TARGETED THERAPIES

A targeted therapy is a type of cancer drug that targets melanoma cancer cells. It precisely identifies and attacks cancer cells, while doing less damage to healthy or normal cells. Targeted therapy blocks cancer growth, beyond just interfering with cancer cells. It can kill a cancer cell without harming healthy cells. It differs from standard chemotherapy which acts on all rapidly dividing cancer cells and normal cells.

How do targeted therapies work?

The goal of targeted therapy is to shut down mutated protein molecules to slow the growth of melanoma cells – without harming healthy tissue. Targeted therapy is systemic, which means that the drugs travel through the bloodstream to all parts of your body.

BRAF testing in melanoma

About half of melanoma patients have a particular genetic mutation in the BRAF (pronounced beeraf) protein that is causing the cancer to grow. A BRAF mutation triggers cells to develop abnormally and divide out of control. Targeted therapy drug combinations (below) block the activity of the mutated BRAF protein and the MEK protein that is also a part of this growth pathway. The result may slow or stop the growth and spread of melanoma. The combination of BRAF plus MEK inhibitors shrinks or eliminates tumours for longer periods of time than using either type of drug alone.

If you have advanced unresectable or metastatic melanoma, a biopsy of your tumour will likely be tested to see if the cancer cells have a BRAF mutation. Drugs that target the BRAF protein (or the MEK proteins) aren’t likely to work in patients whose melanomas have a normal BRAF gene.

The following combinations of targeted therapies are being used in Canada:

Vemurafenib (Zelboraf) plus cobimetinib (Cotellic): This is a first-line treatment for patients with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma or metastatic melanoma. Vemurafenib targets the mutated BRAF protein, while cobimetinib acts against the MEK protein. The drugs are administered as pills taken daily. Side effects can include rash, nausea, diarrhea, swelling, fatigue and extreme sensitivity to sunlight (UV radiation). Rare but serious side effects can include heart damage, excess bleeding, loss of vision, lung problems and skin infections. Some side effects (such as the development of other skin cancers) are actually less common with the combination therapy.

Dabrafenib (Tafinlar) plus trametinib (Mekinist): This is a first-line treatment for patients with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma for metastatic melanoma. Dabrafenib acts as an inhibitor of the BRAF protein and slows down or stops the growth of cancer cells while trametinib acts against the MEK protein. The drugs are administered as pills taken daily. Side effects can include rash, nausea, fevers, headaches, anemia, changes in eyesight, diarrhea, swelling, and fatigue. Rare but serious side effects can include heart damage, excess bleeding, loss of vision, lung problems, and skin infections.

Braftovi (Encorafenib) plus mektovi (Binimetinib): BRAFTOVI is an oral small molecule BRAF kinase inhibitor and mektovi is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in melanoma. In Canada, BRAFTOVI plus mektovi are approved for the treatment of unresectable or metastatic melanoma with a BRAF V600 mutation, as detected by a validated test.

Current mono targeted therapies in Canada

Vemurafenib (Zelboraf): Is a first line treatment for patients with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma or metastatic melanoma. About half of all melanoma skin cancers make too much BRAF due to a change in a gene. Vemurafenib slows down or stops the growth of cancer cells. The drug is administered as pills taken daily. ZELBORAF targets proteins made from the mutated BRAF gene and slows down or stops the growth of cancer cells.

Trametinib (Mekinist): MEK inhibitors block the activity of a cell protein called MEK, a molecule that helps regulate cell growth. MEK is part of a signaling pathway that includes BRAF, another protein. A BRAF mutation signals cells, via MEK, to develop abnormally and divide out of control and grow into a melanoma tumour. MEK inhibitors act on melanomas that have the V600E or V600K mutations in the BRAF protein. These drugs interfere with abnormal BRAF signals to slow or stop the out-of-control cell growth.

Dabrafenib (Tafinlar): Is a first line treatment for patients with BRAF V600 mutation-positive unresectable stage IIIC or IV melanoma or metastatic melanoma. About half of all melanoma skin cancers make too much BRAF due to a change in a gene. Dabrafenib acts as an inhibitor of the BRAF protein and slows down or stops the growth of cancer cells. The drug is administered as a pill taken daily.