# Treatment options for metastatic melanoma
The treatment of metastatic melanoma has changed dramatically over the past years. Where chemotherapy was once the first choice, immunotherapy and targeted drugs (directed at specific mutations in tumor cells) now take the lead. The choice depends on the type of melanoma, the location of metastases, and whether specific genetic changes have been found in the tumor cells. Below, standard treatment approaches are described per group.
Immunotherapy (anti-PD-1 and anti-CTLA-4)
Immunotherapy works by releasing the brakes on the immune system, so the body can recognize and destroy cancer cells itself.
**Anti-PD-1 inhibitors (for example nivolumab, pembrolizumab)**
ProveniIncluded in official guidelines, or approved by EMA or FDA
These drugs block a protein (PD-1) that tumor cells use to escape the immune system. This allows the immune system to fight cancer better. Anti-PD-1 inhibitors are used as first-line treatment, both for melanoma with and without known mutations.
Common side effects are fatigue, skin rash, diarrhea and joint complaints. More serious side effects can occur because the immune system turns against the body itself (autoimmune reactions), for example inflammation of the lungs, liver, kidneys, intestines or hormone glands. These can occur acutely, but can also develop months after treatment. Some patients develop vitiligo (white patches on the skin), which may indicate a strong immune response but is not dangerous.
**Anti-CTLA-4 inhibitors (for example ipilimumab)**
ProveniIncluded in official guidelines, or approved by EMA or FDA
These drugs work on a different immune checkpoint. They can be given alone or in combination with anti-PD-1. The combination (ipilimumab + nivolumab) is more effective but causes more side effects. The same immune-related side effects can occur as with anti-PD-1, but more often and more severe.
Most side effects disappear after stopping or become manageable with supportive medication. However, the immune system can react slowly: it can take several weeks to months before an effect on the tumor becomes visible.
Targeted therapy (mutation-directed)
These drugs target specific hereditary changes in tumor cells.
**BRAF inhibitors (for example vemurafenib, dabrafenib)**
ProveniIncluded in official guidelines, or approved by EMA or FDA
About half of melanomas have a mutation in the BRAF gene. BRAF inhibitors block the faulty signal that drives the cancer cell. They work quickly, often within several weeks, and are usually combined with MEK inhibitors (see below).
Common side effects are skin rash, foot infections (painful swellings around the nails), diarrhea and fatigue. Because these drugs block an important signaling pathway, new skin tumors can also develop, especially in sun-exposed areas. These are usually not melanomas and can be removed surgically.
Cancer resistance usually develops after several months; therefore, combination with MEK inhibitors is recommended.
**MEK inhibitors (for example trametinib, cobimetinib)**
ProveniIncluded in official guidelines, or approved by EMA or FDA
MEK lies further down the same signaling pathway as BRAF. The combination of BRAF and MEK inhibitors slows resistance development and improves overall effect. MEK inhibitors are rarely used alone.
Side effects can include: skin rash, diarrhea, fatigue and eye inflammation. Heart rhythm disorders and fluid accumulation around the heart (very rare) are known.
**NRAS inhibitors**
ResearchediPositive results in clinical studies, not yet standard treatment
NRAS mutations occur in approximately 15–20% of melanomas. Traditionally, there were few targeted drugs for this. Newer NRAS inhibitors (sonomutide and similar ones) are being investigated, often in combination with MEK inhibitors and immunotherapy. The first results are encouraging, but they are not yet standard treatment everywhere.
Side effects seem similar to MEK inhibitors, but experience is still limited.
**c-Kit inhibitors**
ResearchediPositive results in clinical studies, not yet standard treatment
Some melanomas, especially the acral subtype (on hands and feet), can have c-Kit mutations. Imatinib (also used in certain blood cancers) has been investigated. The evidence is less strong than for BRAF- or NRAS-directed therapy.
**Mechanism of action and side effects**: the same as other tyrosine kinase inhibitors; generally well tolerated.
Combination approach: immunotherapy + targeted therapy
ResearchediPositive results in clinical studies, not yet standard treatment
The idea is that the immune system better reaches the area where the targeted drugs have damaged cancer. For example: ipilimumab + nivolumab + BRAF/MEK inhibitors, or anti-PD-1 + NRAS inhibitors + MEK inhibitors.
This offers greater anti-tumor effect but with significant side effects. This is mainly investigated in clinical trials and is not yet standard practice everywhere.
Chemotherapy
Proven (second and further lines)
Chemotherapy (for example dacarbazine or platinum-containing agents) is used less now that immunotherapy and targeted therapy are available. However, it can still be given as first-line treatment in certain subtypes (for example eye melanoma, uveal melanoma) or as follow-up treatment after immunotherapy or targeted agent.
Side effects are considerable: nausea, vomiting, anemia, reduced white blood cells (infection risk), fatigue and hair loss.
Radiotherapy for brain and bone metastases
ProveniIncluded in official guidelines, or approved by EMA or FDA
Brain metastases can be an emergency. Stereotactic radiosurgery (targeted radiation on small brain tumors) or conventional radiotherapy can quickly relieve symptoms and reduce brain swelling. For bone metastases, radiotherapy can provide pain relief and stabilization.
Radiotherapy directly damages cells but also affects healthy tissue. For brain treatment, side effects can include: fatigue, hair loss in the radiation area, and very rarely long-term effects on memory or hormone production.
Surgical removal of metastases
ProveniIncluded in official guidelines, or approved by EMA or FDA
If there are only one or a few metastases (for example one brain metastasis, one lung metastasis, one liver metastasis), surgical removal can prolong disease-free interval and in some cases improve survival. This is especially considered in patients in otherwise reasonable condition.
Supportive and palliative measures
Pain, jaundice (with liver metastases), cough (with lung metastases) and other symptoms can be managed by oncology specialists in collaboration with general practitioners and palliative care. This is independent of tumor-directed therapy and often essential for quality of life.
Experimental approaches
**CAR-T cell therapy and adoptive T-cell therapy (TIL therapy)**
ExperimentaliOngoing in study setting, outcome still unknown
This treatment collects T-cells from the blood or from the tumor itself, grows them in the laboratory and then reintroduces them into the body to fight cancer. TIL therapy (tumor-infiltrating lymphocytes) is used in trials for melanoma and shows promising results, especially when combined with immunotherapy.
Side effects can include: infusion reactions themselves (chills, fever) and immune-related side effects as with immunotherapy.
**Vaccination and bacterial immunomodulators**
ExperimentaliOngoing in study setting, outcome still unknown
Various types of vaccines (for example BCG-based vaccines, peptide vaccines) and immune-activating bacterial preparations are being investigated to stimulate the natural immune response against melanoma. These are not yet in routine use.
**Nanoparticles and new intravascular treatment**
ExperimentaliOngoing in study setting, outcome still unknown
For melanomas that spread to the liver, percutaneous hepatic perfusion (placement of a catheter to inject high doses of chemotherapy directly into the liver) is being investigated. This limits side effects on the body.
New nanoparticles and biological platforms are under investigation.
Resistance and sequential treatments
If tumors do not respond to immunotherapy or targeted therapy, or become resistant over time, switching to another drug or combination can occur. Some patients benefit from sequential anti-PD-1 and anti-CTLA-4 (or vice versa), or from switching BRAF/MEK inhibitors to immunotherapy or chemotherapy.
Recent studies show that certain biomarkers (for example, the level of circulating thymidine kinase in the blood) can help predict which patients benefit from certain treatment sequences. However, these tests are not yet routinely available.
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_This information never replaces a doctor's judgment. Always discuss your situation with your own healthcare provider._