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 BRAF^V600E or BRAF^V600K 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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The National Comprehensive Cancer Network (NCCN^©) updated the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Melanoma to include encorafenib (BRAFTOVI) in combination with binimetinib (MEKTOVI) as a Category 1 first-line treatment option for patients with metastatic or unresectable melanoma with a BRAF^V600-activating mutation.*

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.

PHASE 3 BEACON CRC TRIAL

BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and cetuximab in patients with BRAF^V600E-mutant metastatic colorectal cancer (mCRC) whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAF^V600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAF^V600E mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only 1 patient. The triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial.

Based on consultation with the FDA and EMA, Array plans to amend the BEACON CRC protocol to allow for an interim analysis of trial endpoints. Should a planned analysis based primarily on confirmed overall response rate (ORR) and durability of response be supportive, Array plans to use it to seek accelerated approval in the U.S. The interim analysis may also support regulatory submissions in other regions. Array anticipates topline results from this analysis in the first half of 2019. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated.

In August 2018, the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and cetuximab for the treatment of patients with BRAF^V600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

BEACON CRC Safety Lead-In Results

In June 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 ESMO 20^th World Congress on Gastrointestinal Cancer. 

At the time of the updated analysis, in patients with BRAF^V600E mutation, the overall survival (OS) data were fully mature through 12.6 months and the median OS had not yet been reached. The one-year overall survival rate for this cohort was 62%. The median progression-free survival (mPFS) for patients treated with the triplet was 8 months [95% CI 5.6-9.3] and is similar between patients receiving one prior line of therapy and patients receiving two prior lines of therapy. The confirmed overall response rate (ORR) was 48% and among the 17 patients who received only one prior line of therapy the ORR was 62%. In the updated analysis, the triple combination was generally well-tolerated with no unexpected toxicities. One patient discontinued treatment with the triplet combination due to treatment-related adverse events. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased blood creatine kinase (10%) and increased aspartate aminotransferase (10%).

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. 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. The risk of mortality in CRC patients with the BRAF^V600E mutation is more than two times higher than for those with wild-type BRAF. Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established clinical activity benchmarks in BRAF^V600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. Prognosis for patients treated for BRAF-mutant CRC whose disease has progressed after one or two prior lines of therapy, range between 4% to 8% ORR, 1.8 and 2.5 months mPFS and 4 and 6 months mOS.

Clinical Trials

To learn more about encorafenib clinical trials, click here.

Publications and Presentations

Expanded Access Policy

Array BioPharma Expanded Access Policy.pdf

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Continuing Medical Education / Grant Requests

Array BioPharma Guidelines for the Support of Independent Medical Education.pdf

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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.