Binimetinib

Target: MEK | Disease State: Melanoma and Colorectal Cancer

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Overview

Binimetinib is a late-stage small molecule MEK inhibitor that targets key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer (CRC). Binimetinib is being studied in clinical trials in combination with other medications in BRAF-mutant melanoma and colorectal cancer (CRC), and in combination with immuno-oncology PD-1/PD-L1 checkpoint inhibitors in several solid tumor populations.

National Comprehensive Cancer Network (NCCN®) Guidelines

The NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cutaneous Melanoma v2.2019 include encorafenib in combination with binimetinib as a Category 1* first-line systemic therapy option for patients with metastatic or unresectable melanoma with a BRAFV600-activating mutation.

NCCN also updated the NCCN Guidelines® for Colon Cancer and the NCCN Guidelines for Rectal Cancer to include encorafenib in combination with binimetinib and cetuximab or panitumumab as a Category 2A treatment option for patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC), after one or two prior lines of therapy for metastatic disease.§

BRAF-mutant melanoma

Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumors. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma.

More information on BRAF-mutant melanoma.

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BRAF-mutant colorectal cancer

Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, it was estimated that 140,250 patients would be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 were estimated to die of their disease. BRAF mutations are estimated to occur in up to 15% of patients with metastatic colorectal cancer (mCRC) and represent a poor prognosis for these patients. The V600 mutation is the most common BRAF mutation, and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. Several irinotecan- and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established certain observed historical published benchmarks in BRAFV600E-mutant mCRC patients whose disease has progressed after one or two prior lines of therapy. These benchmarks include a general overall response rate (ORR) of 4% to 8%, median progression-free survival (mPFS) of 2 to 3 months and median overall survival (OS) of 4 to 6 months. BRAFV600E-mutant mCRC is an area of high unmet need, as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC.

More information on BRAF-mutant metastatic colorectal cancer.

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Phase 3 BEACON CRC trial

BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and cetuximab in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAFV600E mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only 1 patient. Based on an encouraging safety profile and with clinical activity observed in the safety lead-in, the randomized portion of the trial was initiated and has completed enrollment.

In August 2018, the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and cetuximab for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

ANCHOR CRC trial

ANCHOR CRC is an international trial designed to assess the efficacy and safety of the combination of BRAFTOVI, MEKTOVI and cetuximab in patients with  BRAFV600E-mutant mCRC in the first-line setting. The ANCHOR CRC trial is being conducted in collaboration with Pierre Fabre and Ono Pharmaceutical Co., Ltd., and with support from Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

Immuno-oncology collaborations with Bristol-Myers Squibb, Merck and Pfizer

Array is developing binimetinib in combination with PD-1/PD-L1 checkpoint inhibitors in separate, strategic collaborations with Bristol-Myers Squibb, Merck and Pfizer. Each collaboration is pursuing a different rationally designed clinical approach in several solid tumor populations, including metastatic colorectal cancer patients with microsatellite stable tumors (BMS and Merck) and patients with non–small cell lung and pancreatic cancer (Pfizer). These approaches are characterized by their focus on earlier lines of therapy and the addition of a third regimen.

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These compounds and their uses are investigational and have not been approved by the U.S. Food and Drug Administration. This information is presented only for purposes of providing a general overview of our clinical trials.

*Category 1: based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cutaneous Melanoma V.2.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 12, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Category 2A: based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

§Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer and the NCCN Guidelines for Rectal Cancer V.1.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed March 15, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims and responsibility for their application or use in any way.