Binimetinib, sold under the brand name Mektovi, is an

anti-cancer medication Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...

used to treat various cancers. Binimetinib is a selective inhibitor of MEK, a central

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

in the tumor-promoting MAPK pathway. Inappropriate activation of the pathway has been shown to occur in many cancers. In June 2018 it was approved by the FDA in combination with

encorafenib Encorafenib, sold under the brand name Braftovi, is an anti-cancer medication used for the treatment of certain melanoma cancers. It is a small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway. This pathway occu ...

for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma. In October 2023, it was approved by the FDA for treatment of NSCLC with a BRAF V600E mutation in combination with

. It was developed by Array Biopharma.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor. MEK is part of the

RAS pathway Ras, from "Rat sarcoma virus", is a protein family, family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in trans ...

, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer. Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis. MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types. Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling. As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including

interleukin-1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

, -6 and

tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

Development

In 2015, it was in phase III clinical trials for ovarian cancer, BRAF mutant

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

, and NRAS Q61 mutant melanoma. In December 2015, the company announced that the mutant-NRAS melanoma trial was successful. In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazine treatment. NDA submitted Jun 2016, and the FDA should decide by 30 June 2017. In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy. In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the

New Drug Application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

was withdrawn. In June 2018, it was approved for the treatment of certain melanomas by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) in combination with encorafenib. The FDA approved binimetinib based primarily on evidence from one clinical trial (NCT01909453) of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery. The trial was conducted at 162 sites in Europe, North America, and various countries around the world. In October 2023, the US

approved

with binimetinib for adults with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

References

External links

{{Authority control Benzamides Cancer treatments Fluorobenzene derivatives MEK inhibitors Bromobenzene derivatives Orphan drugs Drugs developed by Pfizer Hydroxyethyl compounds