Deciding the right time for treatment

By Emily Margosian, Assistant Editor, May 1, 2025

“The melanoma landscape, especially in the last decade or so, has changed remarkably in ways I never thought I would see in my career,” said Vernon Sondak, MD, chair of the department of cutaneous oncology at Moffitt Cancer Center. “Now even in the most advanced cases — patients with widespread melanoma, brain metastases, conditions we never thought we could really impact at all — we’re routinely getting very strong responses to treatment.”

Thanks to modern systemic therapy, outcomes for many patients with advanced metastatic melanoma have dramatically improved. The success of these therapies has attracted much scientific interest as immunotherapy has made its way into the treatment of earlier stages of disease. However, most recently, these therapies have gained traction in the neoadjuvant, preoperative setting.

Surgery has long been the mainstay of melanoma treatment, especially in dermatology. As new research emerges, how does neoadjuvant therapy followed by surgery compare with upfront surgery followed by adjuvant therapy? Could neoadjuvant immunotherapy eventually replace the need for surgery altogether? This month, experts discuss the latest research and implications for melanoma care.

Progress in melanoma outcomes

Since 2011, 11 therapeutic agents have been approved by the FDA for patients with metastatic cutaneous melanoma. “The introduction of immunotherapy and targeted therapies goes back nearly 15 years. Since then, we’ve seen this rapid explosion of new agents come into the market,” said John Miura, MD, assistant professor of surgery at the University of Pennsylvania.

“A decade ago, a large clinical trial was done called the CheckMate 067 trial. It compared three different kinds of immunotherapy: two single agents — the anti-CTLA-4 drug ipilimumab and the anti-PD-1 nivolumab — given separately, or the combination of both given together,” recalled Dr. Sondak. “We now have 10 years of data from that study, and among the patients who got the single agent anti-PD-1 as their first treatment, more than 40% of them are still alive. Of the ones who got the combination, about 50% are alive 10 years after getting started on treatment for metastatic melanoma. This is remarkable.”

Evolution of adjuvant immunotherapy for melanoma

Adjuvant therapy — treatment after successful surgery in patients who are at a high risk for recurrence — has been of interest to cancer researchers for many years. “Our mainstay of treatment in the early years of my career was interferon. It had some benefits, but a lot of side effects and a limited impact on survival. It was sort of kicking the can down the road and hoping that when the can finally came to rest, maybe we’d have something better. Lo and behold, now we do,” said Dr. Sondak. “We found that the anti-PD-1 drugs, nivolumab and pembrolizumab, could decrease the risk of the melanoma coming back with less toxicity than interferon.”

The success of adjuvant immunotherapy prompted the question: could treatment be just as effective at earlier stages in patients with a high risk of recurrence? “What we’re learning is that not all early-stage melanoma patients have the same long-term prognosis. In fact, while surgery with or without sentinel lymph node biopsy remains the focal point for their treatment, a lot of patients will still recur. It’s a sobering fact,” said Dr. Miura. “These are often patients with thicker melanomas. These, before surgery, are any melanomas greater than two millimeters in thickness with ulceration or greater than four millimeters in thickness irrespective of ulceration status. Even among these patients that have negative lymph nodes, many will have a long-term prognosis that parallels some of our stage III patients who have known lymph node involvement, highlighting a very aggressive underlying tumor biology.”

“It’s great to know that, for patients who present at a later stage or recur despite treatment, we have some really successful options.”

In 2017, the FDA approved nivolumab and pembrolizumab for the treatment of earlier stage melanoma. “What they were able to demonstrate in these landmark studies is that the addition of immunotherapy in the adjuvant setting decreases relapses, which is excellent,” said Dr. Miura. “As it currently stands, adjuvant therapy is approved for stage IIB, IIC, as well as stage III patients. There is an ongoing clinical trial right now looking at adjuvant targeted therapy for stage II patients, but that hasn’t been reported yet.”

Despite the success of adjuvant immunotherapy, its true impact remained unclear. “A lot of people were being exposed to treatment, but we don’t know who is directly benefiting because we’re giving it to everyone. That led us right into the concept of neoadjuvant therapy,” said Dr. Sondak. “Neoadjuvant therapy meant turning this process around. Instead of surgery first, let’s use the drug or drugs first while the tumor is still there, and find out if it’s working so we aren’t giving the patient side effects after surgery for nothing.”

Advantages of a neoadjuvant approach

In the last few years, immunotherapy for melanoma has been gaining traction in the neoadjuvant setting with promising results.

“A lot of the impetus behind the neoadjuvant approach arose from our understanding of how immunotherapy works,” said Dr. Miura. When you have an intact tumor in place, the abundance of neoantigens on its surface has the potential to generate a stronger signal to elicit an immune response. That resulted in a lot of interest about how we sequence our treatments.”

Recent clinical trials have supported the advantages of neoadjuvant therapy for melanoma. A 2024 study in the New England Journal of Medicine found neoadjuvant immunotherapy to be more efficacious than adjuvant immunotherapy in patients with stage III melanoma, resulting in longer event-free survival with 83.7% in the neoadjuvant group versus 57.2% in the adjuvant group.

“What was exciting about this particular trial, was that in the neoadjuvant arm, patients who received ipilimumab plus nivolumab for two doses at the time of surgery, reported a nearly 60% major pathologic response rate,” explained Dr. Miura. “What’s also interesting about this trial was that if you had a major pathologic response or a pathologic complete response, the trial design was created such that you didn’t receive adjuvant therapy afterwards. It was a very tailored approach that was dictated by the tumor’s pathologic response.”

“We now have two major randomized clinical trials that show it was substantially better to give the immunotherapy first and do the surgery later,” said Dr. Sondak. “When I say better, I mean you are more likely to be alive and free of disease if the drugs are given earlier rather than after surgery in the standard adjuvant approach. Doing better is obviously the goal, but it’s more than that. We can give less treatment and stop treatment after two or three doses of ipi/nivo or pembrolizumab versus a year of treatment, which is what we were doing with adjuvant treatment.”

Re-examining the extent of surgery

The success of neoadjuvant therapy has raised questions not only about the timing and duration of immunotherapy, but also the extent of surgery.

“On top of all those positives of neoadjuvant therapy, we’re starting to ask, ‘Well, if it’s really working out well, can we do less surgery? Can we scale back the extent of the operation that we’re doing?’ Usually when I see a new patient with metastatic melanoma in their lymph nodes, they say, ‘Get this out of me right now!’ But I reply, ‘not so fast,’” said Dr. Sondak. “If this hypothetical patient who shows up with an enlarged lymph node and a melanoma on their back has a good response to two or three doses of immunotherapy, they might get a smaller wide excision than they would have otherwise, and only a single node removed when before they would have had a complete node dissection.”

“This isn’t science fiction; this isn’t the future. Nearly every single day in our clinic we consider this approach to neoadjuvant therapy for advanced disease. ”

This represents a significant paradigm shift, according to Dr. Sondak. “If the pathologist concludes that everything is dead in that single “index” node specimen, then the patient is done, and no further treatment is required. They’re not only done with treatment, but they’ve got a very good chance of having been cured by just that limited intervention. This isn’t science fiction; this isn’t the future. Nearly every single day in our clinic we consider this approach to neoadjuvant therapy for advanced disease.”

However, for earlier stage disease, surgery will likely remain the mainstay treatment, according to Dr. Miura. “Typically for stage I cases, especially for thin melanomas, surgery is extremely effective and can often be achieved by just a simple excision. What limits neoadjuvant therapy’s broad application is its overall toxicity. Surgery for early-stage disease is pretty low risk and can be extremely effective. Would I omit that and say just give me immunotherapy? For me personally, no. I’d say please give me the excision.”

Ultimately, more research is needed to determine the extent to which surgery may or may not be scaled back following neoadjuvant therapy. “Obviously we’re excited about neoadjuvant therapy, but there is plenty that we need to learn. We don’t want to go too far and leave cancer behind in people who otherwise might have been cured by an operation,” said Dr. Sondak.

In practice

While neoadjuvant and adjuvant therapy for melanoma show immense promise, several critical questions persist.

“How do we make cross comparisons among all these different trials? I don’t think we’re ever going to have a head-to-head trial out there that compares these different regimens, because the landscape is constantly changing so quickly,” said Dr. Miura. “Which one do I choose? How many doses do they need? Can we hold off on adjuvant therapy if they have a favorable response? These are the questions I wrestle with.”

Dr. Sondak agrees that further research is needed. “Many studies were in patients who never had any previous immunotherapy. Increasingly, we have patients who are still good candidates for a neoadjuvant approach but have had immunotherapy before. We need to know a little bit more about those patients. There are also people for whom this approach just isn’t possible. For example, those who have had an organ transplant. We still want to improve our approaches for patients who need an alternative to neoadjuvant immunotherapy. Its success has raised the bar, but it hasn’t gotten everyone over the bar. Going from 5% long-term survival to 50% long-term survival is amazing, but that still leaves the other 50% who aren’t surviving. That’s a huge group and we still need to find answers.”

“We still want to improve our approaches for patients who need an alternative to neoadjuvant immunotherapy. Its success has raised the bar, but it hasn’t gotten everyone over the bar.”

Physicians must also weigh the overall benefit of therapy in the context of the individual patient.

“I don’t think it will ever be something that’s given to all melanoma patients, because we have to think about the risk-benefit calculus. If you’re just looking at relapse-free survival, it gets smaller as you move to earlier stages. In that case, the toxicity of the medication may outweigh its benefits, and I don’t think that’s something we can justify,” said Dr. Miura. “There are so many different regimens out there that have been studied with neoadjuvant therapy. What is the best one? Yes, a dual checkpoint blockade of ipilimumab and nivolumab results in the highest complete response rates, but at the same time it’s also associated with the highest toxicity. How do we factor that into the decision-making?”

Takeaways for dermatologists

While questions remain, researchers agree: the future is full of promise. “Neoadjuvant therapy is helping our patients and it’s clearly here to stay,” said Dr. Sondak. “Dermatologists are often the ones following the patient who may have had a melanoma removed a year or two ago or even much further in the past, and now notices a lump in their armpit, groin, or neck. We want you to know that the next step isn’t to send them off to the surgeon to have it all removed, because if the tumor is out, then it’s back to adjuvant therapy. It’s not that it doesn’t work, but neoadjuvant is an approach that we think works better and gives the patient advantages. It’s important for dermatologists to at least be aware that this concept is out there, and that these approaches need the tumor to be intact so that they can advise patients appropriately.”

As always, early detection is the best defense. “From a dermatologist perspective, as good as these treatments are, if you can find melanoma in situ, the chance of survival skews closer to 99%,” said Dr. Sondak. “Obviously, we don’t intend for a minute to discard the importance of early detection and treatment at earlier stages, but it’s great to know that, for patients who present at a later stage or recur despite treatment, we have some really successful options.”

Additional DermWorld Resources