Binimetinib plus encorafenib for metastatic melanoma

Source: NPS MEDICINEWISE, November 2019

Many cases of melanoma involve the BRAF mutation. This results in the production of an abnormal protein kinase which promotes tumour cell growth. Drugs, such as vemurafenib and dabrafenib, that can inhibit this BRAF kinase may therefore improve survival in patients with melanoma. Another step in the pathway leading to tumour cell growth involves the MEK enzymes. These are the targets of drugs such as cobimetinib and trametinib. For patients with BRAF mutations, current treatment involves a combination of a BRAF inhibitor and a MEK inhibitor.1 Encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) are an example of such a combination for the treatment of unresectable or metastatic melanoma.

Both drugs should be swallowed whole with water. Grapefruit juice should be avoided as it interacts with encorafenib. At the recommended doses steady state is reached within 15 days. Both drugs are mainly cleared by metabolism. As the metabolism of encorafenib involves cytochrome P450 (CYP) 2C19, 2D6 and 3A4, there are many potential drug interactions. Strong inhibitors of CYP3A4 such as clarithromycin and itraconazole should be avoided. Liver disease will increase the concentrations of both drugs. A reduced dose of encorafenib is advised in mild hepatic impairment (Child Pugh A) and the combination should not be used at all with greater impairment.

The terminal half-life is about nine hours for binimetinib and six hours for encorafenib. Little active drug is excreted in the urine. No dose reductions are required in patients with mild or moderate renal impairment, but there are no data about the combination in severe impairment (<30 mL/min/1.73 m2).

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