Research has identified a number of molecular pathways and mutated genes in melanoma. The new targeted therapies benefit patients whose melanoma cells have the specific mutation that make a particular pathway important in the survival, growth, or multiplication of their melanoma cells.
BRAF mutations have been shown to occur in about 50% of all melanoma patients, and these mutations activate a particular pathway known as the MAP kinase pathway. If a patient’s cancer has the BRAF mutation, a treatment that targets that mutation can be helpful. Patients who do not have this mutation, do not benefit. As well, patients can have a C-KIT or NRAS mutation.
The following are FDA approved targeted therapies:
- Mekinist (trametinib) and Tafinlar (dabrafenib) Combination: Learn about the Mekinist and Tafinlar combination by clicking here.
- Mekinist (trametinib): Learn about Mekinist by clicking here.
- Tafinlar (dabrafenib): Learn about Tafinlar by clicking here.
- Zelboraf (vemurafenib): Learn about Zelboraf by clicking here.
Experimental Approaches in Targeted Therapy Include:
BRAF Inhibitors in Combination
Listed below is a combination that is being investigated.
- Zelboraf + Cobimetinib combines a targeted therapy with a MEK inhibitor. In the Phase III trial, progression free survival (the time a patient lives without cancer growing or spreading) was 12.3 months for patients on Zelboraf and Cobimetinib vs. 7.2 months for patients treated with Zelboraf alone.
BRAF Inhibitors for Brain Metastasis
Patients with melanoma frequently suffer from brain metastasis and most drugs are not able to get to the brain. In a phase II clinical trial of Tafinlar in patients with a BRAF V600E mutation, 18% of the patients showed a shrinkage in their brain metastases. Clinical trials are now going on and/or being designed to determine the safety and effectiveness of combining BRAF inhibitors with other treatments used for brain metastases.
MEK is a critical member of the MAPK pathway involved in growth and survival of cancer cells.
Mutations in KIT are most frequently seen in certain melanoma subtypes, particularly acral lentiginous melanoma (melanoma of the palms, soles, and nail beds), mucosal melanomas, as well as those melanomas associated with extensive sun damage. In those patients treatment with KIT inhibitors such as imatinib and sunitinib has been reported to be beneficial.
- Gleevec (Imatinib) is approved for the treatment of chronic myeloid leukemia and Gastrointestinal Stromal Tumors (GIST). Tumor shrinkage has been reported in melanoma patients with KIT mutations and multiple Phase II trials are currently testing imatinib alone or in combination with chemotherapy for this group of patients.
- Tasigna (Nilotinib) is approved for the treatment of chronic myeloid leukemia and is currently being tested in melanoma patients with KIT mutations.
- Sprycel (Dasatinib) is approved for chronic myeloid leukemia and is being tested in multiple Phase II trials for melanoma patients with KIT mutations.
Several other pathways and targets are currently being explored in melanoma. The following is a list of some targets for which drugs are being tested in early phase clinical trials: CDK2, CDK4, and ERBB4.