Encorafenib (LGX818)

Target: BRAF | Disease State: Melanoma and Colorectal Cancer

Introduction / Brief Description

Encorafenib is a late-stage small molecule BRAF inhibitor which targets key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma and colorectal cancer (CRC). Encorafenib is being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial. 

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

The COLUMBUS trial is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of the combination of encorafenib and binimetinib compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. Prior immunotherapy treatment was allowed. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial. Patients were randomized into two parts:

In Part 1, 577 patients were randomized 1:1:1 to receive the combination of encorafenib 450 mg daily and binimetinib 45 mg twice daily (COMBO450), encorafenib, 300 mg daily (ENCO 300), or vemurafenib, 960 mg twice daily alone. The dose of encorafenib in the combination arm is 50% higher than the single agent maximum tolerated dose of 300 mg. A higher dose of encorafenib was possible due to improved tolerability when combined with binimetinib. The primary endpoint for the COLUMBUS trial was a median Progression Free Survival comparison of the COMBO450 arm versus vemurafenib. mPFS is determined based on tumor assessment (RECIST version 1.1 criteria) by a Blinded Independent Central Review (BICR). Secondary endpoints include a comparison of the mPFS of COMBO450 arm to that of ENCO300 and a comparison of overall survival (OS) in patients treated in the COMBO450 arm to that of vemurafenib alone.

Results from Part 1 of the COLUMBUS trial previously presented at the 2016 Society for Melanoma Research Annual Congress, showed that COMBO450 more than doubled mPFS in patients with advanced BRAF-mutant melanoma, with a mPFS of 14.9 months compared with 7.3 months observed with vemurafenib [HR 0.54, (95% CI 0.41-0.71, p<0.0001)]. In the secondary mPFS comparison of COMBO450 to ENCO300, ENCO300 demonstrated a mPFS of 9.6 months [HR 0.75, (95% CI 0.56-1.00, p=0.051)].

In Part 2, 344 patients were randomized 3:1 to receive encorafenib 300 mg plus binimetinib 45 mg twice daily (COMBO300) or ENCO300. Part 2 was designed to provide additional data to help evaluate the contribution of binimetinib to the combination of encorafenib and binimetinib.

As the secondary endpoint comparison of mPFS between the COMBO450 arm and ENCO300 arm in Part 1 did not achieve statistical significance, the protocol specified analysis of OS is descriptive.

In February 2018, Array announced that treatment with COMBO450 reduced the risk of death compared to treatment with vemurafenib 960 mg daily [hazard ratio (HR) of 0.61, (95% CI 0.47, 0.79, p<0.001)] in patients with BRAF-mutant melanoma in the Phase 3 COLUMBUS trial. The Phase 3 trial showed mOS of 33.6 months for patients treated with COMBO450, compared to 16.9 months for patients treated with vemurafenib as a monotherapy.

As previously reported, the combination of encorafenib and binimetinib was generally well-tolerated. Grade 3/4 adverse events (AEs) that occurred in more than 5% of patients receiving the combination were increased gamma-glutamyltransferase (GGT) (9%), increased blood creatine phosphokinase (CK) (7%) and hypertension (6%). The incidence of selected any grade AEs of special interest, defined based on toxicities commonly associated with commercially available BRAF+MEK-inhibitor treatments for patients receiving the combination of encorafenib and binimetinib included: rash (22%), pyrexia (18%), serous retinopathy including retinal pigment epithelial detachment (20%) and photosensitivity (5%). Full safety results of COLUMBUS Part 1 were published in The Lancet Oncology.

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 

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

06/04/2018

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.

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.

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.

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.