In June 2024, outgoing president of the American Society of Clinical Oncology (ASCO), Lynn M. Schuchter, MD, delivered a heartfelt message at the group\u2019s meeting in Chicago: \u201cFor more than 35 years, I\u2019ve specialized in melanoma<\/a>, 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.<\/p>\n \u201cBut even then,\u201d continued Dr. Schuchter, director of the Tara Miller Medicine Center at Penn Medicine, \u201cclues 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.\u201d<\/p>\n She then showed a slide of two dozen of her patients, all of whom once had stage IV melanoma,<\/a> some even with brain metastases. They were now all melanoma-free and off therapy, some even a decade later. That\u2019s progress!<\/p>\n Of course, there\u2019s plenty of work left to be done. Though melanoma can usually be eradicated surgically if it\u2019s caught in situ (that is, before it spreads), it\u2019s 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\u2019s because about half of the 100,000 cases diagnosed annually in this country are already at the invasive stage, meaning that they\u2019ve penetrated beyond the very top layer of skin. Treatment for these melanomas <\/a>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.<\/p>\n The taming of melanoma began in 2011, when the FDA approved ipilimumab <\/a>\u2014 the first of a new class of drugs known as checkpoint inhibitors<\/a>. These immunotherapies work by blocking molecular \u201coff\u201d switches on T cells, the immune system\u2019s robocops, enabling them to morph into relentless killers of tumor cells.<\/p>\n 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\u2019s more, nearly a quarter of patients survived for three years or longer \u2014 most of them for over a decade. The drug\u2019s side effects, though sometimes serious, were generally tolerable. And as two more checkpoint inhibitors were approved for the disease, pembrolizumab<\/a> and nivolumab<\/a>, the numbers continued to improve.<\/p>\n \u201cIf you were diagnosed with stage IV melanoma in January 2000, odds were high that you would not live to see 2001,\u201d says Vernon Sondak, MD, chair of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. \u201cAs recently as 2010, your likelihood of surviving five years was just 5 percent. Today, if you\u2019re on checkpoint inhibitors, you\u2019ve got a 50 percent chance of living that long. That\u2019s what \u2018transformative\u2019 looks like.\u201d<\/p>\n Another illustration: ex-President Jimmy Carter\u2019s death <\/a>at age 100 last December, nine years after pembro (as it\u2019s nicknamed) saved his life.<\/p>\n Yet the transformation in melanoma treatment didn\u2019t stop with those drugs. The same year ipilimumab arrived, the FDA approved vemurafenib<\/a>, the first \u201ctargeted\u201d medication for advanced melanoma. Targeted therapies block the growth of cancers that are driven by a specific mutation \u2014 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.<\/p>\n 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 \u2014 say, a BRAF inhibitor with a MEK inhibitor \u2014 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<\/em> found, 60 percent remained alive at the five-year mark.<\/p>\n In 2015, the FDA approved another precision-guided weapon against advanced melanoma: talimogene laherparepvec<\/a> (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\u2019s 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.<\/p>\n Still, many patients who receive immunotherapies don\u2019t 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. \u201cWe\u2019re asking, how do we use these drugs best?\u201d says Dr. Sondak. \u201cWhat\u2019s the right combination and the right sequence?\u201d<\/p>\n 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 <\/a>and atezolizumab<\/a>, which were previously available only via intravenous infusion. The shots are far quicker to administer (around five minutes versus 30 to 60) and don\u2019t require patients to travel to specialized clinics.<\/p>\n Then there\u2019s 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 \u2014 common tumor sites for metastatic melanoma.<\/p>\n 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.<\/p>\n 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.<\/p>\n Last year, for example, the FDA approved the first tumor infiltrating lymphocyte (TIL) therapy for melanoma \u2014 lifileucel<\/a>, a \u201cliving drug\u201d developed by researchers at the National Cancer Institute. For this type of immunotherapy, doctors collect a patient\u2019s 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\u2019s other immune cells (which might suppress response), the TILs are infused back into the bloodstream, where they start hunting down cancer.<\/p>\n TIL therapy leverages the immune memory of T cells that know how to bypass a particular tumor\u2019s defenses and can identify molecular targets unique to the patient\u2019s malignancy. And because TILs come from that person\u2019s body, the risk of off-target effects is low. The treatment can help many patients who haven\u2019t responded to standard therapies, with efficacy comparable or even superior to that of checkpoint inhibitors.<\/p>\n 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\u2019s Perlmutter Cancer Center reported a groundbreaking finding: an mRNA vaccine targeting proteins expressed by an individual\u2019s cancer, in combination with pembrolizumab, was nearly twice as effective as pembro alone at preventing recurrence in over 100 melanoma patients who\u2019d 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.<\/p>\n Researchers are also working on personalized tests designed to predict which patients will respond best to which therapeutic approach \u2014 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.<\/p>\n \u201cWe\u2019ve always made decisions about surgery based on tiny differences in physiology, like a 0.1 mm variance in a melanoma\u2019s thickness,\u201d Dr. Sondak notes. \u201cThe next step is basing decisions on genetics and molecular features of both the patient and their cancer.\u201d 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.<\/p>\n \u00a0<\/strong>Whatever the future brings to the treatment of melanoma, the distance we\u2019ve 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\u2019s 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).<\/p>\n \u201cAfter a few doses, the treatment didn\u2019t seem to be working,\u201d Dr. Sondak recalls. \u201cOne node was a little bigger. There were hot spots on the PET scan, too.\u201d 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\u2019s astonishment, the patient\u2019s prospects for long-term survival had flipped from dismal to excellent.<\/p>\n \u201cToday, thanks to these therapies, I see cases like that several times a week,\u201d Dr. Sondak says. \u201cI marvel every time.\u201d<\/p>\n Kenneth Miller<\/strong><\/a> is a journalist based in Upstate New York. Learn about similar breakthroughs for patients with advanced nonmelanoma skin cancers in his article here<\/a>.\u00a0<\/em><\/p>\n <\/p>\n","protected":false,"gt_translate_keys":[{"key":"rendered","format":"html"}]},"excerpt":{"rendered":" If you\u2019re looking for some good news, you can find it in the fight against advanced skin cancers \u2014 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.<\/p>\n","protected":false,"gt_translate_keys":[{"key":"rendered","format":"html"}]},"author":24,"featured_media":8984,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[10,2880],"tags":[],"class_list":["post-9000","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-skin-cancer-information","category-the-skin-cancer-foundation-journal"],"acf":[],"yoast_head":"\nAn Unfolding Revolution<\/h3>\n
Building on Past Breakthroughs<\/h3>\n
Unlocking the Promise of Personalized Medicine<\/h3>\n
Marveling at Today\u2019s Miracles<\/h3>\n
\n