Melanoma Pioneers: In her speech at the 2024 ASCO Annual Meeting, Lynne M. Schuchter, MD, honored “all those we have lost to cancer. We will continue to fight.” Photo credit: Julie Bain
If you’re looking for some good news, you can find it in the fight against advanced skin cancers — and melanoma has led the way. Over the past 15 years, metastatic melanoma has gone from a likely death sentence to an often-curable disease.
In June 2024, outgoing president of the American Society of Clinical Oncology (ASCO), Lynn M. Schuchter, MD, delivered a heartfelt message at the group’s meeting in Chicago: “For more than 35 years, I’ve specialized in melanoma, a cancer once considered hopeless. In fact, when I began my fellowship, people often asked why I chose melanoma. There were no treatments beyond surgery. Outcomes were bleak. In the early days, I was essentially a hospice doctor.
“But even then,” continued Dr. Schuchter, director of the Tara Miller Medicine Center at Penn Medicine, “clues from the emerging science suggested the potential power of immunotherapy and targeted therapy. And indeed, gradually, over decades, laboratory and clinical researchers translated this promising science into new, powerful therapies, turning what was once a treatment desert into a tropical rainforest of options for our patients with melanoma.”
She then showed a slide of two dozen of her patients, all of whom once had stage IV melanoma, some even with brain metastases. They were now all melanoma-free and off therapy, some even a decade later. That’s progress!
Of course, there’s plenty of work left to be done. Though melanoma can usually be eradicated surgically if it’s caught in situ (that is, before it spreads), it’s still the most dangerous of the three most common types of skin cancer, leading to more than 8,000 deaths each year in the U.S. That’s because about half of the 100,000 cases diagnosed annually in this country are already at the invasive stage, meaning that they’ve penetrated beyond the very top layer of skin. Treatment for these melanomas is more complex, and less likely to be successful. But to understand how far we still have to go in the fight against this too-often lethal disease, it helps to know how we got where we are today.
An Unfolding Revolution
The taming of melanoma began in 2011, when the FDA approved ipilimumab — the first of a new class of drugs known as checkpoint inhibitors. These immunotherapies work by blocking molecular “off” switches on T cells, the immune system’s robocops, enabling them to morph into relentless killers of tumor cells.
Ipilimumab accomplished something no previous medication had done: It significantly expanded median survival rates in patients with advanced melanoma, from six months to 11. What’s more, nearly a quarter of patients survived for three years or longer — most of them for over a decade. The drug’s side effects, though sometimes serious, were generally tolerable. And as two more checkpoint inhibitors were approved for the disease, pembrolizumab and nivolumab, the numbers continued to improve.
“If you were diagnosed with stage IV melanoma in January 2000, odds were high that you would not live to see 2001,” says Vernon Sondak, MD, chair of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. “As recently as 2010, your likelihood of surviving five years was just 5 percent. Today, if you’re on checkpoint inhibitors, you’ve got a 50 percent chance of living that long. That’s what ‘transformative’ looks like.”
Another illustration: ex-President Jimmy Carter’s death at age 100 last December, nine years after pembro (as it’s nicknamed) saved his life.
Yet the transformation in melanoma treatment didn’t stop with those drugs. The same year ipilimumab arrived, the FDA approved vemurafenib, the first “targeted” medication for advanced melanoma. Targeted therapies block the growth of cancers that are driven by a specific mutation — for vemurafenib, in a gene called BRAF; for its successors, in genes including MEK and c-KIT. This mode of action limits the scope of their utility: They only work for those cancers, and they often stop working as the cancer adapts to the drug. However, they bolster the weapons against melanoma in a couple of important ways.
First, targeted drugs sometimes cure melanoma outright when given after surgery, and they can extend life at least modestly for a subset of patients who (for assorted reasons) are ineligible for checkpoint inhibitors. Second, they can be combined with other treatments to the benefit of both. Pairing two targeted therapies — say, a BRAF inhibitor with a MEK inhibitor — often improves efficacy while reducing side effects in people whose cancers have the relevant mutations. And among patients who received checkpoint inhibitors and BRAF inhibitors, a recent study published in the New England Journal of Medicine found, 60 percent remained alive at the five-year mark.
In 2015, the FDA approved another precision-guided weapon against advanced melanoma: talimogene laherparepvec (T-VEC), the first-ever oncolytic immunotherapy. For this approach, a virus is genetically modified to infect and destroy cancer cells and is then injected into a solid tumor. As the tumor shrinks, it releases chemicals that stimulate the patient’s immune system to attack metastases throughout the body. Although T-VEC is less effective than checkpoint inhibitors on its own, it can enhance the effects of those drugs when used alongside them.
Building on Past Breakthroughs
Still, many patients who receive immunotherapies don’t respond or may stop responding over time. Nor are targeted drugs yet available for several of the mutations that commonly drive melanomas. To move the needle further, researchers are developing new medications in those areas, while testing both novel and older drugs in numerous combinations. “We’re asking, how do we use these drugs best?” says Dr. Sondak. “What’s the right combination and the right sequence?”
Some of these investigations are aimed at broadening the patient pool for such therapies; others are meant to boost their performance; and still others to improve their user-friendliness or versatility. Early in 2025, for example, the FDA approved injectable versions of the checkpoint inhibitors nivolumab and atezolizumab, which were previously available only via intravenous infusion. The shots are far quicker to administer (around five minutes versus 30 to 60) and don’t require patients to travel to specialized clinics.
Then there’s RP1, an experimental oncolytic immunotherapy being developed. Like its predecessor, T-VEC, it uses a modified herpes virus to attack cancer cells. But unlike the older drug, which can be used only for tumors or lymph nodes easily accessible through the skin, RP1 can be injected into internal organs such as the liver or lung — common tumor sites for metastatic melanoma.
Preliminary results from clinical trials suggest that RP1, combined with nivolumab, can significantly extend survival for many patients for whom standard therapies alone have failed. The FDA awarded the drug a coveted Breakthrough Therapy designation in November 2024.
Unlocking the Promise of Personalized Medicine
Along with such tweaks of established remedies, more radical transformations in melanoma treatment are also underway. If the trend since 2011 has been toward increasingly personalized approaches, these techniques represent a quantum leap.
Last year, for example, the FDA approved the first tumor infiltrating lymphocyte (TIL) therapy for melanoma — lifileucel, a “living drug” developed by researchers at the National Cancer Institute. For this type of immunotherapy, doctors collect a patient’s tumor tissue and isolate T cells that have managed to penetrate it. Billions of those TILs are then grown in a lab. After chemotherapy is administered to deplete the patient’s other immune cells (which might suppress response), the TILs are infused back into the bloodstream, where they start hunting down cancer.
TIL therapy leverages the immune memory of T cells that know how to bypass a particular tumor’s defenses and can identify molecular targets unique to the patient’s malignancy. And because TILs come from that person’s body, the risk of off-target effects is low. The treatment can help many patients who haven’t responded to standard therapies, with efficacy comparable or even superior to that of checkpoint inhibitors.
Another potentially transformative technique is a personalized revamp of an old immunotherapy: vaccines. Scientists have long struggled to adapt that weapon to the war on cancer, with limited success. But in 2023, researchers at NYU Langone’s Perlmutter Cancer Center reported a groundbreaking finding: an mRNA vaccine targeting proteins expressed by an individual’s cancer, in combination with pembrolizumab, was nearly twice as effective as pembro alone at preventing recurrence in over 100 melanoma patients who’d previously had surgery. Since then, this and other vaccine/checkpoint-inhibitor combos have entered later-phase clinical trials, and one or more could be approved in the next few years.
Researchers are also working on personalized tests designed to predict which patients will respond best to which therapeutic approach — and when. One key question for many two-stage therapies, for example, is which part of the combo should be used first. Depending on the circumstances, for example, a drug may be more effective when given as either neoadjuvant or adjuvant therapy (that is, before or after surgical removal of the primary tumor). However, different patients may respond better to different approaches at different stages of their treatment.
“We’ve always made decisions about surgery based on tiny differences in physiology, like a 0.1 mm variance in a melanoma’s thickness,” Dr. Sondak notes. “The next step is basing decisions on genetics and molecular features of both the patient and their cancer.” Commercially available gene panels can already provide data on the risk of melanoma spreading or recurring and are expected to be capable of suggesting treatment pathways beyond the use of targeted drugs within the next few years.
Marveling at Today’s Miracles
Whatever the future brings to the treatment of melanoma, the distance we’ve come in just a decade and a half is head-spinning. Recently, Dr. Sondak treated a patient who was found to have melanoma cells in a sentinel lymph node after his skin lesion was surgically removed. When the patient’s melanoma recurred in a nearby lymph node, the team started him on a checkpoint inhibitor. Then they monitored that node and its neighbors via CT scans (to detect swelling that could indicate tumor growth) and PET scans (to detect abnormal cellular activity).
“After a few doses, the treatment didn’t seem to be working,” Dr. Sondak recalls. “One node was a little bigger. There were hot spots on the PET scan, too.” When he removed the suspect lymph nodes, their swollen and blackened appearance made him certain they were cancerous. Yet a pathologist determined that the tumors they contained were 95 percent dead. To everyone’s astonishment, the patient’s prospects for long-term survival had flipped from dismal to excellent.
“Today, thanks to these therapies, I see cases like that several times a week,” Dr. Sondak says. “I marvel every time.”
Kenneth Miller is a journalist based in Upstate New York. Learn about similar breakthroughs for patients with advanced nonmelanoma skin cancers in his article here.
