Chemotherapy was developed in the 1950’s to kill cancer cells. Newer cancer treatments, called targeted therapy, have focused on scrambling the signals that cause cancer cells to grow and spread, and cause the death of those cancer cells. Many of these new targeted therapy agents have been successful in treating various cancers. Generally speaking, they are more specific for cancer cells than conventional chemotherapy, are frequently in pill form, and have much less toxicity than conventional chemotherapy.
Research has identified a number of molecular pathways and activated or mutated genes in melanoma. The new targeted therapies benefit patients whose cancer cells have the specific mutations that make a particular pathway important in the survival, growth, or multiplication of their cancer cells.
As an example, 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 the cancer of a particular patient has the BRAF mutation, new drugs like vemurafenib (Zelboraf) can be helpful. Patients who do not have these mutations do not benefit.
Listed below are different agents that are being investigated, one of which has been approved in melanoma. They are arranged according to which signaling pathway they are meant to “target”.
About half of all melanoma patients have a mutation in the gene called BRAF V600E and this mutation has been linked to melanoma progression from melanocytes (normal pigment cells) in the skin. This gene by itself is not solely responsible for melanoma development since mutations in BRAF have been found in mole pigment cells as well. Multiple drugs have targeted this pathway.
- Vemurafenib (brand name Zelboraf) has been approved by the Federal Drug Administration. This drug should only be used by patients who have the BRAF V600E mutation. For more about Zelboraf click here.
- Dabrafenib (brand name Tafinlar) was the second drug of this class to be approved by the Federal Drug Administration. This drug should only be used by patients who have the BRAF V600E mutation. For more about Tafinlar click here.
- RAF-265 is a potent inhibitor of Raf with a highly selective profile and inhibits all 3 isoforms of RAF, as well as mutant BRAF, with high potency. RAF265 is now being investigated in Phase I and II clinical trials in malignant melanoma.
- XL281 is a specific inhibitor of RAF kinases, including the mutant form of BRAF, and has finished Phase I testing.
BRAF Inhibitors in Patients with 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.
Vemurafenib will be tested in children ages 12 to 17.
BRAF Inhibitors in Combination
Listed below are different combinations that are being investigated, one of which has been approved.
- Dabrafenib + Trametinib (brand names Tafinlar and Mekinist) combines a targeted therapy with a MEK inhibitor. In the Phase I/II trial, progression-free survival (the time a patient lives without cancer growing or spreading) was 10.5 months for patients on Tafinlar and Mekinist, versus 5.6 months for patients treated with Tafinlar alone.
- Vemurafenib + Ipilimumab (brand name Yervoy) is a combination of a targeted therapy and an immunotherapy in patients with the BRAF V600 mutation.
- Vemurafenib + Bevacizumab (brand name Avastin) is a combination of a targeted therapy and an anti-angiogenic therapy.
- Vemurafenib + BKM120 combines two targeted therapies. BKM120 is a targeted agent that inhibits a molecule called phosphatidylinositol 3-kinase (PI3K).
MEK is a critical member of the MAPK pathway involved in growth and survival of cancer cells.
- Trametinib (brand name Mekinist) has been approved by the Federal Drug Administration. This drug should only be used by patients who have the BRAF V600E or V600K mutation. Mekinist cannot be used by patients who have already used another BRAF inhibitor. For more about Mekinist click here.
- Selumetinib is given either as a single agent or in combination with MK-2206 (a new compound inhibiting another protein important for cancer growth called Akt). Currently the drug is being tested in melanoma patients with the BRAF V600 mutation whose disease has progressed after being treated with vemurafenib or dabrafenib.
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.
- Imatinib (brand name Gleevec) 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.
- Nilotinib (brand name Tasigna) is approved for the treatment of chronic myeloid leukemia and is currently being tested in melanoma patients with KIT mutations.
- Dasatinib (brand name Sprycel) is approved for chronic myeloid leukemia and is being tested in multiple Phase II trials for melanoma patients with KIT mutations.
Other Targets with Potential in Melanoma
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.