Melanoma Treatment: More Options, More Time

In August 2015, when Carter announced he had been diagnosed with melanoma that had spread (metastasized) to his liver and brain, the prognosis seemed grim. Yet, just months later, Carter announced he was cancer-free. After the standard protocol of surgery and radiation, he had been treated with pembrolizumab (Keytruda), a newly approved immunotherapy drug that empowered his immune system to target and destroy the cancer cells.

Carter’s recovery seemed miraculous, but for those diagnosed with melanoma his story was inspiring. And for doctors, it was a vivid illustration of how far melanoma treatment has come – and how far it could still go.

Melanoma remains a serious concern; it is the fifth most common cancer among American adults, and the rate of new cases rises each year. But the death rate from melanoma, adjusted for age, has fallen by an average of 2.8% each year from 2014 to 2023, according to the National Cancer Institute.

Oncology Improvements: Dr. Leonard Henry, cancer surgeon and medical director, Nancy and J.C. Lewis Cancer & Research Pavilion at St. Joseph’s/Candler

“I think in cancer care… this might be the most stark and glaring [example of] how much different and how much better the outlook is for patients,” says Dr. Leonard Henry, a cancer surgeon and medical director of the Nancy N. and J.C. Lewis Cancer & Research Pavilion at St. Joseph’s/Candler in Savannah.

“So all this [innovation] in the last 10 years has absolutely exploded,” he says. “If you were a practicing cancer surgeon 20 years ago and then time warped to today, it would seem all different.”

For many people, it is a difference between life and death.

From Carter’s case to current clinical trials, melanoma treatment today is no longer just about fighting a deadly disease – it’s about living with it, and often beyond it.

“There’s no stage in melanoma now where I would tell a patient that it is automatically a death sentence,” says Henry. “That’s not to say that everybody is cured. That is not the case, but there is a significant percentage of people even with Stage 4 disease who are living years with the disease – sometimes in complete remission.”

Melanoma 101

Melanoma accounts for only about 1% of skin cancers in the U.S. but is the deadliest form of skin cancer because of its propensity to metastasize. Most melanomas begin on areas of sun-exposed skin, although they can occur in hidden spots like the soles of the feet, under the nails or even inside the mouth or eyes.

Two other kinds of skin cancer – squamous cell carcinoma and basal cell carcinoma – are more common but less deadly. They are named for where the cancer starts – in the outer layer of skin for squamous cell cancer and the inner layer of skin for basal cell cancer. Both rarely spread to other areas of the body, unlike melanoma.

Melanoma is often discovered during a skin exam or when a person notices a new or changing mole, says Dr. Zachary Buchwald, assistant professor of radiation oncology at Winship Cancer Institute of Emory University. Despite its reputation, it is rarely fatal if found and treated early.

“Cancer cells are remarkable, and they can turn your immune system off – sort of saying, ‘Ignore us; we’re OK. Don’t come and fight us; don’t come and kill us.’” – Dr. Paul Dale, chief of surgical oncology at Atrium Health Navicent Anderson Cancer Center

“Surgery is almost always the first-line treatment for melanoma and the vast majority are early stage, treated surgically,” says Henry. In fact, in about 80% of cases, melanoma is found early enough that surgical removal followed by routine surveillance is enough.

However, the prognosis is worse once the cancer spreads beyond the original site. Deeper or more aggressive tumors – particularly those that invade lymph nodes or are found in distant organs – need more intensive treatment. Today, that treatment usually consists of drugs that help the person’s own immune system kill cancer cells, such as the ones Carter received.

Lasting Remission: Dr. Paul Dale, chief of surgical oncology at Atrium Health Navicent and medical director of the Peyton Anderson Cancer Center. Photo credit: Matt Odom

Harnessing The Immune System

Not long ago, the prognosis of advanced melanoma was grim because traditional chemotherapy was not only notoriously weak in fighting it, but made people very sick in the process, says Dr. Nikita Amin, a medical oncologist and hematologist at the Piedmont Cancer Institute, a private practice affiliated with Piedmont Hospital in Atlanta.

The outlook began to change with the advent of immunotherapy, which revolutionized melanoma care by targeting the disease in a completely different way.

Most of the time, your immune system keeps you healthy by attacking and killing any invading cells that might make you sick. “Cancer cells are remarkable, and they can turn your immune system off – sort of saying, ‘Ignore us; we’re OK. Don’t come and fight us; don’t come and kill us,’” says Dr. Paul Dale, chief of surgical oncology at Atrium Health Navicent and medical director of the Peyton Anderson Cancer Center. “So the cancer is sneaky, and it turns your immune system off well.”

Drugs such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy) target certain “checkpoint” proteins in the body that act like brakes on the immune system. Blocking these immune checkpoints releases the brakes, allowing the immune system to recognize and attack cancer cells.

Fighting Cancer: Dr. Nicole Kounalakis, far left, medical director of the melanoma and skin cancer program at Northside Hospital Cancer Institute, with her team: Ingrid Davenport, medical assistant; Elena Schroeder, front desk associate; Kristen Andino, medical assistant; and Courtney Robinson, practice coordinator. Photo credit: Kevin Garrett

“These drugs have made a significant impact on survival in our patients who present with metastatic disease,” Dale says.

In fact, before the advent of immunotherapy for melanoma, the five-year survival rate for advanced melanoma was 5% or less. With the use of immunotherapy, five-year survival has increased to approximately 50%, according to the Cancer Research Institute.

In many cases, people get immunotherapy after surgery to stop the cancer from coming back. People who have more aggressive cancer may get immunotherapy before and after surgery.

“If a patient has a reason to … meaning they have more advanced or aggressive disease, they will get immunotherapy,” says Buchwald.

Depending on the situation, one immunotherapy drug may be used alone (monotherapy) or with another immunotherapy drug (dual therapy).

“The main situation where dual therapy is used is when patients have metastatic disease,” Buchwald says. “So in those circumstances, assuming the patient is healthy enough and able to tolerate it, most of the time, they’ll get dual immunotherapy.”

For some people, this approach leads to lasting remission. One large 2024 study tracked 945 patients across 137 sites in 21 countries and found that about half of people treated with a combination of immunotherapy drugs survived cancer-free for 10 years or more. It also found no significant health effects from taking the drugs for a long period of time.

Turning to Targeted Therapies

For most people, immunotherapy drugs work to control melanoma, but they aren’t effective for everyone. Some tumors develop resistance to the drugs, while others may not respond at all. For these people, another powerful tool exists: targeted therapy. Targeted therapy targets and kills cancer cells, usually by honing in on a protein or pathway the cancer cells use to grow and spread. It’s a more focused treatment than chemo, which kills cells that are rapidly dividing – that includes cancer cells but also some healthy cells.

For example, about half of melanomas have changes (mutations) in a particular gene called the BRAF gene. Those changes can cause the BRAF protein to become overactive, leading to uncontrolled cell growth.

“We check on all of the advanced stage melanoma patients for the BRAF mutation because that is another tool in the shed for medical oncologists for melanoma treatment,” says Henry.

For patients with the BRAF mutation, treatment often involves a combination of drugs that inhibit the BRAF protein and help slow tumor growth. These drugs are called BRAF inhibitors and include vemurafenib (Zelboraf) and dabrafenib (Tafinlar).

Another kind of drug, called an MEK inhibitor, targets a protein called MEK that also regulates cell growth. The MEK gene and the BRAF gene are connected: When the BRAF gene is mutated, it can cause the MEK protein to be overactive, which can make tumors grow. MEK inhibitors, such as trametinib (Mekinist) and cobimetinib (Cotellic), are often combined with BRAF inhibitors and work better than either drug alone for people with BRAF-mutated melanoma.

Genetic testing is typically done on a biopsy specimen and results can help guide personalized treatment decisions, often within days.

“You have to test the tumor for the mutation,” says Dr. Nicole Kounalakis, medical director of the Northside Hospital Cancer Institute melanoma and skin cancer program. “It’s not prognostic – meaning that if you have that mutation, you’re better off cancer-wise – but it does make you eligible for a different treatment.”

Future Treatments

Researchers are developing next-generation treatments that use a person’s own immune system in more precise and personalized ways. “The more we learn about the disease itself, the neurogenomics and molecular data of these cells, and as our technology improves, we’re able to do things that focus on the individual’s cancer and the makeup of their tumor,” says Amin.

Such treatments include the following:

Tumor-infiltrating lymphocyte (TIL) therapy: TIL is a kind of immunotherapy that uses the body’s own white blood cells (T cells, or lymphocytes), to kill cancer cells. Doctors remove a tumor where the lymphocytes are already inside and attacking the cancer. They collect the TIL cells from the tumor and grow more of them in a lab. Then the TIL cells are put back into the patient’s body to fight other cancerous tumors. TIL therapy is available at a few cancer centers in the U.S. including Northside Hospital in Atlanta, which was the first hospital in Georgia to offer it in 2024.

“You send the tumor to the company and they make a treatment that helps fight the cancer,” Kounalakis says. “You’re actually making T cells – immune cells that can fight the patient’s cancer.”

Amin considers TIL therapy as perhaps the biggest breakthrough in melanoma treatment. “TILs have been showing very promising responses in the treatment of advanced melanoma,” she says.

The first TIL treatment, lifileucel (Amtagvi), received accelerated FDA in 2024 for people with advanced melanoma that progressed after standard immunotherapy. TIL therapy may be especially beneficial for people whose tumors don’t have common mutations or those who have exhausted other treatment options.

Melanoma vaccines: After the success of mRNA technology in developing COVID-19 vaccines, companies like Merck and Moderna are applying it to cancer treatment. An mRNA vaccine that is still in clinical trials is customized to each person’s specific tumor and cancer cells, teaching their immune system how to recognize and kill the cancer. The vaccine has to be created in a lab for each individual. In the clinical trials, it has significantly reduced the chance of the cancer coming back in people with high-risk melanoma, especially when it’s combined with Keytruda.

TCR-T cell therapies: T cell receptor-engineered T cell therapies are another form of personalized cancer treatment that uses a person’s own T cells. Doctors collect T cells from the patient’s blood and send them to a specialized lab, where they are engineered to help them better recognize and attack cancer cells based on unique features of the tumor. One such therapy for melanoma is being studied in clinical trials.

With the use of immunotherapy, five-year survival has increased to approximately 50%, according to the Cancer Research Institute.

Advances in Surgery

While many studies focus on developing new therapies, others are exploring how different surgical techniques – and even the timing of treatment – can influence effectiveness.

For example, Buchwald says there are studies happening now to see if smaller margins – the removal of less healthy tissue around the tumor – can be used when removing a tumor. For areas such as the face, where a large incision would be disfiguring, some doctors are using Mohs, a precise step-by-step surgical technique developed for non-melanoma skin cancers that preserves as much healthy tissue as possible. In a Mohs procedure the surgeon removes thin layers of skin and immediately examines each under a microscope. If the layers still contain cancer cells, the surgeon removes more layers and repeats the process until no cancer cells remain.

Other research is examining whether the timing of treatment – that is, the time of day the treatment is administered – can lead to better results. Buchwald and his colleagues published a paper in 2021 that compared responses of patients who got infusions of certain immunotherapy drugs at different times of the day.

“The idea is that the immune system that’s getting triggered by those drugs may be triggered better at one time of day versus another time of day,” Buchwald says. “Some of that work was based on vaccination studies that showed that vaccinating folks for certain ailments earlier in the day may stimulate their immune system better than later in the day. We knew this, and so we looked at that in our patient population at Emory.”

As it turned out, patients had better responses to the immunotherapy and lived longer if they got more infusions early in the day, he says. But he adds that the study was retrospective, meaning it looked back at patients who had already been treated to see if the time of day they got treatment mattered. That’s not the same as the “gold standard” of a randomized clinical trial. Buchwald says he and a colleague are beginning a trial that would randomize patients to various treatment times to better understand the difference timing makes.

The growing menu of treatments continues to transform melanoma care, from a field once defined by limitations to one marked by optimism.

For people seeking the most advanced options, the Georgia Center for Oncology Research & Education (www.georgiacancerinfo.org) has a searchable database of clinical trials.

Protection is Still Best

Despite the remarkable gains in treatment, all the experts agree: Sun protection and early detection remains the best defense against melanoma.

“Use sunscreen with SPF over 30,” Dale says. “Avoid sun during the peak hours and wear a hat and sunglasses. Especially children — they are in and out of swimming pools – reapply the sunscreen. That’s very important. The data shows that if you have three blistering sunburns in your lifetime, you increase your risk of getting skin cancer.”

Dermatologists recommend the ABCDE rule for spotting suspicious moles:

• Asymmetry
• Border irregularity
• Color variation
• Diameter larger than a pencil eraser
• Evolving shape, size, or color

People should be looking for new moles or freckles of changes in existing ones, says Dale. “If people are concerned about something on their body that is changing, it probably deserves a biopsy.”

Kids Get Melanoma, Too

While melanoma is one of the most common cancers in teenagers and young adults, the disease is extremely rare in children under 10. Fewer than 500 cases are diagnosed each year, says Dr. Sarah Mitchell, pediatric oncologist at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta, which treats one or two cases a year.

Treating Children: Dr. Sarah Mitchell, pediatric oncologist at the Aflac Cancer and Blood Disorders Center at Children’s Healthcare of Atlanta, studies a specimen under a microscope. Photo credit: contributed

When melanoma does occur in children, it presents differently than it does in adults, Mitchell says. In children, melanomas may present as “pink or flesh-colored spots” and appear quickly. Parents should pay attention to lesions that “pop up out of nowhere” or existing spots that begin to bleed, itch or grow rapidly, as these are potential red flags, she says.

If the doctor thinks it could be melanoma, they will do a biopsy. But traditional biopsy results often are not definitive in children. Many lesions suspected or even identified as melanoma are actually lesions called atypical melanocytic tumors, which can’t be definitively determined to be either malignant or benign and may require less aggressive surgical approaches, she says. An experienced dermatopathologist is crucial to distinguishing between these tumors and true melanoma.

For confirmed melanoma cases, treatment includes surgery and possibly immunotherapy or targeted therapies. “If it’s classified as a true adult melanoma, then we follow standard adult guidelines,” Mitchell says.

As with adults, treatment advances – mainly immunotherapy – have significantly improved outcomes for children, too. “Treatments are good, outcomes are good,” she says.