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

In November 2016, new results from the pivotal Phase 3 COLUMBUS trial were presented at the Society for Melanoma Research Annual Congress. The study met its primary endpoint, with the combination of bini/enco significantly improving progression free survival (PFS) compared with vemurafenib, a BRAF inhibitor, alone. The combination of bini/enco was generally well-tolerated and reported adverse events (AEs) were overall consistent with previous published clinical trial results for the bini/enco combination in BRAF-mutant melanoma patients. 

In the analysis of the primary endpoint, the median PFS (mPFS) for patients treated with the combination of bini/enco was 14.9 months versus 7.3 months for patients treated 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 chart below outlines the mPFS results, as determined by both assessments, for the combination of bini/enco versus vemurafenib, bini/enco versus encorafenib, and encorafenib versus vemurafenib:

   

mPFS BICR

 

mPFS Local Review

Bini/Enco vs. 
Vemurafenib 

 

Bini/Enco

Vemurafenib

 

Bini/Enco

Vemurafenib

 

14.9 months

7.3 months

 

14.8 months

7.3 months

 

HR (95% CI): 0.54 (0.41-0.71); P<0.001 

 

HR (95% CI): 0.49 (0.37-0.64); P<0.001 

 

Bini/Enco vs. 
Encorafenib 

 

Bini/Enco

Encorafenib

 

Bini/Enco

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 

The combination of bini/enco also demonstrated an improvement in confirmed overall response rate (ORR; complete response plus partial response), as well as favorable median duration of exposure, high median dose intensity and consistent activity in patients with prior immunotherapy treatment as well as an advantage in terms of maintaining quality of life for patients.

 

Confirmed ORR BICR

Confirmed ORR Local Review

Bini/Enco

63% (95% CI:  56-70%)

75% (95% CI:  68-81%)

Vemurafenib 

40% (95% CI:  33-48%)

49% (95% CI:  42-57%)

Encorafenib 

51% (95% CI:  43-58%)

58% (95% CI:  50-65%)

  • Median duration of exposure was approximately 51 weeks for patients receiving bini/enco, versus 31 weeks and 27 weeks for the encorafenib and vemurafenib monotherapy arms, respectively
  • Median dose intensity for patients treated with bini/enco was 100% (encorafenib) and 99.6% (binimetinib)
  • 5% of bini/enco patients had received prior treatment with check-point inhibitors, including ipilimumab, anti-PD-1 and/or anti-PD-L1 therapies, and the observed clinical activity for these patients was consistent with that of bini/enco patients who had not received prior immunotherapy
  • The Quality of Life (QoL) measures were consistent between two scales and showed an advantage in terms of maintaining quality of life for patients receiving bini/enco compared to patients treated with either encorafenib or vemurafenib single agent therapy. The QoL scales used were the EORTC Quality of Life Questionnaire Core 30 and FACT-Melanoma Scale Score (Functional Assessment of Cancer Therapy).

The combination of bini/enco was generally well-tolerated and reported AEs were overall consistent with previous bini/enco combination clinical trial results in BRAF-mutant melanoma patients.

  • Grade 3/4 AEs which occurred in more than 5% of patients receiving bini/enco included increased gamma-glutamyltransferase (GGT), increased blood creatine phosphokinase (CK), and hypertension
  • The incidence of AEs of special interest (toxicities commonly associated with commercially available MEK+BRAF-inhibitor treatments), for patients receiving bini/enco included (% of patients): rash (23%), pyrexia (18%), retinal pigment epithelial detachment (13%) and photosensitivity (5%)

In September 2016, Array announced that the FDA has accepted its NDA for binimetinib with a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2017. Array completed its NDA submission of binimetinib in late June 2016 based on findings from the pivotal Phase 3 NEMO trial in patients with NRAS-mutant melanoma. The FDA also indicated that it plans to hold an advisory committee meeting (ODAC) as part of the review process, which is expected in the first half of 2017. Results from the NEMO trial were presented at the 2016 ASCO Annual Meeting. The study met its primary endpoint of improving progression-free survival (PFS) compared with dacarbazine treatment. The median PFS on the binimetinib arm was 2.8 months, versus 1.5 months on the dacarbazine arm. 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, compared with 1.6 months for those receiving treatment with dacarbazine. While the results in the pre-specified sub-group of patients who had received prior treatment with immunotherapy are of interest, interpretation beyond overall consistency with the primary result should be made with care. Array anticipates that the primary consideration for marketing approval will be the results for the primary endpoint of the trial.  In addition to improving PFS, binimetinib also demonstrated improvement in overall response rate (ORR) and disease control rate. While there was no statistically significant difference demonstrated in overall survival (OS), the median overall survival (mOS) favored the binimetinib arm. Under the NEMO protocol, and in accordance with accepted statistical practice, the subgroup analyses of OS are formally conducted only if the key secondary endpoint of OS reached statistical significance. Binimetinib was generally well-tolerated and the adverse events reported were consistent with previous results in NRAS-mutant melanoma patients.

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: 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

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

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.

Binimetinib / Cancer

11/07/2016

2016 Society for Melanoma Research (SMR) Annual Congress

Management of MEK inhibitor (MEKi) toxicities of binimetinib (BINI) in the NEMO trial

Paolo A. Ascierto, M.D., et al.

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.

 


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