Metastatic melanoma is melanoma that has spread from the skin to distant parts of the body, such as the lungs, liver, brain, or bones. It is classified as stage IV melanoma, and it carries a five-year survival rate of about 16%. While that number is sobering, treatments developed over the past decade have dramatically changed outcomes for many patients.
How Melanoma Becomes Metastatic
Melanoma begins in melanocytes, the cells that give skin its color. In its earliest stages, it stays in the top layers of the skin and is highly curable with surgery. As it grows deeper, cancer cells can enter the lymphatic system or bloodstream and travel to other organs. Once they settle and grow in a distant site, the melanoma is considered metastatic.
The initial sites of distant spread are most commonly the skin, the tissue just beneath it, and lymph nodes far from the original tumor, accounting for 42% to 59% of first distant recurrences. When it reaches internal organs, the lungs are the most frequent destination (18 to 36% of cases), followed by the brain (12 to 20%), liver (14 to 20%), and bone (11 to 17%). Melanoma can also reach the spinal cord, gastrointestinal tract, and muscle, though less commonly.
Genetic Mutations That Drive Growth
Melanoma cells often carry specific genetic mutations that fuel their growth, and identifying these mutations shapes the entire treatment plan. About 38.5% of melanoma patients carry a mutation in the BRAF gene, making it the most common driver. Another 16.4% have an NRAS mutation, and roughly 10% carry changes in the KIT gene. Testing for these mutations happens through a biopsy of the tumor tissue and is one of the first steps after a metastatic diagnosis.
The BRAF V600E mutation is particularly important because it activates a signaling pathway that tells cancer cells to multiply. Drugs exist that specifically block this pathway, so knowing whether the tumor carries this mutation directly determines which treatments are available.
Symptoms of Distant Spread
Metastatic melanoma often causes symptoms tied to wherever the cancer has landed. Lung metastases can cause a persistent cough or shortness of breath. Liver involvement may lead to abdominal pain, nausea, or jaundice. Bone metastases typically cause deep, aching pain in the affected area. Brain metastases can produce headaches, seizures, vision changes, or personality shifts.
More general symptoms are common too. Unexplained weight loss, persistent fatigue, and loss of appetite can all signal that melanoma has spread beyond the skin, even before organ-specific symptoms appear. Some people first learn they have metastatic disease when a new lump appears under the skin or in a lymph node far from the original mole.
How Metastatic Melanoma Is Diagnosed
Diagnosis typically involves imaging scans (CT, PET, or MRI) to locate tumors throughout the body, followed by a biopsy to confirm the cells are melanoma. A blood test measuring lactate dehydrogenase (LDH), an enzyme released when cells are damaged, plays a role in staging and prognosis. Higher LDH levels at diagnosis are associated with shorter survival. Each 100-unit increase in LDH roughly corresponds to a 44% increase in the risk of death, making it a useful but imperfect marker that doctors track alongside imaging.
Immunotherapy: Reactivating the Immune System
The immune system has built-in “brakes” that prevent it from attacking the body’s own cells. Melanoma exploits these brakes to hide from immune detection. Immunotherapy drugs called checkpoint inhibitors release those brakes, allowing immune cells to recognize and destroy cancer.
Two types of checkpoint inhibitors are used. PD-1 inhibitors (pembrolizumab and nivolumab) block a protein on immune cells that melanoma uses to switch them off. Used alone, they produce tumor shrinkage in about 30 to 40% of patients in clinical trials, though real-world response rates in some studies have been higher, reaching around 63%. The second type, a CTLA-4 inhibitor (ipilimumab), targets a different immune brake. When combined with a PD-1 inhibitor, response rates in trials reach 50 to 60%.
Combination immunotherapy tends to cause more side effects, including inflammation of the colon, liver, or skin, because the immune system becomes broadly more active. The choice between single-agent and combination therapy depends on how widespread the cancer is, how quickly it’s growing, and how well the patient tolerates treatment.
Targeted Therapy for BRAF-Mutant Tumors
For the roughly half of metastatic melanoma patients whose tumors carry a BRAF V600 mutation, targeted therapy offers a different approach. These drugs directly block the overactive signaling pathway driving tumor growth. Treatment pairs a BRAF inhibitor with a MEK inhibitor, since combining the two works better than using a BRAF inhibitor alone. In clinical trials, the combination delayed cancer progression for a median of about 9.3 to 9.4 months, compared to 5.8 to 8.8 months with a BRAF inhibitor by itself.
Targeted therapy tends to work quickly, often shrinking tumors within weeks. This makes it especially valuable when cancer is causing urgent symptoms, like swelling in the brain. The downside is that most tumors eventually develop resistance and start growing again, which is why doctors sometimes sequence targeted therapy with immunotherapy or vice versa.
Brain Metastases: A Common Challenge
Up to 60% of patients with advanced melanoma develop brain metastases during the course of their disease, making it one of the most serious complications. Before modern treatments, patients with brain involvement survived a median of just six months. Options now include surgical removal of brain tumors, focused radiation (stereotactic radiosurgery), whole-brain radiation, and the same systemic therapies used elsewhere in the body.
For patients without a BRAF mutation, immunotherapy with combined PD-1 and CTLA-4 blockade is the primary approach for brain metastases. For those with a BRAF mutation, the decision between immunotherapy and targeted therapy depends on whether the brain tumors are causing symptoms, how many there are, and how rapidly they’re growing. Both approaches have shown meaningful benefit in shrinking brain tumors, a space where almost nothing worked a decade ago.
TIL Therapy: A Newer Option
In February 2024, the FDA approved a new type of treatment called tumor-infiltrating lymphocyte (TIL) therapy for patients with metastatic melanoma who have already tried other treatments. The therapy, called lifileucel, works by extracting immune cells that have already migrated into the patient’s tumor, growing billions of copies in a lab, and infusing them back into the patient. It’s approved for adults whose melanoma has progressed after PD-1 immunotherapy (and after BRAF-targeted therapy if their tumor carries that mutation). This represents an option for patients who have run out of standard treatments.
Survival and Outlook
The five-year survival rate for distant-stage melanoma is 16.2%, according to the National Cancer Institute’s SEER database. That statistic, however, reflects outcomes across many years of data collection, including patients diagnosed before current immunotherapy regimens became standard. For patients who respond to checkpoint inhibitors, long-term survival is possible. Some patients treated with combination immunotherapy remain in remission years after completing treatment.
Several factors influence individual prognosis: where the cancer has spread (brain and liver metastases carry a worse outlook than skin or lung involvement), how high the LDH level is at diagnosis, how many sites are affected, and whether the tumor responds to the first line of treatment. The presence of a targetable BRAF mutation also expands treatment options, which can improve outcomes. While metastatic melanoma remains a serious diagnosis, the landscape has shifted considerably from the era when no systemic treatment meaningfully extended life.