Dr Jeffrey Weber on the Staging of Melanoma and Choosing Treatment Options

Jeffrey S. Weber, MD, PhD, spoke with The American Journal of Managed Care® (AJMC®) about how treatment options have improved for more advanced melanoma cases and the role that genetic mutations play in choosing therapy. He is the deputy director and head of experimental therapeutics, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, in New York.

AJMC®: I'd like to start our conversation off talking about some baseline specifics about melanoma, in particular staging. How is this disease staged? Really, when we're talking about more advanced melanomas like stage III and IV, what does it mean to have those levels of melanoma?

Weber: Melanoma historically has always been staged into 3 categories. Remember, this idea of staging cancer is to group the tumors or pigeonhole them into categories by outcome and prognosis. In melanoma, almost, not all, but most melanomas are cutaneous. We also, of course, have ocular melanomas that begin in the eye. We have mucosal melanomas that begin in the mucosal tissues. The nasopharynx, the pharynx; the urethra, anus, anorectal area. Those are pretty rare. We're talking a thousand or so a year, maybe or more in the United States, but the vast majority, 95% plus, of melanomas are cutaneous.

When we stage melanoma, we think of, is it in the skin, and of course, that means at the epidermal-dermal junction where the primary melanomas of the skin begin. Has it escaped the skin and become locoregional disease, meaning it's in the area around the primary tumor or it's gotten into the draining lymph nodes, or has it disseminated distantly. The higher the stage, the worse the outcome. Patients with early-stage IA and IIB melanoma tend to do very well. Those are very curable lesions. IIA, IIB, and IIC begin to have a significant chance of metastasizing or spreading and potentially causing the death of the patient. Stage III, IIIA, B, C, D, those patients have locoregional disease generally in the lymph nodes, although they can be not in the lymph nodes, they could be, say, in an adjacent soft tissue part of the body near the original primary in the skin.

So, let's say you had a primary on the arm, on the forearm. A locoregional disease would be if you had a lesion on the upper arm, it spread in the limb but not disseminated distantly to other parts of the body. Then stage IV melanoma, meaning it's spread at a distance, not in the area of the draining lymph node. If it started on your left arm, if it's on the right arm, that's definitely stage IV because the right arm is not a lymph node draining area of the left arm, I assure you. However, most of the stage IV patients are in the lungs. Distant lymph nodes, liver, brain, bone, adrenal, other what we call visceral areas, and that’s stage IV disease, and that is when there's a significant likelihood of killing the patient. We obviously do not much more than surgery for the early stage I melanomas. For the stage II melanomas after surgery, we now have, for the stage IIB, IICs adjuvant immunotherapy. For the stage IIIs, we have both adjuvant immunotherapy and targeted therapy after surgery and I should add most stage III patients are resected to render them free of disease, so they get surgical removal. Stage IV, you generally don't resect them, although it could happen if it's an isolated metastasis, especially, in the lungs or the lymph nodes. But most of those patients get what we call systemic therapy and that could be immunotherapy or it could be so-called targeted therapy, which is generally oral and rarely, thank God, these days, we use chemotherapy which, again, is just not commonly used much anymore. Radiation can be used, especially for brain metastases and sometimes for palliative purposes for local disease.

Let's say, you have a thick primary melanoma stage IIC and you remove it from the scalp. You can't get under it very well, you have a positive deep margin. Those patients would get radiated after surgery and then they would potentially go on to adjuvant immunotherapy. But that's how we stage it, it's really by location and by outcome. The most important factor that determines staging is how can you group it by outcome, meaning good, mediocre, bad.

AJMC®: When you talk about these patients who are being staged, how often do you see a patient walk into your office, newly diagnosed melanoma who has early stage, you know, I or II, versus those who might present with later stage? Is it common to see people coming in with a later-stage melanoma?

Weber: Remember, the early-stage melanomas, these stage Is and the stage IIs are operated on by the surgeons, so they get seen by the dermatologist. They get sent to our excellent surgeons. They will do the surgery and almost all those patients get some operation. Then the stage IA, IB, IIAs, we never see because their outcome, frankly, is very good. Their chance of dying of melanoma across the board is 10% or less, so they get followed by the surgeon and the dermatologist. These days, because we now have adjuvant therapy that's FDA approved for a IIB and a IIC resected patient, we then get them sent by the surgeon or dermatologist to us. Of course, we see all the stage IIIs and the stage IVs. Sometimes, the stage IVs will come directly to us. As an example, yesterday, I saw a patient who had been to his pulmonologist because he has emphysema, and got admitted and had an X-ray that showed a surprising finding adjacent to his liver, an abnormal mass. It was biopsied, everybody's surprise, it was melanoma. In retrospect, he had melanoma 8 years ago on the skin that was removed by the surgeon. This is what you call a late recurrence. But he came straight from the pulmonologist, he didn't come from the surgeon or the dermatologist. Sometimes, we'll see patients straight from initial workup by an internist, or a pulmonologist, or a cardiologist, and surprise, surprise, they turn out to have an abnormality and it turns out to be melanoma. Most of the time, for us, we get them from the surgeons after surgery.

AJMC®: I'd like to ask you a little bit about the outcomes. You touched on for some of these patients with a stage III or stage IV melanoma. What are the 5-year survival rates looking like for this disease right now? How we ended up where we are in terms of the outcomes in melanoma?

Weber: Take us back 20 years, or actually not even 20, take us back 12 or 13 years. The 5-year survival in metastatic melanoma across the board was about 10% or maybe even a little less, about 8%. That was almost all the patients who had isolated metastatic lesions that were surgically removed and they potentially could be cured. That's pretty poor, 8%-9% survival at 5 years, not very good, that takes us back, just take us back to 2010. After 2010, beginning in 2011-2012, drugs that were really effective began to be approved for melanoma. There have been 3 sets of targeted therapies, totaling 6 drugs. There's T-VEC, the injectable. There's 2 different PD-1 antibodies. There's 2 separate combinations of antibodies. We have a lot of new drugs that are approved for melanoma. In the right scenario, half of those patients will probably be alive to probably cure it in 5 years. In reality, only about 35% to 40% of patients will be alive, doing well and potentially be cured of melanoma past 5 years, of those who have stage IV disease. If you're in that select category, where you can get the most aggressive therapy, that number could be pushed up to 50%, but as of yet not everybody gets the most aggressive therapy, not everybody can tolerate it. I would say a safe bet is about 35% of patients have the chance to be cured, by being alive and free of disease at 5 years. Again, in the CheckMate 067 study which has the longest follow-up at 7 years, the median survival in those patients was 6 years. That's a phenomenal figure, that means half alive, half dead at 6 years. ¹ That's better than colon cancer, that's as good as breast cancer, that's better than prostate cancer, that's a phenomenal thing. That admittedly is all those who got the most aggressive therapy. Like I said if you put everybody together, that number could be 35% but that beats 8% or 9% which is what it was back in 2010, so we've made a lot of progress. But anybody who tells you the melanoma problem is licked, they're not looking at the data and they're absolutely unequivocally dead wrong. There's still a major unmet need in patients with metastatic disease, even in patients with stage III resected disease, so we've got a long way to go to cure this disease in a comprehensive manner. Can we cure many patients? You bet. We do very well but still a long way to go. The stage IIIs, probably 70% of them will be alive and doing well in 5 years across the board. The early-stage IIIAs, 90% plus cure rate. The stage IIIC, IIIDs, 50% to 70% cure rate but the stage IVs, it's probably on the best day about 50/50.

AJMC®: In order to leverage perhaps the best outcomes in some of these patients with advanced melanoma, we want to get them on targeted therapies. There are therapies that will work the very best for their unique disease and that typically involves some molecular characterization of their melanoma. Can you walk us through how your institution conducts this characterization and at what point in the disease process is it done?

Weber: For everybody who has stage III disease [or more advanced], at the time of surgery, as a default we send off a gene panel of about 50 genes. This has just been updated to 500 genes, and [its use will start] literally in the next few days. We get a 500-gene mutation panel; it takes 2 weeks to do. But if it's done at the time of surgery, the patient will need at least that amount of time to recover. If we see a new patient with metastatic disease, we'll send it off. But as you'll hear in a moment, having that information will have no immediate impact on most, not all, but most patients at the time they present with stage IV disease. We have a pretty good molecular characterization. We usually don't do Foundation [Medicine] testing because we have our own panel. But let's say we were in the community, and we didn't have our own gene panel, we would send Foundation [Medicine] testing on those patients at the time of surgery. Now, how do we use that information? Interestingly, it's more useful in the short term with the stage III patients than for the metastatic stage IV patients. It turns out that whether you're BRAF mutated or not, immunotherapy will be your first treatment of choice. Because when BRAF mutated patients were tested in a large trial of almost 400 patients called the DREAMseq trial, that was quarterbacked by a guy named Mike Atkins from Georgetown. ² If you randomly allocated patients to get immune therapy first then targeted therapy upon progression or targeted therapy with the BRAF/MEK drugs, 1 of the 3 combinations. Then if you progressed, you got immunotherapy. Survival was clearly superior if you got immunotherapy first. Now, almost all of us knew this a priori, but Mike did the almost impossible. Actually, [this was] a very well-conducted study and has definitively shown that, for almost all patients with metastatic melanoma, your first treatment should be immunology. That's not to say that targeted therapy isn't very useful. That's what you keep in your back pocket to use if immunotherapy doesn't work. That's in stage IV melanoma. Stage III melanoma, interestingly, no one's ever done an adjuvant study, comparing adjuvant targeted therapy to adjuvant immunotherapy. I don't think that's ever going to get done. But if you look at the data and try to compare apples to apples, actually BRAF targeted adjuvant therapy looks just about as good as adjuvant immunotherapy. Interestingly, in the first year, the patients actually do better in terms of their relapse-free survival. We don't have any comparisons of overall survival yet. That'll be very interesting to see. But the urban legend was that the adjuvant targeted therapy patients would do well for a certain amount of time and then they would relapse more quickly than the immune therapy patients. The relapse-free survival curves would be higher in the first year and then lower in subsequent years for the targeted therapies, lower than the immune therapy. That ain't the case. Again, you're comparing 2 different trials. But if you compare them and superimpose them, they look really close. The 5-year relapse-free survival for an equivalent stage patient population is really close for targeted therapy and immune therapy. Therefore, a lot of us in the field will take the low-risk patients and put them on targeted therapy, which has a higher chance of overall toxicity and discontinuation but a very low risk of permanent side effects, in preference to using immunotherapy, which has fewer side effects overall, less chance of discontinuation but more permanent side effects. So you do this risk-adjusted thing. I'll admit, I have colleagues who only use targeted therapy for adjuvant treatment. I will risk adjust it and for the low-risk patients use the targeted therapy, immune therapy for the higher-risk patients. There are various and sundry explanations we don't need to go to in detail to justify my position, but I acknowledge that there are arguments either way. Yet in metastatic disease that's not the case. Almost no one's getting targeted therapy upfront in metastatic treatment unless you have rapidly growing high LDH, high tumor burden, symptomatic disease, in which case we'll give 8 weeks of targeted therapy to shrink the tumor and then move on to immune therapy.

AJMC®: You touched on how a BRAF mutation might impact your treatment versus those who do not have that mutation. Is there anything else you'd like to add? Perhaps, you have a patient who has non-mutated melanoma. How does your approach differ for those 2 patients?

Weber: If it's metastatic, there will actually be no difference in their frontline treatment. Of course, in a BRAF wild-type patient, if you're a BRAF wild-type and you fail frontline immunotherapy you got a problem. You don't have any obvious effective targeted therapy to move on to. Those patients will tend to go on trials. They might get tumor-infiltrating lymphocyte therapy, which will, we hope, be approved sometime by the end of the year. We'll see if that happens. That can be an effective therapy for those who fail immunotherapy, typically BRAF wild-type patients. Again, in the stage III setting, the way it guides your treatment approach is, if you're BRAF wild-type and you have early-stage III disease, the only option you have is adjuvant immunotherapy. That's a conversation with the patient about whether it's worth the potential of permanent side effects. In the mutated population, a lot of us will give the low-risk patients just the targeted therapy. But if it's BRAF wild-type, not an option of course. That's a tough conversation with the patient and they have to accept the potential for toxicity, even though their risk could be modest, modest being a 25% risk of relapse in 5 years. If somebody has an 80% risk of relapse in 5 years, I feel perfectly comfortable putting them on adjuvant therapy when they're BRAF wild type, not a problem. I think almost all patients who have stage IIIB and IIIC disease which are in IIID disease, that's resected, should get adjuvant therapy, no question.

AJMC®: We have a few different options available both for targeted therapy. For immunotherapy now in our armamentarium against melanoma, what are some of the patient or disease-related factors that you consider when ultimately choosing which specific therapy you're going to put a patient on?

Weber: As we briefly mentioned, if someone has rapidly growing disease that's BRAF mutated with a high LDH, I need to cytoreduce them because immunotherapy is not going to work. I'm going to give them a brief course of targeted therapy. The problem there is, in the targeted therapy arena, at the end of the day, over time the patients who do worst are the ones with the biggest burdens. Even though it's useful to debulk, it's not useful to keep them on targeted therapy because they're going to crash and burn. They may do very poorly. So we get the maximum initial benefit out of those first 8 weeks and then we'll switch to immune therapy, which we would do at a time when the tumor burden is lowered by the use of the targeted therapy. Again, like targeted therapy, if you start the immunotherapy have a lower tumor burden, you're probably going to do better than if you have a higher tumor. We'll give that first 8 weeks but it's got to be a patient with high tumor burden disease. If someone has an allograft transplant, a transplanted kidney, heart, liver, we pray that there'll BRAF mutated. Because the last thing you want to do is give them immunotherapy and have them reject allograft, so that's a tough one. In fact, we'll operate, we'll use chemotherapy. We'll do anything to avoid giving them immunotherapy. Imagine if it's a heart transplant and your back is to the wall. You only have immunotherapy. You reject the heart transplant? You're dead. That's a real problem. Those are the nightmare scenarios. People with active autoimmune diseases like rheumatoid arthritis, systemic lupus, Sjogren’s syndrome that's systemic, that's a real problem. Those patients you're going to give targeted therapy too if they're if they're BRAF mutated, and you hope and pray that they're BRAF mutated. Because if they're wild type, you don't have a lot of options.

The patient with rheumatoid arthritis, or lupus, or whatever, or scleroderma, that's become very systemic and widespread, when they're BRAF wild type, you got a problem. When they're BRAF mutated, you'll generally going to want to avoid immunotherapy for as long as you can. It's the allograft transplant patients, it's the autoimmune disease patients, we try our best to give them targeted therapy, not immunotherapy.

AJMC®: Do you have any closing thoughts around managing melanoma or these actionable mutations that we have and at our fingertips today? Anything that you find noteworthy you'd like to share with your colleagues?

Weber: The actionable mutations, ironically, I think better serve us as adjuvant therapy than metastatic therapy. That being said, in the neoadjuvant space, meaning you are giving treatment before surgery to cytoreduce it, make the surgery easier and potentially do or give less adjuvant therapy. Actually, there's some interesting data that will come out at ASCO about combining targeted and immunotherapy. Neoadjuvant therapy, I should add, it doesn't work well with targeted therapy, it works much better with immunotherapy, so go figure. Neoadjuvant therapy is a bit of the thing of the moment, a lot of investigators are evaluating its utility. You can give neoadjuvant ipilimumab and nivolumab for 2 cycles and you can get a very high rate of complete disappearance of the locoregional tumor. Of course, it's only given for locoregional disease and you then have surgery, which is simpler and much lesser disease. Some of those patients then have gone on to get no further adjective therapy and they haven't relapsed. So the ability to create a pathologic complete response in a palpable nodal patient is probably a marker for a very sensitive tumor that doesn't need any further treatment. We would reserve the further adjuvant treatment for those who don't have a pathologic complete or near-complete response. In addition, there are some very interesting observations that I've made here—again small numbers—but we've treated patients with adjuvant immunotherapy after surgery, they progressed, could be re-resected again rendered free of disease because the recurrence was locoregional and then they would be BRAF mutated, so the subset, of a subset, of the subset. Then they went on adjuvant dabrafenib and trametinib and, interestingly, we're 6 for 6. Nobody's relapsed. I've called around the world to the 20 usual suspects who are key opinion leaders in melanoma, and a lot of them feel that may be the case. We're going to collect a bunch of cases of these patients and see whether my initial observation holds true. That's another interesting scenario for targeted therapy.

Would it work the other way? Good question. It would be nice to collect from other institutions the patients who fail adjuvant dabrafenib and trametinib, and then get re-resected when they recur, then get adjuvant immunotherapy. You wonder whether they'll do just as well but we'll see. Those are some of the interesting questions that we face. I guess the final message is, "Boy, we made a lot of progress." Keep in mind, 8% or 9%, 5-year survival to 35% to 40% 5-year survival across the board, is a huge increase. In the patients who get most aggressive therapy which can be toxic, ipilimumab and nivolumab, they have immediate survival in 6 years, almost no cancer, that's metastatic is as good as that. We've made a lot of progress. But anyone who says we've got it licked, frankly needs their head examined because that's not the case. I wish it were the case. If it were, I'd be out of business. I could retire and go be a docent at a history museum somewhere but that's not gonna happen for the remainder of my career. I think we'll continue to make progress slowly but steadily and eventually lick this disease, but it's not there yet.

References

1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. JCO. Published online November 24, 2021. doi:10.1200/JCO.21.02229

2. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq: A phase III trial—ECOG-ACRIN EA6134. ASCO Plenary Series. Abstract 356154. Presented November 16, 2021.