Latest Advances in Melanoma Treatment

In this interview, The Dermatologist met with Dr Vernon Sondak to discuss his recent session, “Update on the Latest Advances in Treatment of Melanoma,” at the 2023 AAD Annual Meeting.

Vernon Sondak, MD, is chair of the department of cutaneous oncology at the Moffitt Cancer Center and Research Institute in Tampa, FL.

The Dermatologist: What are the latest advances in melanoma treatment?

Dr Sondak: We've really been living in an exciting time and there have been lots of advances in melanoma treatment in the past 10 years for people with very advanced metastatic melanoma, what used to be an essentially incurable disease with an average survival of about 9 months and 75% of patients dead within a year of being diagnosed with stage IV disease. [This diagnosis] has been transformed by new treatments such as immunotherapy, especially combination immunotherapy using several drugs at once or targeted therapy for patients who have a BRAF mutation. Now we're seeing the average patient live 3 to 5 years after a diagnosis of stage IV disease, with more than 60% 5-year survival if they have a BRAF mutation. Clearly, the implication of that is if we use these same effective treatments earlier, we could potentially get even better results.

There has been a lot of interest and research in the last few years on how do we use these drugs earlier? Now I think what we're seeing is the use of immunotherapy but also BRAF-targeted therapy before surgery is done. And I think the single biggest bombshell, if you will, in the last few months published in the New England Journal of Medicine, was a randomized trial in which every patient got surgery for operable, resectable, node positive stage III disease and adjuvant postoperative immune therapy for a year, but half the patients got 3 doses of the immunotherapy before surgery and the rest after. The others got the exact same surgery and all their treatment afterward. And the ones who got just 3 doses of what we now call neoadjuvant immunotherapy before surgery did much better than the ones who got all the immunotherapy afterward. So, it isn't just the drug, it isn't just the surgery, it's the timing of the surgery and the timing of the drug in relation to it. Is this because the immune system is better able to react and attack the tumor when the drugs are administered, with the tumor still there in a large mass? Perhaps. Is it because the surgery itself is suppressing the immune system a little bit? Perhaps.

And in addition to being better for the outcome, you have the incredible advantage of being able to take the tumor out and look at it under the microscope and see that with only 3 doses of drug, 20% to 30% of the time, the cancer is totally dead. It has completely responded to treatment. And those patients who have a complete response do much better than the average stage III melanoma patient. Now, the study I've been talking about used standard single agent anti PD-1, just 3 doses, and got, as I said, about 20% to 30% pathologic complete responses. If we use more aggressive combination immunotherapy, there are more side effects, but many more pathologic complete responses, 40% to 50% of the time. I just did a node dissection today on a patient who'd had combination immunotherapy and had a lot of side effects. But the tumor shrank dramatically, half the size of what it was before he started the treatment. In the operating room, when I took that tumor out, it was dead. It was yellowish, white, cheesy. I've never seen a melanoma look like that. This is what dead cancer looks like.

There are 2 [future] directions. Use it even earlier. Are there some patients with stage II melanoma that we might use immune therapy before or after surgery or both? Are there some people where if they get a great response like this patient did, they might not need all their lymph nodes removed and they might not need a year of treatment? If the patient I operated on today who had several doses of combination immunotherapy really and truly is found by the pathologist to have no residual viable tumor, he will not get any more treatment. So instead of a year of immunotherapy after surgery, he's going to get zero immunotherapy after surgery and only a few weeks of immunotherapy before surgery. Not only does he have less treatment, but he also has less side effects. We can tell him, "This is great news, we know exactly what this did and here's why you don't need more treatment." Of course, if it didn't work, if it continues to grow or we still see a lot of viable tumor, then we can say, "Okay, we need to continue or we need to change plans. Maybe try a BRAF inhibitor and alter what we're doing." So the ability to treat before surgery is a tremendous advance in and of itself just because of all the information we get and how it allows us to potentially steer the treatment after surgery. But now we know that just giving the drugs ahead of time is good as well.

I think surgeons around the world had this fear. Melanoma, it grows quickly. If we don't let the person go straight to surgery, bad things are going to happen. In fact, it has turned out to be the opposite. It is better to wait and gain that treatment benefit, gain that information from the pathologist, and that's the direction we're going. And, as I said, we're taking it even into earlier cases. We did a study in which patients with desmoplastic melanoma were treated even before it got into lymph nodes. Stage II disease on the scalp was treated with just 3 doses of single agent anti PD-1. And 55% of the time, not 20% to 30% like in the nondesmoplastic study, the desmoplastic melanoma was totally gone.

We're seeing remarkable results. We've got to figure out exactly when, exactly how, to do this and what to do about it. But what's clear is that we are transforming the way we think about melanoma treatment, using drug treatment earlier, even before surgery in many cases, and someday maybe instead of surgery. Already in the desmoplastic melanoma patients, these were patients who would normally get radiation and they're not needing to have radiation because of the success of the drug treatment. Is that a good trade? Is it better to get 5 weeks of radiation or 6 weeks of immunotherapy? We're going to have to find that out. And there are certainly going to be individual patients, maybe it's not better to give them drug treatment. Maybe it's better to give them radiation. But this is opening new doors and really changing the way we're thinking about treatment.

For the dermatologist, though, one thing must be kept in mind. The best treatment for melanoma is still when we can diagnose it early and treat it early. And that is surgery alone. We don't need any of these drug treatments, and that cures melanoma most of the time. Another big area of study in those early melanomas is looking for predictive signals. Is there a way we could predict which melanomas are going to spread, which melanomas are going to come back? And treat them differently even with the surgical approach? And I would have to say we aren't as far along there as we are with the drug treatments. There are gene expression profiles. Some of them are commercially available and being heavily marketed directly to dermatologists. We don't use them, we don't recommend them. We are testing them in a prospective clinical trial. We're leading a national trial of over 2000 patients targeted to get a sentinel node biopsy and all of them will get a piece of their original melanoma biopsy submitted for a gene expression profile that was designed specifically to predict which cases would or would not spread to the lymph nodes.

If we can show that some people don't need a sentinel node biopsy, we can make their surgical treatment easier and limit the amount of surgery people need. But I'll tell you that we think this is a high bar. To change that kind of practice, we need prospective studies. That's what we're doing. We have over a thousand patients on this study already. So, we hope within a year to a year and a half to have enough patients to really learn whether a gene expression profile can at least predict who might or might not need a sentinel biopsy.

The Dermatologist: Can you go over the key points from your session?

Dr Sondak: The key points, number one, early detection, early treatment, still matters. Even with a 60% 5-year survival for stage IV metastatic disease, no dermatologist is going to go back and tell their patients in the office, "Oh, don't worry, it's only melanoma. I'm not going to biopsy it. Come back when you've got widespread metastatic disease and then one of those oncologists will cure it." No, obviously point number one, early detection still matters. Early diagnosis and early treatment are still better. And what we're trying to do is refine our understanding of early melanoma, identify the early melanomas that might be at highest risk and, in a sense, make the punishment fit the crime. Balance the amount of surgery with the risk a patient has. But key point number two, today, the standard approach of surgery wide excision and sentinel lymph node biopsy is still the best treatment for RT1B, T2 melanomas.

Today, we don’t use any other gene tests or other predictive tests to decide who should and shouldn't have sentinel node biopsy. Once they have a sentinel node biopsy, if the node is positive, there's clearly a role for immune treatments or BRAF-targeted treatments to decrease the risk of it coming back. For very thick melanomas, T3B and T4 melanomas, even if the sentinel node is negative, there's a role for some of them to get immunotherapy. But even in those T3B and T4 thick melanomas, the sentinel node biopsy is still helping us decide exactly what kind of treatment and is decreasing the need for lymph node dissection. And the final key point is when it does already get to an advanced stage, whether it's an advanced stage II desmoplastic melanoma or a palpable stage III melanoma of any histologic type, earlier treatment with immune drugs before surgery is really showing some positive benefits. So, early diagnosis, still treated aggressively early on, and multimodality treatment, combined treatment with surgery and drug therapy. Clearly better than either one alone.

The Dermatologist: Is there anything else you would like to share with your colleagues about treating melanoma?

Dr Sondak: I think the overarching point I would make is that we've gotten these great results. We've made these big improvements by working together, dermatologists, surgeons, plastic surgeons, medical oncologists. This is still a team sport. It's still a team process. We're not at the point where anybody should be saying, "Oh good, I don't need the other guys anymore. We're doing so well, I can just take care of this." The more we work together, the better it is for our patients. Are there some patients who just need a dermatologist and a simple excisional melanoma? Of course. But for most of our melanomas today, a combined team approach is still the best. And, of course, whether it's a melanoma in situ or a very advanced stage IV disease that has a great response to immune therapy, they're still at risk for other cancers of the skin. I always say, "The sun didn't shine on just one place." So that surveillance, sun avoidance, protecting your skin, going to the dermatologist, is if anything more important now than ever.

Reference
Sondak V. Update on the latest advances in treatment of melanoma. Presented at: AAD Annual Meeting; March 17–21, 2023; New Orleans, LA.