Treatment Options for Stage IV Melanoma

Once your stage of melanoma has been determined, your doctor will discuss a treatment plan with you. Several new drugs, including ipilimumab (Yervoy), dabrafenib (Tafinlar) in combination with trametinib (Mekinist), pembrolizumab (Keytruda), vemurafenib (Zelboraf), dabrafenib (Tafinlar), and trametinib (Mekinist), have been FDA approved, and have shown improvements in survival.

Many experimental treatments are under investigation and may be available by enrolling in a clinical trial.

Surgery

To remove the cancerous tumors or lymph nodes that have metastasized or spread to other areas of the body, if they are few in number and/or are causing symptoms.

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Treatment Options

Treatment given in addition to a primary cancer treatment (such as surgery) is recommended for Stage IV melanoma. These are systemic therapies that go through the bloodstream to reach and affect cancer cells throughout the body. The goal of systemic treatment is to try and control the melanoma and treat symptoms. Treatments can be divided into immune or biologic therapies, molecularly targeted therapies, or chemotherapies.

Immunotherapies

KEYTRUDA (pembrolizumab)

Pembrolizumab (brand name: Keytruda) is a humanized monoclonal antibody that has been approved by the FDA to treat patients with unresectable or metastatic melanoma, after they have progressed on ipilimumab and, if they the carry the BRAF 600 mutation, after they have progressed on a BRAF inhibitor.

Purpose and Effectiveness 

  • It is designed to block a cellular target known as PD-1, which restricts the body’s immune system from attacking melanoma cells. It works by increasing the ability of the body’s immune system to fight advanced melanoma.
  • In a large Phase 1 clinical trial, half of the participants received pembrolizumab at the recommended dose of 2 mg/kg. Of these patients, approximately 24% had their tumors shrink. This effect lasted at least 1.4 to 8.5 months and continued beyond this period in most patients.

Treatment Side Effects

OPDIVO (nivolumab)

Purpose and Effectiveness

  • Opdivo is a humanized monoclonal antibody. It is designed to block a cellular target known as PD-1, which results in an anti-tumor immune response.
  • The approval of Opdivo was based on the results of a Phase III clinical trial of 120 patients with unresectable (cannot be removed by surgery) or metastatic (advanced) melanoma. Of these patients 32 percent had a response to Opdivo. This effect lasted for more than six months in approximately one-third of the patients. Responses to Opdivo were demonstrated in both patients with and without the BRAF V600 mutation.
  • This indication was approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Treatment Side Effects 

PROLEUKIN (IL-2 / Interleukin 2)

High Dose Interleukin-2 (brand name: HD IL-2, Proleukin) is a cytokine therapy approved by the FDA for the treatment of advanced metastatic melanoma. It appears to benefit approximately 16% of patients with disease shrinkage, of which 6% appear to derive long term durable responses. Purpose and Effectiveness 

  • HD Interleukin-2 is designed to restore and strengthen the immune system.
  • This treatment requires that the person is in very good health with no other significant health problems, including no heart problems. Not everyone is a candidate for HD interleukin-2 and it must be administered by trained physicians and clinical staff inside a hospital.

Treatment Side Effects

YERVOY (ipilimumab)

Ipilimumab (brand name: Yervoy) is a monoclonal antibody that has been approved by the FDA (Food and Drug Administration) for the treatment of unresectable or metastatic melanoma. Unresectable melanoma is such that all sites of melanoma tumors cannot be completely removed surgically.

Purpose and Effectivenss:

  • Ipilimumab is designed to restore and strengthen the immune system by successfully activating T-cells (T lymphocytes), a critical component of the immune system, with the hope of sustaining an active immune response to fight the cancer cells for a long time.
  • Studies indicate that it improves overall median survival by 4 months compared to a vaccine treatment. In a 2013 analysis from 12 prospective and retrospective studies it was shown that the median overall survival for patients treated with ipilimumab was 11.4 months. Among these patients, 22% were still alive after three years. There were no deaths among patients who survived beyond seven years, at which time the overall survival rate was 17%.

Treatment Side Effects

Targeted Therapies

MEKINIST (trametinib) and TAFINLAR (dabrafenib) Combo

Trametinib (brand name: Mekinist) in combination with Dabrafenib (brand name: Tafinlar) has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation.

Purpose and Effectiveness

  • The BRAF gene and protein is normally involved in regulating cell growth, but is mutated in about half of patients with melanoma.  Dabrafenib works by blocking the function of the V600E or V600K-mutated BRAF protein. Trametenib is a kinase inhibitor that works by blocking the function of the MEK protein.
  • In a phase III trial comparing dabrafenib in combination with trametinib versus vemurafenib alone in patients with BRAF V600E or V600K mutations, the combination group had a progression free survival of 11.4 months compared to 7.3 months in the vemurafenib only group.

Treatment Side Effects 

MEKINIST (trametinib)

Trametinib (brand name: Mekinist) is a kinase inhibitor that inhibits another protein, named MEK, and has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma that have a BRAF V600E or V600K mutation. Trametinib has not shown to benefit patients who have already taken another BRAF inhibitor and is only used alone in patients who cannot take vemurafenib or dabrafenib.

Purpose and Effectiveness

  • The BRAF protein is normally involved in regulating cell growth, but is mutated in about half of the patients with late-stage melanomas. Mekinist works by blocking the function of the MEK protein, which is overactive inV600E-mutated or V600K-mutated melanoma.
  • In a trial comparing trametinib to chemotherapy (dacarbazine or paclitaxel) in patients with metastatic melanoma with a BRAF V600E or V600K mutation, the trametinib group had improved overall survival compared with chemotherapy.

Treatment Side Effects 

TAFINLAR (dabrafenib)

Dabrafenib (brand name: Tafinlar) is an oral kinase inhibitor that inhibits another protein, named MEK, and has been approved by the FDA for the treatment of patients with unresectable or metastatic melanoma that have a BRAF V600E or V600K mutation. Trametinib has not shown to benefit patients who have already taken another BRAF inhibitor and is only used alone in patients who cannot take vemurafenib or dabrafenib.

Purpose and Effectiveness

  • The BRAF protein is normally involved in regulating cell growth, but is mutated in about half of the patients with late-stage melanomas. Mekinist works by blocking the function of the MEK protein, which is overactive inV600E-mutated or V600K-mutated melanoma
  • In a trial comparing dabrafenib to dacarbazine (chemotherapy) in patients with the BRAF V600E mutation, the dabrafenib group had progression free survival (the time a patient lives without cancer growing or spreading) of 6.9 months compared to 2.7 months for those on dacarbazine. Median overall survival in the dabrafenib group has been reported at 18.2 months, compared with 15.6 months in the dacarbazine group.

Treatment Side Effects 

ZELBORAF (vemurafenib)

Vemurafenib (brand name: Zelboraf) is an oral kinase inhibitor that interferes with the action of mutated BRAF and have been approved by the FDA for the treatment of patients with the BRAF V600E/K mutation with unresectable or metastatic melanoma.

Purpose and Effectiveness

  • The BRAF protein is normally involved in regulating cell growth, but is mutated (abnormal) in about half of patients with late-stage melanomas. Vemurafenib and dabrafenib work by blocking the function of the V600E-mutated BRAF protein.
  • In a trial comparing vemurafenib to dacarbazine (chemotherapy) in patients with the BRAF V600E mutation, the dacarbazine group had a median survival time of 9.7 months, with 44% still living at one year. Median survival time in the vemurafenib group was 13.6 months, with 56% still living at one year.

Treatment Side Effects 

Chemotherapy

DTIC (dacarbazine)

Dacarbazine (brand name: DTIC) is approved by the FDA for the treatment of advanced metastatic melanomas. It appears to benefit approximately 5-15% of patients with disease shrinkage. It has not been shown to change overall survival.

Purpose and Effectiveness

  • Chemotherapy uses toxic drugs to destroy cancer cells. These are established and experimental systemic therapies that ago through the bloodstream to reach and affect cancer cells throughout the body.
  • Other chemotherapy medicines are also used to treat advanced melanoma.

Treatment Side Effects

Radiation Therapy

Radiation is used in some situations to slow tumor growth or shrink a tumor in organs where surgery is not possible or is not recommended, and for relieving symptoms that a particular tumor in causing, such as in the  brain or bone.

Radiation therapy uses x-rays to kill cancer cells.

Learn more about Radiation Therapy

Clinical Trials

Clinical trials are research studies to evaluate new therapies and improve cancer care. These studies are responsible for most of the advances in cancer prevention, diagnosis, and treatment. If you have melanoma, you may be eligible to participate in a clinical trial.

Several experimental treatments are currently being tested in clinical trials.

  • Immunotherapies: designed to boost the body’s immune response to tumors. Ongoing clinical trials include antibodies against CTLA4, PD1, and PD-L1, as well as other immunotherapies.
  • Targeted Therapies: designed to inhibit mutations and pathways that promote the growth and survival of tumor cells. Some clinical trials are designed for patients with specific mutations in their tumors (for example, BRAF), and thus require testing to determine if patients are appropriate for a given therapy.
  • Vaccines
  • Adoptive Cell Transfer [ACT]: the transfer of immune cells that have been selected or engineered to attack tumors, particularly with tumor infiltrating lymphocytes [TIL].
  • Chemotherapy
  • Combinations: trials to combine different systemic treatments, as well as trials to test whether combining systemic treatments with surgery, radiation, and other therapies can improve outcomes in patients.

In addition to performing clinical trials to test the safety and effectiveness of new treatments, many investigators are also working to determine why therapies work in some patients but not in others, as well as why they sometimes stop working after initial success.  This research depends on the participation of patients in clinical trials, and sometimes in parallel studies that allow researchers to analyze samples of blood, tumor tissue, or other materials.  Some studies have the potential to help patients with melanoma currently, but also to help melanoma patients in the future.

Learn more about Clinical Trials

Clinical Trials

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Stage IV Follow Up

It's important to follow up with your melanoma specialist after any procedure. Learn more about the process.

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