an immunotherapy comparator arm, it has an uncertain role in patients with stage IV disease at this point.

So the landscape is clearly quite broad at this point with many different options. And that idea of how do you again pick the optimal regimen for each patient, remains one of the challenges we have. The good part is we're choosing between multiple good options. And we do know that even if these agents don't work in the first-line, they often can be used in the second-line setting. Particularly, when we're thinking about the appropriate sequencing of targeted therapy and immunotherapy. So again, a long way from where we started, when we only had surgery as an option for these patients.

Dr Ariyan: It is a remarkable, remarkable thing. But even if you look at the CheckMate 067 with the single agent PD-1, or ipi, or the combination, a lot of people progress over time. Almost 70% of patients progress, and yet the survival's better. And so it suggests we're rescuing some of the people. So can you talk to a little bit about what we're doing? Most people are getting single agent PD-1 on the whole. And so, what do we know about secondary treatments after failure on single agent PD-1, and how do you kind of choose what to do in that scenario?

Dr Davies: Yeah, it's a great question. It remains really sort of the dominant challenge we have to overcome. So you're right, it really is about 70% of patients will progress on frontline immunotherapy. And so what do we do in the second-line? So we actually have a randomized clinical trial that looked at patients who had progressed on single agent anti-PD-1 and asked, "Do they have better outcomes if you just use single agent ipilimumab in the second-line setting, or should use combination immunotherapy with ipilimumab and nivolumab?" And as was presented at American Association for Cancer Research (AACR) Annual Meeting, we saw significantly higher response rates with the ipi/nivo combination and better progression-free survival. And we'd seen very similar results with an ipilimumab pembrolizumab combination. So for patients who've progressed on single agent PD-1, the combination of Ipi and anti-PD1 is an option.

I think the other therapy that's really shown impressive results in the second-line setting is tumor infiltrating lymphocytes. And this is where we start looking at how medical oncologists and surgical oncologists really are working together in the care of these patients. So if you want to talk a little bit about what TIL therapy is.

Dr Ariyan: Sure. Tumor infiltrating lymphocytes are these lymphocytes that are within the tumor, and patients come who have what we deem as resectable disease, and the tumor is removed. In general, you need about 2 centimeters of tumor, and then it is processed, and the tumor reactive cells are removed and expanded. And then once we have that, the patient's admitted for a cytoablative chemotherapy, and the tumor infiltrating lymphocytes are infused back into the patient in an expanded fashion, once they are lymphodepleted, and with some IL-2 or other growth factors to help. And I don't know, maybe there's been some very exciting data looking at that as well. So maybe you want to talk about that trial.

Dr Davies: TIL is a therapy that's really been in academic centers for a long time, led by Steve Rosenberg at the NCI. Over the last few years, we've actually seen a commercial product, Lifileucel, also called LN-144, which in a very large single arm trial showed in patients who had progressed on PD-1 alone, or on ipi/nivo, a response rate in the refractory setting of 36%. And what was most impressive is that almost all of those responses were lasting at least a year, and so durable responses.

At the ESMO meeting this year, a new clinical randomized trial showed in PD-1 refractory patients that TIL resulted in higher response rates and better progression-free survival compared to ipilimumab. So again, TIL is something that I think many of us are very hopeful will become more widely available for patients in the near future.

Now as we started off alluding to, there can be a role for surgery or local therapies in these patients. While we sometimes see patients progressing everywhere, there's clearly also a subset of patients with oligo metastatic progression. And at Sloan Kettering you and your team have led some investigations looking at the role of surgery in these patients, can you talk about some of that data.

Dr Ariyan: We looked at patients who were selected for surgical resection. And what we found is, if we categorize people by their response, not unlike how we're categorizing neoadjuvant patients by response, that resecting disease in patients who are otherwise responding to immune therapy but maybe had one tumor that was progressing, was associated with a survival of about 60%. So, better than what we would think. And I think our hypothesis is that overall, the immune system's working. One tumor maybe has had some selection to something that's not as accessible for the immune system, or maybe there's some other change. And surgical resection is a quite effective way to take care of that one tumor. And again, we've seen this in other tumors and other times, but I think in the setting of immune therapy, it's slightly augmented the potential benefit.

Dr Davies: A multidisciplinary approach is very important for those patients who have disease that's accessible, and we certainly discuss with our surgical colleagues the possibility of surgical resection. But we also think about intratumoral therapies or radiation as other local approaches, sometimes combined with immunotherapy as well.

Dr Ariyan: And I think this is a new emerging field as well, the idea that you could use this tumor as almost an in vivo vaccine for a patient. By injecting something into the tumor, a chemotherapy, a viral therapy, IL-2, other, anything that will cause some element of either cell death or immune activation, and allow the immune system to see it in a different way. And there's certainly a lot of excitement with that. And we've had approval of things like TVEC, which is a modified herpes virus, and is definitely shown to have response rates. I think the question for the future is how to integrate all of these different treatments into effective systemic therapies, and whether any of these treatments can really reverse some of the resistance we've seen to PD-1 alone.

Dr Davies: So I think the take-home message is, that while we've had tremendous progress in systemic therapies, this still remains a setting where a multidisciplinary approach can really benefit our patients.

Dr Ariyan: Absolutely.

Dr Davies: Very good. Thank you so much.

Dr Ariyan: Thank you.

Chapter 3: Practical Considerations for the Real World

Michael A. Davies, MD, PhD: Welcome to "A New Era of Progress for Melanoma: Leveling-Up With Immunotherapy." Again, my name is Dr Michael Davies and it's my pleasure to welcome you to segment 3, "Practical Considerations for the Real World." Our guest today is Dr Kelly Nelson, who is professor of dermatology here at the University of Texas MD Anderson Cancer Center. So Kelly, you and I have worked together on the care of many different melanoma patients.

I think it's natural that medical oncologists and dermatologists would really be partners in taking care of patients with melanoma at multiple different stages of their care. And so looking forward to talking with you today about the role that dermatology can play, how we interact together, and some real world tips for people.

Kelly Nelson, MD: Absolutely. I'm excited to chat as well. And when we talked about how to organize our approach for today, we thought that we would start with talking about how to manage cutaneous adverse events from immunotherapy, and then talk through some of these other parts of taking good care of melanoma patients together.

Dr Davies: Yeah, that sounds perfect. And so just leading off, in the last 2 segments, we've really talked about the impact that immunotherapy can have. First it was approved in patients with stage IV metastatic disease, but immunotherapy is now also approved in the adjuvant setting for earlier and earlier stages. And so therefore, more and more melanoma patients are receiving immunotherapy. And certainly, there's many different types of toxicities, but cutaneous toxicities are very common. Can you talk about when I refer a patient to you for cutaneous toxicity, what's your approach to the management of these patients?

Dr Nelson: My number 1 goal is to try to keep people on their therapy. And while we could spend an hour just talking about cutaneous reactions, I wanted to highlight 2 specific types of cutaneous reactions today. The first on the left are lichenoid drug reactions, and then the second, which is on the right, are immunobullous reactions. The lichenoid reactions, thankfully, we can treat people through. They don't have to pause their immunotherapy. We can start them on topical agents and then bump up to oral agents if needed. Low dose Acitretin or systemic retinoids can be really helpful at low doses to keeping people on treatment. The immunobullous on the right, this is a patient who had bullous pemphigoid. What's really notable about patients who develop bullous pemphigoid due to immunotherapy agents is that it can be subtle. These aren't the really big tense blisters that we learn about in medical school. It can just look like really rotten folliculitis. But if you have a clinical index for this happening in the appropriate patient cohort, you can diagnose it with a blood test for the anti BP antigens and then get them on appropriate therapy. Dupilumab has really been amazingly helpful in keeping these patients on treatment. Sometimes they need a pause, but we've started re-challenging more patients with immunotherapy, even after developing bullous pemphigoid, once they're under good control.

Dr Davies: So Kelly, just thinking again about these types of issues, rashes are quite common. What do you think is the threshold for a medical oncologist to really involve a patient's dermatologist in the management of these types of cutaneous toxicities?

Dr Nelson: I think if you're thinking about taking patients off treatment, call in your dermatology colleagues, because we have a lot of tricks up our sleeve that we can use to try to keep people on their therapeutic timelines so they don't have to pause or stop therapy altogether.

Dr Davies: That's great advice. And certainly, I know that we've had patients where, again, we've been at that threshold. And again, as you mentioned, with the assistance of you and your colleagues we've really been able to get toxicities under control and been able to continue treatment. Now, as we've also talked about in some of the other sessions, what we also fortunately now see with patients with melanoma treated with immunotherapy is long-term responses. And so another critical part of our interaction becomes the monitoring for disease recurrence. Because again, these are patients who start with melanoma in the skin, and certainly melanoma is a disease that can metastasize to the skin as well.

Dr Nelson: Right. And where I think we as dermatologists are particularly helpful is in detecting small diameter metastases that are primarily located in the skin, which is the left example in this picture. This was something that was not highlighted on this patient's re-staging scans, but what I found through my examination of him. The other part where we're particularly helpful is in highlighting what can be fairly subtle local recurrence. On the right is a picture of a patient who had recurrent amelanotic melanoma, where it had been thought that maybe he had a rash around his excision site, but it was actually his melanoma coming back.

And so we as dermatologists can be really helpful in the careful examination of patients, using dermoscopy to try to help identify these when they're subtle and early, as opposed to later stage down the road.

Dr Davies: And certainly a key point to this too, again, as a medical oncologist, we lean very heavily on our imaging modalities and positron emission tomography (PET) scans and computed tomography (CT) scans, but we're now often talking about lesions that won't show up on those types of scans. And so again, really reinforcing that a good skin exam is part of the monitoring that we have for recurrence in these patients.

The other interesting feature that we do sometimes see is not so much necessarily recurrence, but these patients are also at risk of developing new primary tumors. We do see many patients presenting with multiple primaries over time. Can you talk about your approach in patients with melanoma who've been treated with immunotherapy, how you look for and maybe even distinguish between metastatic lesions versus new primary tumors?

Dr Nelson: Right. So for patients who've had one cutaneous melanoma, 10 to 12% of them will have a second. The good thing is, if they're plugged in with dermatology, we can often find that second primary earlier than their initial presentation. So when we're looking for a second primary melanoma or for the development of keratinocytic carcinomas, like the 2 basal cells pictured on the right here, it's really, again, coming back to that foundational full skin examination as really the cornerstone of finding these.

For complex patients, like the patient on the left, you can see an amelanotic melanoma that I found through just a routine examination for a follow-up patient who had metastatic melanoma. For complex patients, total body photography can be enormously helpful in detecting change early, while also not having to remove a whole lot of normal moles from patients to find those second primary melanomas. But for the patient on immunotherapy, they can certainly make new primaries even through their immunotherapy treatment. So the immunotherapy isn't sufficient to fully protect them from making a second primary while they're on treatment.

Dr Davies: So I think it's always one of the take-home messages we have with our patients, including those who are now rendered free of disease, either in the adjuvant setting or the metastatic setting, is that cancer surveillance is a really important part of their care. Again, we really are excited about the durability of responses that we've seen with immunotherapy, but certainly, we know for any new melanoma that pops up, the best strategy is to diagnose them as early as we possibly can.

Dr Nelson: And for patients who may have had one primary melanoma but are covered in profound sun damage and are making a lot of squamous cell or basal cell skin cancers, we as dermatologists have things we can use in the chemo prevention area for those types of skin cancers. It's just good to know that we can use oral nicotinamide, we can use topical fluorouracil. There are things that we can do to try to reduce that burden, especially at the actinic squamous cell type of skin cancers, so patients have a better quality of life.

Dr Davies: So Kelly, one of the other frequent questions that I get from my patients is actually not just concern about themselves, but about their family members and particularly their children. Can you talk about how you counsel melanoma patients about the risk that their family members may have, and what are strategies that they can utilize to reduce the risk of being diagnosed with melanoma?

Dr Nelson: Absolutely. This is something that we talk about a lot with our patients, not only due to just concern for their family members, but also because this is something they can actually control. And so there's a lot of reassurance that goes into taking action on some of these fronts. One of the things that we talk about is germline mutational testing or testing for inherited melanoma risk.

We usually look for a patient who's had 3 invasive melanomas or 3 family members on the same side of the family who have had invasive melanoma or pancreatic cancer. The testing panel has expanded. These guidelines are in a bit of a transition phase right now, but they're much more broadly available than they used to be.

The second thing is, when do I start getting my children checked? We usually recommend having children get that first skin examination as they approach puberty. Childhood melanoma is an entirely different ball of wax than grownup melanoma. We could spend a whole hour just talking about that. But really, the risk starts to accrue with that transition into puberty. And then primary prevention or just being safe with your skin is the things that we regularly talk about in terms of trying to go outside earlier or later in the day, wearing sun protective clothing, wearing high SVF sunscreen, all the things that can really reduce your risk of skin cancer, but also just reduce the cumulative aging burden on your skin overall.

Dr Davies: Well, Dr Nelson, I think that's a great overview. Again, I think this addresses a lot of the questions that we hear and ask ourselves on a daily basis. And so thank you again so much for participating in our series today.

Dr Nelson: It's my pleasure. Thank you.

Dr Davies: Thank you very much for participating in this activity. Please now proceed to the post test.

This transcript has not been copyedited.

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