MEK Inhibitors for the Treatment of Melanoma

Alex A. Adjei, MD, PhD, Professor and Chair, Department of Medicine, Katherine Anne Gioia Chair in Cancer Medicine, Senior Vice President, Clinical Research, Roswell Park Cancer Institute, discusses the use of MEK inhibitors when treating patients with melanoma.

Adjei states that MEK inhibitors are a class of compounds that have been tested for 13 years. Researchers are interested in MEK because it is highly expressed without the presence of a mutation, since a number of proteins that drive cancer tumors signal through the MEK pathway, Adjei says. As a result, researchers believed that if they blocked MEK they would be able to affect a lot of different types of cancers.

The third generations of MEK compounds seem to have ideal properties and are more potent than earlier generations, Adjei says. The first MEK compound was approved to treat patients with melanoma. This is not surprising, since MEK is downstream from RAF, which is also effective in the treatment of melanoma, Adjei notes.

Since BRAF inhibitors are approved and work well in patients with melanoma, some doctors may argue that there is no place for a MEK inhibitor. However, Adjei believes, having two inhibitors that work well in the same space is beneficial because patients react differently to each medication. As a result, a patient that does not respond to a BRAF inhibitor may respond to a MEK inhibitor, Adjei says.

Each agent has a unique side effect profile, Adjei says. BRAF inhibitors can cause skin cancers while MEK inhibitors do not. However, MEK inhibitors can cause blurred vision, Adjei says. Stopping treatment and then continuing at a reduced dose can reverse this side effect.

The fact that two oral medications are approved for melanoma is exciting, Adjei says. More exciting, Adjei states, is that a BRAF inhibitor and a MEK inhibitor actually work better together than they do alone. Moreover, the two drugs are actually less toxic together than they are apart, which is uncommon.

Clinical Pearls

• Some cancer cells have high MEK expression
• Since a number of proteins that drive cancer tumors signal through MEK, blocking MEK may affect a variety of different types of tumors
• Since MEK is downstream of RAF, which is active in melanoma, it makes sense that MEK is also active in melanoma
• Although similar, MEK and RAF inhibitors are not identical
• RAF inhibitors can cause side effects such as skin cancers while MEK inhibitors do not
• MEK inhibitors can cause temporary blurred vision
• Having two inhibitors that work well is beneficial, since patients respond differently to each
• Using BRAF and MEK inhibitors together is less toxic than using them as single agents