Binimetinib (MEK162)

Target: MEK | Disease State: Melanoma and Colorectal Cancer

Introduction / Brief Description

BRAFTOVI® (encorafenib) is an oral small molecule BRAF kinase inhibitor and MEKTOVI® (binimetinib) is an oral small molecule MEK inhibitor which target key enzymes in in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer, thyroid and others.

In the United States, BRAFTOVI in combination with MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

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The National Comprehensive Cancer Network (NCCN©) updated the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma to include encorafenib (BRAFTOVI) in combination with binimetinib (MEKTOVI) as a Category 1 first-line treatment option for patients with metastatic or unresectable melanoma with a BRAFV600-activating mutation.*

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.

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 metastatic colorectal cancer (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. The triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial.

Based on consultation with the FDA and EMA, Array plans to amend the BEACON CRC protocol to allow for an interim analysis of trial endpoints. Should a planned analysis based primarily on confirmed overall response rate (ORR) and durability of response be supportive, Array plans to use it to seek accelerated approval in the U.S. The interim analysis may also support regulatory submissions in other regions. Array anticipates topline results from this analysis in the first half of 2019. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated.

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.

BEACON CRC Safety Lead-In Results

In June 2018, Array announced updated results from the 30 patient safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, binimetinib, and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant metastatic CRC whose disease has progressed after one or two prior regimens. The data were presented at the ESMO 20th World Congress on Gastrointestinal Cancer. 

At the time of the updated analysis, in patients with BRAFV600E mutation, the overall survival (OS) data were fully mature through 12.6 months and the median OS had not yet been reached. The one-year overall survival rate for this cohort was 62%. The median progression-free survival (mPFS) for patients treated with the triplet was 8 months [95% CI 5.6-9.3] and is similar between patients receiving one prior line of therapy and patients receiving two prior lines of therapy. The confirmed overall response rate (ORR) was 48% and among the 17 patients who received only one prior line of therapy the ORR was 62%. In the updated analysis, the triple combination was generally well-tolerated with no unexpected toxicities. One patient discontinued treatment with the triplet combination due to treatment-related adverse events. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased blood creatine kinase (10%) and increased aspartate aminotransferase (10%).

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, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients. 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 clinical activity benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. Prognosis for patients treated for BRAF-mutant CRC whose disease has progressed after one or two prior lines of therapy, range between 4% to 8% ORR, 1.8 and 2.5 months mPFS and 4 and 6 months mOS.

Clinical Trials

Trial Data
Trial Title
Program: Binimetinib (MEK162)
Phase: 3
Status: Active, not recruiting
Disease: BRAF V600 mutant melanoma
Sponsor: Array BioPharma
Trial Information: NCT01909453
Trial Title: Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)
Program: Binimetinib (MEK162)
Phase: 3
Status: Recruiting
Disease: BRAF-mutant colorectal cancer
Sponsor: Array BioPharma
Trial Information: NCT02928224
Trial Title: Study evaluating the efficacy and safety of binimetinib, encorafenib and Erbitux in BRAFm metastatic CRC (BEACON CRC)
Program: Binimetinib (MEK162)
Trial Information: ClinicalTrials.gov
Trial Title: Other clinical Trials

To learn more about binimetinib clinical trials, click here.

Publications and Presentations

Binimetinib and Encorafenib

10/24/2018

2018 Society for Melanoma Research (SMR) Annual Congress

Characteristics of Pyrexia With Encorafenib (ENCO) Plus Binimetinib (BINI) in Patients With BRAF-Mutant Melanoma

M. Mandala, et al.

Binimetinib and Encorafenib

09/12/2018

The Lancet Oncology

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

R. Dummer, M.D., et al.

Binimetinib and Encorafenib

06/23/2018

ESMO World Congress on Gastrointestinal Cancer

BEACON CRC Study Safety Lead-in: Assessment of the BRAF Inhibitor Encorafenib + MEK Inhibitor Binimetinib + Anti–Epidermal Growth Factor Receptor Antibody Cetuximab for BRAFV600E Metastatic Colorectal Cancer

E. Van Cutsem, M.D., et al.

Binimetinib and Encorafenib

06/04/2018

ASCO Annual Meeting

Adverse Events of Special Interest in the Phase 3 COLUMBUS Study

Helen J. Gogas, M.D., et al.

Binimetinib and Encorafenib

06/04/2018

ASCO Annual Meeting

Overall Survival in COLUMBUS: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) vs Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma

R. Dummer, M.D., et al.

Binimetinib

01/20/2018

2018 Gastrointestinal Cancers Symposium (ASCO GI)

Phase 1b/2 Study of Binimetinib in Combination With Nivolumab (NIVO) or NIVO Plus Ipilimumab in Patients With Previously Treated Microsatellite-Stable Metastatic Colorectal Cancer With RAS Mutation

J. Bendell, et al.

Binimetinib

09/10/2017

European Society for Medical Oncology Annual Congress

Quality of Life in COLUMBUS Part 1: A Phase 3 Trial of Encorafenib Plus Binimetinib vs Vemurafenib or Encorafenib Monotherapy in BRAF-Mutant Melanoma

H. J. Gogas, et al.

Binimetinib

09/10/2017

European Society for Medical Oncology Congress

Hospitalization Rates in COLUMBUS Part 1: A Phase 3 Trial of Encorafenib Plus Binimetinib vs Vemurafenib or Encorafenib Monotherapy in BRAF-Mutant Melanoma

A. Arance, et al.

Binimetinib

09/09/2017

European Society for Medical Oncology Congress

BEACON CRC: Safety Lead-In (SLI) for the Combination of Binimetinib (BINI), Encorafenib (ENCO), and Cetuximab (CTX) in Patients (Pts) with BRAFV600E Metastatic Colorectal Cancer (mCRC)

S. Huijberts, et al.

Binimetinib

06/03/2017

American Society of Clinical Oncology Meeting

Phase 1b/2 Trial of Ribociclib + Binimetinib in Metastatic NRAS-Mutant Melanoma: Safety, Efficacy, and Recommended Phase 2 Dose

Martin Schuler, et al.


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Expanded Access Policy

 

Continuing Medical Education / Grant Requests

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.

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma V.3.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed July 12, 2018. 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.