Recurrent melanoma was historically treated with chemotherapy or biologic therapy.  Since 2011 several new, targeted therapies have completed evaluation in clinical trials and demonstrated improved outcomes for individuals with advanced melanoma leading to their approval by the FDA.  Individuals with advanced melanoma now have numerous treatment options and additional clinical studies are ongoing in order to determine the best way to use these new drugs in sequence or combination therapy.

Patients with recurrent or refractory metastatic melanoma may be divided into 2 groups: patients who have failed initial systemic therapy and experience progression or recurrence after an initial response to treatment or patients who have local recurrences (skin and/or regional lymph nodes) after initial surgery or surgery and adjuvant therapy.

Individuals with metastatic melanoma who have failed initial systemic therapy are infrequently cured with additional therapy. There are many choices of therapy and access to newer treatment strategies in clinical trials. These therapeutic choices may prolong survival, reduce symptoms of progressive cancer and/or offer the chance of cure. Patients need to assess their treatment options and consider their individual goals for receiving additional treatment.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19

Targeted Therapy

Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable cancer to grow.  A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Cancer treatments that “target” cancer cells may offer the advantage of reduced treatment-related side effects and improved outcomes. Think of a light switch that’s stuck in the on position, as long as the switch is on, the cancer keeps growing. What these new drugs do is cut the wire or turn the switch off.  Several targeted therapies are now available for the management of malignant melanoma.

Zelboraf® (vemurafenib) was the first to be approved in a new class of drugs known as BRAF inhibitors. It turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma, which allows melanoma cells to grow uncontrollably. The results of a recent clinical trial demonstrated that patients taking Zelboraf® lived for nearly 16 months on average, compared with about six months for patients who took the chemotherapy drug dacarbazine. Nearly one in four patients treated with Zelboraf® developed squamous cell cancer, a type of non-melanoma skin cancer. Other common side effects included joint pain, skin rash, hair loss, and sun sensitivity.2

Tafinlar® (dabrafenib) also targets the BRAF V600 mutation. Tumor growth was delayed by about five months in patients taking Tafinlar®, compared with two to three months for patients taking dacarbazine.8Serious side effects included new skin cancers (both squamous cell and melanoma), high fever, high blood glucose, and eye inflammation. Other, more common side effects included headache, joint pain, hair loss, and redness, swelling, and pain in the hands and the feet.3

Mekinist® (trametinib) is a BRAF inhibitor that targets the BRAF mutation in a different way than Zelboraf or Tafinlar® does. Tumor growth was delayed for about five months in patients taking Mekinist, compared with about six weeks for patients taking either dacarbazine or another chemotherapy drug, Taxol® (paclitaxel).9Serious side effects included heart disease, lung diseases, and skin and eye complications. Other, more common side effects included rash, diarrhea, and swelling in the arms or legs.4

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation.  Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.5

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