Binimetinib (MEK162)

Target: MEK | Indication: Melanoma and Colorectal Cancer

Introduction / Brief Description

Binimetinib is an oral small-molecule MEK inhibitor invented by Array. MEK is a key protein kinase in the RAS/RAF/MEK/ERK pathway, which regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, in particular through mutations in BRAF, KRAS and NRAS.

There are two Phase 3 trials with binimetinib in advanced cancer patients: COLUMBUS (encorafenib in combination with binimetinib in BRAF-mutant melanoma) and BEACON CRC [encorafenib, binimetinib and Erbitux® (cetuximab) in BRAF-mutant colorectal cancer].  

In September 2017, Array announced that the U.S. Food and Drug Administration (FDA) has accepted for review its New Drug Applications (NDAs) to support use of the combination of binimetinib 45 mg twice daily and encorafenib 450 mg once daily (COMBO450) for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the FDA informed Array that based on their preliminary review of the applications they have not identified any potential review issues, and that they are not currently planning to hold an advisory committee meeting to discuss these NDAs.  Array completed its NDA submissions at the end of June 2017 based on findings from the pivotal Phase 3 COLUMBUS trial. 

COLUMBUS Results

As presented at the 2016 Society for Melanoma Research Annual Congress, results from Part 1 of the COLUMBUS study showed that COMBO450 significantly extend PFS in patients with advanced BRAF-mutant melanoma, with a PFS of 14.9 months compared with 7.3 months observed with vemurafenib [hazard ratio (HR) 0.54, (95% CI 0.41-0.71, P<0.001)]. As part of the trial design, the primary analysis was based on a Blinded Independent Central Review (BICR) of patient scans, while results by local review at the investigative site were also analyzed. The table below outlines the median PFS (mPFS) results, as determined by both assessments, for COMBO450 versus vemurafenib, COMBO450 versus encorafenib, and encorafenib versus vemurafenib:

 

 

mPFS BICR

 

mPFS Local Review

COMBO450 vs. Vemurafenib 

 

COMBO450

Vemurafenib

 

COMBO450

Vemurafenib

 

14.9 months

7.3 months

 

14.8 months

7.3 months

 

HR (95% CI): 0.54 (0.41-0.71); P

 

HR (95% CI): 0.49 (0.37-0.64); P

 

COMBO450 vs. Encorafenib 

 

COMBO450

Encorafenib

 

COMBO450

Encorafenib

 

14.9 months

9.6 months

 

14.8 months

9.2 months

 

HR (95% CI): 0.75 (0.56-1.00); P=0.051 

 

HR (95% CI): 0.68 (0.52-0.90); P=0.006 

 

Encorafenib vs. Vemurafenib

 

Encorafenib

Vemurafenib

 

Encorafenib

Vemurafenib

 

9.6 months

7.3 months

 

9.2 months

7.3 months

 

HR (95% CI): 0.68 (0.52-0.90); P=0.007

 

HR (95% CI): 0.70 (0.54-0.91); P=0.008 

In this study, COMBO450 was generally well-tolerated, with a median duration of treatment of 51 weeks and median relative dose intensity for encorafenib and binimetinib of 100% and 99.6%, respectively. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving COMBO450 were increased blood creatine phosphokinase (CK) (9%), increased gamma-glutamyltransferase (GGT) (7%) and hypertension (6%). The incidence of any grade of AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO450 included: rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%).  Full safety results of COLUMBUS Part 1 were presented at the 2016 Society for Melanoma Research Annual Congress.

COLUMBUS Part 2 was designed specifically to assess the contribution of binimetinib to the combination of binimetinib and encorafenib by reducing the dose of encorafenib to 300mg in the combination arm to allow for a comparison of equal doses across arms. In COLUMBUS Part 2, the primary analysis compared PFS in patients treated with binimetinib 45mg twice daily plus encorafenib 300mg daily (COMBO300) to patients treated with encorafenib 300mg daily as a single agent.  The median PFS for patients treated with COMBO300 was 12.9 months compared to 9.2 months for patients treated with single agent encorafenib, with HR of 0.77 [95% CI 0.61-0.97, p=0.029]. As part of the trial design, the analysis was based on a BICR of patient scans, while results by local review at the investigative site were also analyzed. COMBO300 was generally well-tolerated and reported dose intensity and adverse events were consistent with binimetinib 45 mg twice daily plus encorafenib 450 mg daily (COMBO450) results in COLUMBUS Part 1. Grade 3/4 adverse events (AEs) that occurred in 5% or more of patients receiving COMBO300 were increased GGT (5%), increased blood CK (5%) and increased alanine aminotransferase (ALT) (5%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments for patients receiving COMBO300 included: pyrexia (17%), rash (15%), retinal pigment epithelial detachment (9%) and photosensitivity (2%). Full safety results of COLUMBUS Part 2 were presented at the 2017 ESMO Congress.

In addition to these registration trials, early-stage studies have been initiated or announced to evaluate binimetinib in numerous solid tumors and hematologic malignancies.  Importantly, Array is collaborating with Merck and Bristol-Myers Squibb to study binimetinib plus anti-PD-1 therapy in patients with microsatellite stable metastatic CRC (MSS CRC).  

BRAF-mutant Melanoma 

Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. 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 

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. Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, an estimated 135,430 patients will be diagnosed with cancer of the colon or rectum in 2017, and approximately 50,000 are estimated to die of their disease. In the United States, BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients.  Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) and 18% a recent Southwestern Oncology Group (SWOG) randomized phase 2 study.  

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 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

Publications

Binimetinib and Encorafenib

09/09/2017

European Society for Medical Oncology Congress

RESULTS OF COLUMBUS PART 2: A Phase 3 Trial of Encorafenib Plus Binimetinib Versus Encorafenib in BRAF-Mutant Melanoma

R. Dummer, et al.

Binimetinib and Encorafenib

11/09/2016

2016 Society for Melanoma Research (SMR) Annual Congress

Results of COLUMBUS Part 1: A Phase 3 Trial of Encorafenib (ENCO) Plus Binimetinib (BINI) Versus Vemurafenib (VEM) or ENCO in BRAF-Mutant Melanoma

Keith T. Flaherty, M.D., et al.

Binimetinib / Cancer

09/10/2017

European Society for Medical Oncology 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

Helen J. Gogas, et al.

Binimetinib / Cancer

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

Ana Arance, et al.

Binimetinib / Cancer

09/09/2017

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)

Huijberts, et al.

Binimetinib / Cancer

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.

Binimetinib / Cancer

11/07/2016

2016 Society for Melanoma Research (SMR) Annual Congress

Efficacy of binimetinib in patients with NRAS-mutant melanoma: subgroup analysis of the phase 3 NEMO study

Ana Arance, M.D., et al.

 


To view all publications, click here.

Continuing Medical Education / Grant Requests
CME@arraybiopharma.com