Identification
- Summary
Encorafenib is a kinase inhibitor used to treat unresectable or metastatic melanoma with specific mutations.
- Brand Names
- Braftovi
- Generic Name
- Encorafenib
- DrugBank Accession Number
- DB11718
- Background
Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations.8 This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung 6.
On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib (BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.8
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Encorafenib (DB11718)
- Weight
- Average: 540.01
Monoisotopic: 539.1517794 - Chemical Formula
- C22H27ClFN7O4S
- Synonyms
- Encorafenib
- External IDs
- LGX-818
- LGX818
- NVP-LGX-818-NXA
- NVP-LGX818
- NVP-LGX818-NXA
Pharmacology
- Indication
Encorafenib is indicated in combination with binimetinib for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.8 It is also indicated in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation.8
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- Contraindications & Blackbox Warnings
Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.- Pharmacodynamics
Encorafenib has shown improved efficacy in the treatment of metastatic melanoma 3.
Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis 7.
Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma 7.
- Mechanism of action
Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM).8
In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.8
Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone.8
Target Actions Organism ASerine/threonine-protein kinase B-raf inhibitorHumans AG1/S-specific cyclin-D1 inhibitorHumans - Absorption
After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed. Administration of a single dose of BRAFTOVI 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC (area under the curve).8
- Volume of distribution
The blood-to-plasma concentration ratio is 0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%).8
- Protein binding
Encorafenib is 86% bound to human plasma proteins in vitro.8
- Metabolism
The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%).8
- Route of elimination
Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine.8
- Half-life
The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%).8
- Clearance
The apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state.8
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib.8
In COLUMBUS, a phase 3 safety and efficacy trial,8 cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. The median time to first occurrence of cuSCC/KA was 5.8 months (range 1 to 9 months).8
Tumor promotion in BRAF Wild-Type Tumors has been observed with encofarenib use.8
Hemorrhage, uveitis, QT interval prolongation are also other adverse events observed while taking this medication.8
Encorafenib, when used as a single agent, is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI therapy alone compared to 2% of patients treated with BRAFTOVI in combination with binimetinib.8
Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.8
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Encorafenib can be increased when it is combined with Abametapir. Abatacept The metabolism of Encorafenib can be increased when combined with Abatacept. Abiraterone The metabolism of Encorafenib can be decreased when combined with Abiraterone. Acebutolol The metabolism of Encorafenib can be decreased when combined with Acebutolol. Acetaminophen The metabolism of Encorafenib can be decreased when combined with Acetaminophen. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Encorafenib. Adagrasib The metabolism of Encorafenib can be decreased when combined with Adagrasib. Adalimumab The metabolism of Encorafenib can be increased when combined with Adalimumab. Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Encorafenib. Ajmaline The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Encorafenib. 
Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - Food Interactions
- Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of encorafenib.
- Exercise caution with St. John's Wort. This herb induces CYP3A metabolism, which may reduce serum levels of encorafenib.
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Braftovi Capsule 50 mg/1 Oral Array BioPharma Inc. 2022-03-01 Not applicable US 
Braftovi Capsule 50 mg/1 Oral Array BioPharma Inc. 2018-06-27 2019-03-13 US Braftovi Capsule 50 mg Oral Pierre Fabre Médicament 2021-03-17 Not applicable EU 
Braftovi Capsule 75 mg Oral Pfizer Canada Ulc 2021-07-05 Not applicable Canada 
Braftovi Capsule 75 mg Oral Pierre Fabre Médicament 2021-03-17 Not applicable EU Braftovi Capsule 75 mg/1 Oral Array BioPharma Inc. 2018-06-27 Not applicable US Braftovi Capsule 75 mg Oral Pierre Fabre Médicament 2021-03-17 Not applicable EU Braftovi Capsule 50 mg Oral Pierre Fabre Médicament 2021-03-17 Not applicable EU
Categories
- ATC Codes
- L01EC03 — Encorafenib
- Drug Categories
- Acids, Acyclic
- Amides
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- B-Raf serine-threonine kinase (BRAF) inhibitors
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Kinase Inhibitor
- Moderate Risk QTc-Prolonging Agents
- Protein Kinase Inhibitors
- QTc Prolonging Agents
- Sulfones
- Sulfur Compounds
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylpyrazoles. These are compounds containing a phenylpyrazole skeleton, which consists of a pyrazole bound to a phenyl group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Azoles
- Sub Class
- Pyrazoles
- Direct Parent
- Phenylpyrazoles
- Alternative Parents
- Sulfanilides / Aminopyrimidines and derivatives / Chlorobenzenes / Fluorobenzenes / Organosulfonamides / Aryl chlorides / Aryl fluorides / Organic sulfonamides / Heteroaromatic compounds / Aminosulfonyl compounds show 8 more
- Substituents
- Amine / Aminopyrimidine / Aminosulfonyl compound / Aromatic heteromonocyclic compound / Aryl chloride / Aryl fluoride / Aryl halide / Azacycle / Benzenoid / Carbamic acid ester show 25 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 8L7891MRB6
- CAS number
- 1269440-17-6
- InChI Key
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N
- InChI
- InChI=1S/C22H27ClFN7O4S/c1-12(2)31-11-16(17-6-7-25-21(28-17)26-10-13(3)27-22(32)35-4)20(29-31)15-8-14(23)9-18(19(15)24)30-36(5,33)34/h6-9,11-13,30H,10H2,1-5H3,(H,27,32)(H,25,26,28)/t13-/m0/s1
- IUPAC Name
- methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate
- SMILES
- COC(=O)N[C@@H](C)CNC1=NC=CC(=N1)C1=CN(N=C1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F)C(C)C
References
- General References
- Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [Article]
- Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [Article]
- Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [Article]
- Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [Article]
- FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
- BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
- Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
- FDA Approved Drug Products: Braftovi (encorafenib) oral capsules [Link]
- Encorafenib review [File]
- External Links
- PubChem Compound
- 50922675
- PubChem Substance
- 347828081
- ChemSpider
- 28536139
- BindingDB
- 221688
- 2049106
- ChEMBL
- CHEMBL3301612
- ZINC
- ZINC000068249103
- PharmGKB
- PA166179872
- Wikipedia
- Encorafenib
- MSDS
- Download (22.4 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Recruiting Treatment Solid Tumors 1 3 Active Not Recruiting Treatment Melanoma 1 3 Completed Treatment BRAF V600E-mutant Metastatic Colorectal Cancer 1 3 Not Yet Recruiting Treatment Biliary Tract Neoplasms 1 3 Recruiting Treatment Melanoma 2 3 Recruiting Treatment Metastatic Colorectal Cancer (CRC) / Stage III Colorectal Cancer 1 3 Recruiting Treatment Neoplasm 1 2 Active Not Recruiting Treatment Anaplastic Astrocytoma (AA) / BRAF V600E Mutation / BRAF V600K mutation / Glioblastoma Multiforme (GBM) / Gliosarcoma / High Grade Glioma (HGG) / Pleomorphic Xanthoastrocytoma, Anaplastic 1 2 Active Not Recruiting Treatment BRAF V600E-mutant Metastatic Colorectal Cancer 1 2 Active Not Recruiting Treatment Melanoma of Unknown Primary / Metastatic Malignant Neoplasm in Lymph Node / Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 / Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 / Pathologic Stage IIID Cutaneous Melanoma AJCC v8 / Recurrent Cutaneous Melanoma 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 50 mg/1 Capsule Oral 50 MG Capsule Oral 75 mg/1 Capsule Oral 75 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9763941 No 2017-09-19 2032-11-21 US US9314464 No 2016-04-19 2031-07-04 US US9850229 No 2017-12-26 2030-08-27 US US8541575 No 2013-09-24 2030-02-26 US US10005761 No 2018-06-26 2030-08-27 US US9850230 No 2017-12-26 2030-08-27 US US9593099 No 2017-03-14 2030-08-27 US US9593100 No 2017-03-14 2030-08-27 US US8946250 No 2015-02-03 2029-07-23 US US9387208 No 2016-07-12 2032-11-21 US US8501758 No 2013-08-06 2031-03-04 US US10258622 No 2019-04-16 2032-11-21 US US9474754 No 2016-10-25 2033-08-05 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0112 mg/mL ALOGPS logP 4.16 ALOGPS logP 2.65 Chemaxon logS -4.7 ALOGPS pKa (Strongest Acidic) 8.45 Chemaxon pKa (Strongest Basic) 3.08 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 7 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 140.13 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 145.6 m3·mol-1 Chemaxon Polarizability 54.11 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein serine/threonine kinase activity
- Specific Function
- Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, a...
- Gene Name
- BRAF
- Uniprot ID
- P15056
- Uniprot Name
- Serine/threonine-protein kinase B-raf
- Molecular Weight
- 84436.135 Da
References
- Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [Article]
- Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [Article]
- Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [Article]
- Encorafenib review [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Transcription factor binding
- Specific Function
- Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S t...
- Gene Name
- CCND1
- Uniprot ID
- P24385
- Uniprot Name
- G1/S-specific cyclin-D1
- Molecular Weight
- 33728.74 Da
References
- Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [Article]
- Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [Article]
- Encorafenib review [File]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Encorafenib review [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Encorafenib review [File]
Drug created at October 20, 2016 20:42 / Updated at March 24, 2023 20:20