Encorafenib (LGX818)

Target: BRAF | 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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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.

BEACON CRC Safety Lead-In Results

In January 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 ASCO 2018 Gastrointestinal Cancers Symposium. 

In patients with the BRAFV600E mutation, the estimated mPFS at the time of analysis was 8 months. The confirmed overall response rate (ORR)* in patients with the BRAFV600E mutation was 48%, and 3 patients achieved complete responses (CR). Further, the ORR was 62% in the 16 patients (10/16) who received only one prior line of therapy. These data represent substantial improvements compared to several separate historical published ORR and mPFS benchmarks in this patient population using standard of care regimens which range between 4% to 8% and 1.8 and 2.5 months, respectively.

In the safety lead-in, the triplet combination was generally well-tolerated. Two patients discontinued treatment due to AEs with only one of these considered related to treatment. The most common grade 3 or 4 AEs seen in at least 10% of patients were fatigue (4/30), urinary tract infection (3/30), increased aspartate aminotransferase (AST; 3/30) and increased blood CK (3/30). 

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

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 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. 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) to 18% in a recent Southwestern Oncology Group (SWOG) randomized phase 2 trial.  

Clinical Trials

Trial Data
Trial Title
Program: Encorafenib
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: Encorafenib
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)
Trial Information: ClinicalTrials.gov
Trial Title: Other clinical Trials

To learn more about encorafenib clinical trials, click here.

Publications and Presentations

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 and Encorafenib

03/21/2018

The Lancet Oncology

Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial

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

Binimetinib and Encorafenib

01/20/2018

2018 Gastrointestinal Cancers Symposium (ASCO GI)

BEACON CRC Study Safety Lead-in (SLI) in Patients With BRAFV600E Metastatic Colorectal Cancer (mCRC): Efficacy and Tumor Markers

Van Cutsem, et al.

Encorafenib

07/01/2016

ESMO World Congress of Gastrointestinal Cancer

Combination of Encorafenib and Cetuximab With or Without Alpelisib in Patients With Advanced BRAF-Mutant (BRAFm) Colorectal Cancer: Phase 2 Results

J. Tabernero, et al.

Encorafenib

06/01/2016

American Society of Clinical Oncology Meeting

Phase 2 results: encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC)

J. Tabernero, et al.

Encorafenib

07/04/2015

ESMO World Congress of Gastrointestinal Cancer

Phase 1b/2 Study of the Selective BRAF V600 Inhibitor Encorafenib (LGX818) Combined With Cetuximab With or Without the α‐Specific PI3K Inhibitor Alpelisib (BYL719) in Patients With Advanced BRAF‐Mutant Colorectal Cancer

E. Elez, et al.

Encorafenib

05/30/2015

American Society of Clinical Oncology Meeting

A Phase 1/b2 Study of BRAF Inhibitor (BRAFi) Encorafenib (ENCO) Plus MEK Inhibitor (MEKi) Binimetinib (BINI) in Cutaneous Melanoma Patients Naive to BRAFI Treatment

R. Sullivan, et al.

Encorafenib

04/20/2015

American Association for Cancer Research Annual Meeting

Personalized pre-clinical trials in BRAF inhibitor resistant patient derived xenograft models of melanoma identify c-Met as an effective second line combination therapy target

C. Krepler, et al.

Encorafenib

04/18/2015

American Association for Cancer Research Annual Meeting

Phase 1 Study of the Selective BRAFV600 Inhibitor Encorafenib (LGX818) Combined With Cetuximab and With or Without the α-specific PI3K Inhibitor Alpelisib (BYL719) in Patients With Advanced BRAF-mutant Colorectal Cancer

J. Schellens, M.D., et al.


To view all publications, click here.

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 only.