Melanoma and LM
Melanoma is a type of skin cancer that begins in the melanocytes, the cells that produce the pigment in your skin. Most melanomas occur on skin exposed to the sun. Melanoma can spread to other parts of the body, making it the deadliest form of skin cancer.
Although cutaneous (skin) melanoma is the most common form of melanoma, melanoma can also start in other parts of your body, for example on your hands, feet and under your nails (called acral lentiginous melanoma), in the mucous membranes throughout the body (mucosal melanoma), in your eyes (uveal melanoma) and extremely rare directly in the central nervous system (primary CNS melanoma or meningeal melanoma).
In addition, there are benign types of tumors that form from melanocytes in the brain, such as meningeal melanocytoma, meningeal melanocytosis and meningeal melanomatosis, which can later mutate into melanoma.
Common Mutations in Melanoma
Cancer is caused by mutations in our DNA that allow cells to grow uncontrollably – and eventually invade surrounding tissue. Mutations in melanoma include:
- BRAF (pronounced bee-raf) – most common in cutaneous melanomas
- NRAS (pronounced en-ras) – second most common mutation in cutaneous melanomas
- KIT proteins – more common in acral and mucosal melanoma
- GNA11 – common in uveal melanoma
- GNAQ – common in uveal melanoma
A person with melanoma may have none of these mutations or one of these mutations (but not more than one) and the mutations vary by what type of melanoma you have.
Metastatic Melanoma and Brain Metastasis
Metastatic melanoma is also known as advanced melanoma. Metastatic melanoma is when melanoma spreads to other areas of the body, such as the lymph nodes, lung, liver, bone and brain. Melanoma is stage 4 when it has spread beyond the skin and lymph nodes to an organ.
Melanoma has one of the highest incidences of brain metastases among solid tumors.
- As many as 40% to 60% of people with metastatic melanoma develop brain metastases.
Metastatic Melanoma and Leptomeningeal Spread
Leptomeningeal metastases (also known as LM, leptomeningeal disease, LMD, or leptomeningeal cancer) differs slightly from brain metastases, as it means that the cancer is growing on the lining of the brain and spinal cord, called the leptomeninges. Most commonly, this occurs along with brain metastases.
Melanoma has one of the highest incidences of LM among solid tumors.
- As many as 10% to 15% of people with metastatic melanoma will develop LM.
Treatment Options for Melanoma
*For up-to-date guidelines for melanoma treatment, visit the NCCN patient guidelines
Surgery: Surgery is the first treatment for most patients and often the only treatment needed for early-stage melanoma.
Immunotherapy: Treatment for later stages of melanoma often involves a specific type of immunotherapy called an immune checkpoint inhibitor (ICI).
How immunotherapy works:
The immune system is made up of organs and cells that help protect your body from viruses, bacteria and abnormal cells in your body, such as cancer cells.
While the immune system detects and attacks infections and abnormal cells, it also is designed to protect normal cells and tissues in the body. Immune checkpoints, which are proteins found on white blood cells called T cells, prevent an immune response from being so strong that it destroys your healthy cells. But sometimes, because of these checkpoints, the immune system ends up protecting cancer cells and allowing them to avoid being destroyed by your immune system. Cancer can find a way to avoid immune destruction.
Immunotherapy is medicine that increases the ability of a person’s own immune system to detect and destroy cancer cells.
Certain types of immunotherapies, called immune checkpoint inhibitors (ICIs), work by removing or blocking checkpoints in the immune system, allowing T cells to recognize and attack cancer cells. However, by blocking these checkpoints and allowing the T cells to become too powerful, the immune checkpoint inhibitor treatments can sometimes lead to side effects.
The immune system is complex, so unfortunately, while some patients benefit from immunotherapies, these treatments do not work for everyone and cancer can continue to grow or recur.
Immune checkpoints targeted in melanoma include CTLA-4, PD-1, PD-L1 and LAG-3. Treatments that inhibit these immune checkpoints include:
- CTLA-4 inhibitor: Ipilimumab (Yervoy)
- PD-1 inhibitors: Pembrolizumab (Keytruda), Nivolumab (Opdivo)
- PD-L1 inhibitors: Atezolizumab (Tecentriq)
- LAG-3 inhibitor: Relatlimab
Often ICIs are used together in combinations, such as:
- Nivolumab + Relatlimab, called Opdualag or referred to as nivo/rela
- Nivolumab (Opdivo) + Ipilimumab (Yervoy), often referred to as nivo/ipi
- Pembrolizumab (Keytruda) + Ipilimumab (Yervoy), often referred to as pembro/ipi
Tebentafusp (Kimmtrak), a bispecific T-cell engager (BiTE), is another type of immunotherapy used for melanoma.
Another type of immunotherapy is an oncolytic virus therapy. Oncolytic viruses are viruses that have been changed to infect and kill mostly cancer cells. They also work by triggering the immune system to help attack the cancer cells.
- T-VEC (Imlygic)
Cellular (cell-based) immunotherapy uses living cells to treat cancer by improving the immune system’s ability to fight disease. Currently, one cellular therapy is approved to treat melanoma
- Tumor-infiltrating lymphocytes (TIL) therapy: Lifileucel (Amtagvi)
Interleukin-2 (IL-2) is another type of immunotherapy. Interleukins are proteins that are made by the body to boost the immune system. IL-2 is made in the lab to treat advanced melanomas. It is not used as often now but may still be an option when immune checkpoint inhibitors are no longer working.
- Aldesleukin (Proleukin)
Targeted therapy: Certain drugs can target mutations (changes), such as BRAF mutations. BRAF is a gene found on chromosome 7 that encodes a protein also called BRAF. This protein plays a role in cell growth by sending signals inside the cell promoting, among other functions, cell division. BRAF inhibitors target the BRAF protein directly. The MEKgene works together with the BRAF gene, so drugs that block MEK proteins can also help treat melanomas with BRAF gene changes. Depending on what mutations you have, the following drugs may be useful for treating your type of melanoma at various stages, including leptomeningeal disease:
- BRAF inhibitors: Encorafenib (Braftovi), Dabrafenib (Tafinlar), Vemurafenib (Zelboraf)
- MEK inhibitors: Trametinib (Mekinist), Binimetinib (Mektovi), Cobimetinib (Cotellic)
- C-Kit: imatinib (Gleevec), nilotinib (Tasigna)
BRAF and MEK inhibitors are used in combination for treatment, such as:
- Encorafenib (Braftovi) + Binimetinib (Mektovi)
- Dabrafenib (Tafinlar) + Trametinib (Mekinist)
- Vemurafenib (Zelboraf) + Cobimetinib (Cotellic)
Chemotherapy: Immunotherapy and targeted therapy are often the first choices for melanoma treatment. But if other treatment options have failed, the following chemo treatments may be used (often in combinations):
- Dacarbazine (DTIC)
- Temozolomide (Temodar)
- Nab-paclitaxel
- Paclitaxel
- Cisplatin
- Carboplatin
- Melphalan (Hepzato Kit), specifically for uveal melanoma that has spread to the liver
Most of these treatments are given intravenously except for the targeted therapy medications, which are oral medications.
For metastatic melanoma and leptomeningeal cancer, a newer approach is to give treatment intrathecally (directly into the spinal fluid) and depending on what is used, along with intravenous (into the bloodstream) treatment. Intrathecal treatment can be given through a lumbar puncture or an Ommaya port.
For melanoma with leptomeningeal spread, intrathecal (IT) nivolumab and intravenous (IV) nivolumab are now being used regularly, and other ongoing clinical trials are assessing the safety and efficacy of nivo/rela and ipi/nivo.
Radiation Therapy: Whole brain radiation with or without focal radiation to the spine for symptomatic areas is the most common way radiation is used for leptomeningeal disease.
For leptomeningeal cancer, proton radiation therapy to the whole brain and spine has shown promise and is being increasingly used.
Resources
For more detailed information about melanoma, please visit: