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.

Please see important safety information below for BRAFTOVI + MEKTOVI.

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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 BRAFV600-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.

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 US alone, it was estimated that 140,250 patients would be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 were estimated to die of their disease. BRAF mutations are estimated to occur in up to 15% of patients with metastatic colorectal cancer (mCRC) and represent a poor prognosis for these patients. The V600 mutation is the most common BRAF mutation, and the risk of mortality in CRC patients with the BRAFV600E 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 certain observed historical published benchmarks in BRAFV600E-mutant mCRC patients whose disease has progressed after one or two prior lines of therapy. These benchmarks include a general overall response rate (ORR) of 4% to 8%, median progression-free survival (mPFS) of 2 to 3 months, and median overall survival (OS) of 4 to 6 months. BRAFV600E-mutant mCRC is an area of high unmet need, as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC.

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 BRAFV600E-mutant 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 BRAFV600E-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 BRAFV600E mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only 1 patient. Based on an encouraging safety profile and with clinical activity observed in the safety lead-in, the randomized portion of the trial was initiated and has completed enrollment.

Following consultation with the FDA and EMA, Array has initiated an amendment to the BEACON CRC protocol to allow for an interim analysis of trial endpoints. Should a planned analysis based primarily on confirmed ORR and durability of response be supportive, the Company plans to use it to seek accelerated approval in the US. The interim analysis may also support regulatory submissions in other regions. The Company 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 BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

ANCHOR CRC Trial

ANCHOR CRC is an international trial designed to assess the efficacy and safety of the combination of encorafenib, binimetinib, and cetuximab in patients with BRAFV600E-mutant mCRC in the first-line setting. The ANCHOR CRC trial is being conducted in collaboration with Pierre Fabre and Ono Pharmaceutical Co., Ltd., and with support from Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

Immuno-Oncology Collaborations with Bristol-Myers Squibb, Merck, and Pfizer

Array is developing binimetinib in combination with PD-1/PD-L1 checkpoint inhibitors in separate, strategic collaborations with Bristol-Myers Squibb, Merck, and Pfizer. Each collaboration is pursuing a different rationally designed clinical approach in several solid tumor populations, including metastatic colorectal cancer patients with microsatellite stable tumors (BMS and Merck) and patients with non–small cell lung and pancreatic cancer (Pfizer). These approaches are characterized by their focus on earlier lines of therapy and the addition of a third regimen.

Clinical Trials

Trial Data
Trial Title
Program: Encorafenib
Phase: 3
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
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)
Program: Encorafenib
Phase: 2
Disease: BRAF-mutant colorectal cancer
Sponsor: Pierre Fabre
Trial Information: NCT03693170
Trial Title: Encorafenib, Binimetinib and Cetuximab in Subjects with Previously Untreated BRAF-mutant Colorectal Cancer (ANCHOR-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

01/19/2019

2019 Gastrointestinal Cancers Symposium (ASCO GI)

Updated Results of the BEACON Colorectal Cancer (CRC) Safety Lead-In: Encorafenib (ENCO) + Binimetinib (BINI) + Cetuximab (CETUX) for BRAF V600E‒Mutant CRC

S. Kopetz, et al.

Binimetinib and Encorafenib

10/24/2018

2018 Society for Melanoma Research (SMR) Annual Congress

Characteristics of Pyrexia With Encorafenib (ENCO) Plus Binimetinib (BINI) in Patients With BRAF-Mutant Melanoma

M. Mandala, et al.

Binimetinib and Encorafenib

09/12/2018

The Lancet Oncology

Overall Survival in Patients With BRAF-Mutant Melanoma Receiving Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib (COLUMBUS): a Multicentre, Open-Label, Randomised Phase 3 Trial

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

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.


To view all publications, click here.

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.

*Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Melanoma V.3.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed July 12, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess LVEF by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings. 

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

ADVERSE REACTIONS

The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS Trial, the most common laboratory abnormalities (≥20%, all Grades): included increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

DRUG INTERACTIONS

Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.