Binimetinib

Binimetinib is a drug (molecular formula: C17H15BrF2N4O3 ) which is suitable for the treatment of advanced melanoma if certain genetic changes are present (mutation in the growth gene BRAF) and further if the melanoma is not or no longer resectable, or if it has already metastasized. Binimetinib is combined with the active substance Encorafenib.

Binimetinib is a non-ATP-competitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. The MEK proteins are upstream regulators of the kinase signal transduction (ERK) pathway associated with extracellular signaling, which promotes cell proliferation. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF that activate MEK. Binimetinib inhibits the activation of MEK by BRAF as well as MEK kinase activity. Binimetinib inhibits the growth of melanoma cell lines with BRAF V600 mutation and shows antitumor effects in animal models of BRAF V600 mutated melanoma.

For melanoma with NRAS mutations, binimetinib can also be used. Because binimetinib and encorafenib both inhibit the MAP kinase pathway, combined administration results in greater antitumor activity. In addition, the combination of encorafenib plus binimetinib prevented the development of resistance in vivo in human melanoma xenografts with BRAF V600E mutation.

Binimetinib together with encorafenib compared to BRAF inhibitor monotherapy increases efficacy with adequate tolerability.

Binimetinib is orally active; the recommended total daily dose of binimetinib is 90 mg. Treatment should be continued until the patient no longer has any benefit or until there is unacceptable toxicity.

The following events were observed very frequently (i.e. >10% of patients treated) during combination therapy with encorafenib and binimetinib at the standard dose: anaemia, peripheral neuropathy, dizziness, headache, visual disturbances, detachment of retinal pigment epithelium, bleeding, hypertension, abdominal pain, diarrhoea, vomiting, nausea, constipation, hyperkeratosis, rash, dry skin, Pruritus, alopecia, arthralgia, muscle diseases / myalgia, back pain, pain in the extremities, pyrexia, peripheral edema, fatigue, increase creatine kinase in the blood, increase transaminases, increase gamma-glutamyl transferase.

In June 2018, the US Food and Drug Administration (FDA) approved binimetinib in combination with encorafenib. The Committee for Medicinal Products for Human Use of the European Medicines Agency approved the preparation in September 2018.

1. Dummer R et al (2018) Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. In: The Lancet Oncology 19:603-615
2. Dummer R et al (w2018) Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology 19: 1315-1327
3. Koelblinger P et al (2018) Development of encorafenib for BRAF-mutated advanced melanoma. In: Current Opinion in Oncology 30: 125-133