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.

Three Phase 3 trials with binimetinib in advanced cancer patients are currently advancing: NEMO (NRAS-mutant melanoma), COLUMBUS (encorafenib in combination with binimetinib in BRAF-mutant melanoma) and BEACON [encorafenib, binimetinib and Erbitux® (cetuximab) in BRAF-mutant colorectal cancer].  Array plans to submit a regulatory filing for binimetinib in NRAS-mutant melanoma in June 2016.  In addition, Array expects top-line results from Part 1 of the COLUMBUS trial in the third quarter of 2016 . 

At the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract No. 9500), full results were presented from the pivotal Phase 3 NEMO trial of binimetinib. The study found binimetinib significantly extended median progression-free survival (PFS), the study’s primary endpoint, at 2.8 months, as compared with 1.5 months observed with dacarbazine [hazard ratio (HR)=0.62 (95% CI 0.47-0.80), p<0.001] – the first trial to ever meet a PFS endpoint in patients with advanced NRAS-mutant melanoma. In the pre-specified subset of patients who received prior treatment with immunotherapy, including ipilimumab, nivolumab or pembrolizumab, patients who received binimetinib experienced 5.5 months of median PFS (95% CI, 2.8–7.6), compared with 1.6 months for those receiving treatment with dacarbazine (95% CI, 1.5–2.8).

In addition to improving PFS, binimetinib also demonstrated significant improvement in overall response rate (ORR) and disease control rate (DCR). While there was no statistically significant difference demonstrated in overall survival, the median overall survival (mOS) favored the binimetinib arm.

  • Confirmed ORR was 15 percent (95% CI, 11-20 percent) in patients receiving binimetinib vs. 7 percent (95% CI, 3-13 percent) in patients receiving dacarbazine.
  • DCR for patients receiving binimetinib was 58 percent (95% CI, 52-64 percent) vs. 25 percent (95% CI, 18-33 percent) for patients receiving dacarbazine.
  • mOS was estimated at 11.0 months in patients receiving binimetinib vs. 10.1 months for patients treated with dacarbazine [(HR) = 1.0 (95% CI 0.75-1.33), p=0.499].

Binimetinib was generally well-tolerated and the adverse events (AEs) reported were consistent with previous results in NRAS-mutant melanoma patients. Grade 3/4 AEs reported in greater than or equal to 5 percent of patients receiving binimetinib included increased creatine phosphokinase (CPK) and hypertension.

In addition to these registration trials, early-stage studies have been initiated to evaluate binimetinib in numerous solid tumors and hematologic malignancies.

BRAF-mutant Melanoma and NRAS-mutant Melanoma

Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with 76,380 new cases and over 10,130 deaths from the disease projected in 2016. Novel therapies that target the RAS/RAF/MEK/ERK pathway have a strong scientific rationale for activity in this disease, as melanoma is often characterized by activating mutations in BRAF (approximately 50% of patients) and NRAS (approximately 20% of patients). There are presently no approved therapies specifically targeting NRAS-mutant melanoma.

BRAF-mutant Colorectal Cancer

Colorectal cancer is the third most common cancer among men and women in the United States, with more than 134,000 new cases and nearly 50,000 deaths from the disease projected in 2016. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients. Historical published PFS and OS results after first-line treatment range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published response rates from various studies for EGFR-based therapy in this population range from 6 percent to 8%.

 

Clinical Trials

Trial Data
Trial Title
Program: Binimetinib (MEK162)
Phase: 3
Status: Active, not recruiting
Disease: NRAS mutant melanoma
Sponsor: Novartis
Trial Information: NCT01763164
Trial Title: Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma (NEMO)
Program: Binimetinib (MEK162)
Phase: 3
Status: Active, not recruiting
Disease: BRAF V600 mutant melanoma
Sponsor: Novartis
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: Not yet 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)
Program: Binimetinib (MEK162)
Trial Information: ClinicalTrials.gov
Trial Title: Other clinical Trials

Publications

Binimetinib / Cancer

06/06/2016

American Society of Clinical Oncology Meeting

Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma

R. Dummer, et al.

Binimetinib / Cancer

01/21/2016

American Society of Clinical Oncology GI 2016

A Phase I Study of MEK162 and FOLFOX in chemotherapy-resistant metastatic colorectal cancer

M. Cho, et al.

Binimetinib / Cancer

09/28/2015

European Cancer Congress

A Phase 1b/2 Study of Ribociclib (LEE011; CDK4/6 inhibitor) in Combination With Binimetinib (MEK162; MEK inhibitor) in Patients With NRAS‐Mutant Melanoma

C. van Herpen, M.D., Ph.D, et al.

Binimetinib / Cancer

09/27/2015

European Cancer Congress

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

Binimetinib / Cancer

05/31/2015

American Society of Clinical Oncology Meeting

SUCCESSFUL IMPLEMENTATION OF A NOVEL TRIAL MODEL – THE SIGNATURE PROGRAM

J. Peguero, et al.

 


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