Research has identified a number of molecular pathways and mutated genes in melanoma, such as the BRAF, C-KIT or NRAS mutation. 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. These mutations activate a particular pathway known as the MAP kinase pathway. If a patient’s melanoma has the BRAF mutation, a treatment that targets that mutation can be helpful. Patients who do not have this mutation do not benefit.
The following are FDA approved targeted therapy combinations for patients with a BRAF mutation:
- Mekinist(trametinib) and Tafinlar (dabrafenib) Combination: Learn about the Mekinist and Tafinlar combination by clicking here.
- Cotellic (cobimetinib)and Zelboraf (vemurafenib): Learn about the Cotellic and Zelboraf combination by clicking here.
It is important to note that although BRAF inhibitors are now routinely given in combination with MEK inhibitors, each of these agents is approved by the FDA for treatment on its own.
- Mekinist (trametinib):Learn about Mekinist by clicking here.
- Tafinlar (dabrafenib): Learn about Tafinlar by clicking here.
- Zelboraf (vemurafenib): Learn about Zelboraf by clicking here.
- Cotellic (cobimetinib): Learn about Cotellic by clicking here.
A newer combination, Encorafenib and Binimetinib has been tested in clinical trials and will be approved shortly by the FDA.
Experimental Approaches in Targeted Therapy Include:
BRAF and MEK Inhibitors
Several studies are evaluating the combination of BRAF/MEK inhibitor targeted therapy with immunotherapy (anti-PD1, anti-CTLA, anti-PDL1), though no final results have been reported.
BRAF Inhibitors for Brain Metastasis
BRAK and MEK inhibitors can also be used in patients with brain metastases (melanoma that has traveled to the brain). The Combi-MB trial tested dabrafenib plus trametinib in brain metastases and found that the combination is active with a manageable safety profile. About 58% of patients achieved tumor shrinkage. However the duration of the response was relatively short at 6.5 months, compared to patients without brain metastases.
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. There are reports of treatment with KIT inhibitors such as imatinib and sunitinib being beneficial in those patients.
Gleevec (Imatinib), Tasigna (Nilotinib) and Sprycel (Dasatinib) are approved for the treatment of chronic myeloid leukemia. Tumor shrinkage has been reported in melanoma patients with KIT mutations and multiple trials are currently testing imatinib alone or in combination with chemotherapy or immunotherapy for this group of patients.
Several other pathways and targets are currently being explored in melanoma. For example, PI3K/mTOR (in combination with a MEK inhibitor), and CDK4/6 inhibitors are being tested in early phase clinical trials. A trial of ERBB4 was terminated early due to slow accrual. One critical question is how to best treat patients whose tumors develop resistance to BRAF/MEK inhibitors.