What is Targeted Therapy?
Targeted therapy is a type of melanoma treatment that uses drugs to more precisely identify and stop the action of molecules that are key to the growth of cancer cells. Targeted therapy ‘targets’ the changes in these cancer cells that help them grow, divide, and spread. Treatment with these drugs is called targeted therapy.
BRAF Mutations
Research has identified a number of molecular pathways and mutated genes in melanoma, such as the BRAF, C-KIT, and NRAS mutations. Targeted therapies benefit patients whose melanoma cells have the specific mutation that makes 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 from medications targeting this pathway.
The following are FDA approved targeted therapy combinations for patients with a BRAF mutation:
Tafinlar (dabrafenib) and Mekinist (trametinib)
Cotellic (cobimetinib) and Zelboraf (vemurafenib)
Mektovi (binimetinib) and Braftovi (encorafenib)
Also approved is an immunotherapy combined with targeted therapy: Tecentriq (immunotherapy) and Cotellic and Zelboraf (targeted combination).
Experimental Approaches in Targeted Therapy Include:
+ BRAF & MEK Inhibitors
Several studies are evaluating the combination of BRAF/MEK inhibitor targeted therapy with immunotherapy (anti-PD1, anti-CTLA, anti-PDL1).
+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 Tafinlar plus Mekinist in brain metastases and found that the combination is active with a manageable safety profile. About 58% of patients achieved tumor shrinkage in the brain; however, the duration of the response was relatively short at 6.5 months, compared to patients without brain metastases.
+C-KIT Inhibitors
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. Clinical trials have demonstrated tumor shrinkage with KIT inhibitors such as imatinib and sunitinib in patients with driver mutations in KIT.
Gleevec (imatinib), Tasigna (nilotinib), and Sprycel (dasatinib) are approved for the treatment of chronic myeloid leukemia. Multiple trials are currently testing KIT inhibitors alone or in combination with chemotherapy or immunotherapy for this group of patients.
+Other Targets
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.