Skip to Content

Encorafenib

Class: Antineoplastic Agents
Chemical 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
Molecular Formula: C22H27ClFN7O4S
CAS Number: 1269440-17-6
Brands: Braftovi

Medically reviewed by Drugs.com. Last updated on May 27, 2019.

Introduction

Antineoplastic agent; an inhibitor of b-Raf serine-threonine kinase (BRAF) with V600E or V600K mutation.1 2

Uses for Encorafenib

Melanoma

In combination with binimetinib for treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation1 2 3 (designated an orphan drug by FDA for this use).4

FDA-approved diagnostic test (e.g., bioMerieux THxID BRAF V600 mutation test) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.1 2

Not indicated for use in patients with wild-type BRAF melanoma.1 (See Tumor Promotion in Wild-type BRAF Melanoma under Cautions.)

Encorafenib Dosage and Administration

General

  • Confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.1

Restricted Distribution Program

  • Obtain encorafenib through specialty pharmacies.27

  • Contact manufacturer at 844-492-7729 or consult the Braftovi and Mektovi website (https://www.braftovimektovi.com/hcp/)27

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Dosage

Adults

Melanoma
Oral

450 mg once daily; use in combination with binimetinib.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

If binimetinib therapy is temporarily interrupted, reduce dosage of encorafenib to a maximum dosage of 300 mg once daily until resumption of binimetinib therapy.1 Consult manufacturer's labeling for information on dosage modifications of binimetinib.1

If concomitant use with moderate or potent inhibitors of CYP3A4 cannot be avoided, reduce dosage of encorafenib.1 (See Interactions.)

Dosage Modification for Toxicity
Oral

Some adverse effects require temporary interruption, dosage reduction, and/or discontinuance of therapy.1

If concomitant therapy with binimetinib is temporarily interrupted or permanently discontinued, reduce dosage of encorafenib.1 (See Melanoma under Dosage and Administration.)

If dosage reduction from 450 mg once daily is necessary, reduce dosage to 300 mg once daily.1 If further dosage reduction necessary, reduce dosage to 200 mg once daily.1 Dosages <200 mg once daily not recommended; permanently discontinue drug if 200-mg daily dosage is not tolerated.1

If interstitial lung disease, pneumonitis, cardiac dysfunction, serum CK elevation, rhabdomyolysis, or venous thromboembolism occurs during combination therapy with encorafenib and binimetinib, no encorafenib dosage adjustment required.1

Development of New Primary Malignancies
Oral

If new primary cutaneous malignancies develop during combination therapy with encorafenib and binimetinib, no dosage adjustment required.1 (See Development of New Primary Malignancies under Cautions.)

If new primary RAS mutation-positive, noncutaneous malignancies develop during combination therapy with encorafenib and binimetinib, permanently discontinue encorafenib.1

Ocular Effects
Oral

If grade 1 or 2 uveitis unresponsive to ocular therapy occurs, interrupt encorafenib therapy for up to 6 weeks until toxicity improves, and then resume therapy at same or reduced dosage.1 If toxicity does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.1 (See Ocular Effects under Cautions.)

If grade 3 uveitis occurs, interrupt encorafenib therapy for up to 6 weeks until toxicity improves, and then resume therapy at same or reduced dosage.1 If toxicity does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.1

If grade 4 uveitis occurs, permanently discontinue drug.1

If adverse ocular reactions other than uveitis, iritis, or iridocyclitis occur during combination therapy with encorafenib and binimetinib, no encorafenib dosage adjustment required.1

Prolongation of QT Interval
Oral

For first occurrence of corrected QT (QTc) interval >500 msec and increase ≤60 msec from baseline, interrupt encorafenib therapy.1 When QTc interval improves to ≤500 msec, resume therapy at a reduced dosage of 300 mg once daily.1 (See Prolongation of QT Interval under Cautions.)

For second occurrence of QTc interval >500 msec and increase ≤60 msec from baseline, interrupt encorafenib therapy.1 When QTc interval improves to ≤500 msec, resume therapy at a reduced dosage of 200 mg once daily.1

For third occurrence of QTc interval >500 msec and increase ≤60 msec from baseline, permanently discontinue drug.1

If the QTc interval >500 msec and increase >60 msec from baseline, permanently discontinue drug.1

Hepatotoxicity
Oral

For grade 2 elevations of serum ALT or AST, continue therapy at same dosage for up to 4 weeks.1 If toxicity persists, interrupt encorafenib therapy until the toxicity improves to grade 1 or less or to baseline, and then resume therapy at same dosage.1 If grade 2 elevations of serum ALT or AST recur, interrupt encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at reduced dosage.1 10 If no improvement of recurrent grade 2 elevations of serum ALT or AST is observed within 4 weeks, permanently discontinue drug.1 10

For first occurrence of grade 3 elevations of serum ALT or AST, interrupt encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1 For recurrent grade 3 elevations of serum ALT or AST, consider permanent discontinuance of encorafenib.1

For first occurrence of grade 4 elevations of serum ALT or AST, permanently discontinue drug or temporarily interrupt therapy.1 If encorafenib therapy is temporarily interrupted, withhold encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or baseline, and then resume therapy at a reduced dosage.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1 For recurrent grade 4 elevations of serum ALT or AST, permanently discontinue drug.1

Dermatologic Effects
Oral

If grade 2 dermatologic reactions occur, continue therapy at same dosage for up to 2 weeks.1 If toxicity persists, interrupt encorafenib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage.1

For first occurrence of grade 3 dermatologic reactions, interrupt encorafenib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage.1 If grade 3 dermatologic reactions recur, interrupt encorafenib therapy until toxicity improves to grade 1 or less, and then resume therapy at a reduced dosage.1

If grade 4 dermatologic reactions occur, permanently discontinue drug.1

Other Toxicities
Oral

If recurrent grade 2 adverse reaction occurs, interrupt encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at reduced dosage.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1

For first occurrence of grade 3 adverse reaction, interrupt encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume at a reduced dosage.1 If toxicity does not improve to grade 1 or less or to baseline within 4 weeks of interrupting therapy, permanently discontinue drug.1 For recurrent grade 3 adverse reaction, consider permanent discontinuance of drug.1

For first occurrence of grade 4 adverse reaction, permanently discontinue drug or temporarily interrupt therapy.1 If encorafenib therapy is temporarily interrupted, withhold encorafenib therapy for up to 4 weeks until toxicity improves to grade 1 or less or to baseline, and then resume therapy at a reduced dosage.1 If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug.1 For recurrent grade 4 adverse reaction, permanently discontinue drug.1

Prescribing Limits

Adults

Melanoma
Oral

Dosages <200 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.1 (See Hepatic Impairment under Cautions.)

Moderate or severe (Child-Pugh class B or C) hepatic impairment: Not studied; no specific dosage recommendations at this time.1

Renal Impairment

Mild or moderate renal impairment (Clcr 30 to <90 mL/minute): No dosage adjustment required.1 (See Renal Impairment under Cautions.)

Severe renal impairment (Clcr <30 mL/minute): Not studied; no specific dosage recommendations at this time.1

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Encorafenib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Combination Therapy

When used in combination with binimetinib, consider cautions, precautions, and contraindications of binimetinib.1

Some adverse effects (e.g., grade 3 or 4 dermatologic reactions) occur less frequently during combination therapy with binimetinib compared to single-agent encorafenib.1

Development of New Primary Malignancies

Cutaneous and noncutaneous malignancies reported in patients receiving combination therapy with encorafenib and binimetinib.1

Cutaneous squamous cell carcinoma (including keratoacanthoma) reported.1 In clinical trials, median time to first appearance of such skin lesions was 5.8 months in patients receiving combination therapy with encorafenib and binimetinib.1

Perform dermatologic evaluations at baseline, every 2 months during therapy, and for up to 6 months following discontinuance of therapy.1 Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.1 Monitor for signs and symptoms of new noncutaneous malignancies.1 If new primary RAS mutation-positive, noncutaneous malignancies develop, permanently discontinue drug.1 (See Dosage Modification For Toxicity under Dosage and Administration.)

Tumor Promotion in Wild-type BRAF Melanoma

In vitro, paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation observed in wild-type BRAF cells exposed to BRAF inhibitors.1

Confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.1

Hemorrhage

Hemorrhage reported in patients receiving encorafenib in combination with binimetinib.1 Most common hemorrhagic events include GI hemorrhage (e.g., rectal hemorrhage, hematochezia, hemorrhoidal hemorrhage) in patients receiving encorafenib in combination with binimetinib in the COLUMBUS study.1 Fatal intracranial hemorrhage also reported.1

If hemorrhagic events occur, temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Ocular Effects

Uveitis (including iritis and iridocyclitis) reported in patients receiving encorafenib in combination with binimetinib.1

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur; to follow new or persistent ophthalmologic findings).1 Monitor patients for visual symptoms at each visit.1 If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Prolongation of QT Interval

Prolongation of QT interval reported.1

Monitor patients with increased risk for QTc-interval prolongation (e.g., history of long QT syndromes, clinically important bradyarrhythmias, severe or uncontrolled heart failure, those receiving concomitant therapy with drugs known to prolong the QT interval).1 Correct hypokalemia and hypomagnesemia prior to administration of encorafenib and as clinically indicated during therapy.1

Avoid concomitant use with drugs known to prolong the QT interval.1

If prolongation of QT interval occurs, therapy interruption followed by dosage reduction or discontinuance of drug may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxicity, fetotoxicity, and teratogenicity demonstrated in animals.1

Encorafenib crosses the placenta in animals.1 (See Distribution under Pharmacokinetics.)

Confirm pregnancy status prior to initiating therapy.1 Avoid pregnancy during therapy.1 Women of childbearing potential should use effective nonhormonal contraception while receiving encorafenib and for 2 weeks after the last dose.1 (See Specific Drugs under Interactions.)

Apprise patients of potential fetal hazard.1

Impairment of Fertility

May reduce male fertility.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether encorafenib is distributed into human milk.1 Effects on breast-fed infants and milk production also unknown.1 Discontinue breast-feeding during therapy and for 2 weeks after the last dose.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No overall differences in safety and efficacy of encorafenib in combination with binimetinib relative to younger adults.1

Hepatic Impairment

Mild hepatic impairment did not substantially affect pharmacokinetics of encorafenib; dosage adjustment not necessary.1

Not studied in patients with moderate or severe hepatic impairment.1

Renal Impairment

Mild or moderate renal impairment did not substantially affect systemic exposure of encorafenib; dosage adjustment not necessary.1

Not studied in patients with severe renal impairment.1

Common Adverse Effects

Combination therapy with binimetinib in patients with unresectable or metastatic melanoma: Fatigue,1 2 3 nausea,1 3 diarrhea,2 3 vomiting,1 2 3 abdominal pain,1 constipation,1 2 3 arthralgia,1 2 3 hyperkeratosis,1 myopathy,1 headache,1 2 3 rash,1 26 asthenia,3 visual impairment,26 serous retinopathy/retinal pigment epithelial detachment (RPED),26 pyrexia.3 elevated Scr concentrations,1 elevated AST or ALT concentrations,1 neutropenia,1 elevated concentrations of CK,2 3 elevated concentrations of γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP),1 anemia,1 elevated alkaline phosphatase concentrations.1

Interactions for Encorafenib

Metabolized principally by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C19 and CYP2D6.1 5

Reversible inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2D6, and 3A.1 5 In vitro, time-dependent inhibitor of CYP3A4 at clinically relevant concentrations.1

Induces CYP isoenzymes 2B6, 2C9, and 3A4.1

In vitro, inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3; does not inhibit OCT1 or multidrug resistance-associated protein (MRP) 2.1

Substrate of P-gp; not a substrate of BCRP, MRP2, OATP1B1, OATP1B3, or OCT1.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Moderate CYP3A4 inhibitors: Possible increased peak plasma concentrations and AUC of encorafenib and increased incidence of adverse effects.1 Avoid concomitant use; if concomitant therapy cannot be avoided, reduce encorafenib dosage to one-half of the dose (e.g., dose of 450 mg reduced to 225 mg) given prior to initiating the moderate CYP3A4 inhibitor.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A4 inhibitors: Possible increased peak plasma concentrations and AUC of encorafenib and increased incidence of adverse effects.1 Avoid concomitant use; if concomitant therapy cannot be avoided, reduce encorafenib dosage to one-third of the dose (e.g., dose of 450 mg reduced to 150 mg) given prior to initiating the potent CYP3A4 inhibitor.1

Moderate or potent CYP3A4 inducers: Possible decreased systemic exposure and reduced encorafenib efficacy.1 Avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP3A4 substrates: Possible increased incidence of adverse effects or reduced efficacy of substrate drug.1 (See Specific Drugs and Foods under Interactions.)

Drugs that Prolong QT Interval

Risk of prolonged QT interval.1 Avoid concomitant use.1 (See Prolongation of QT Interval under Cautions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Binimetinib

No substantial effect on binimetinib exposure1

Diltiazem

Diltiazem increased peak plasma concentrations and AUC of encorafenib by 1.4- and 1.8-fold1 5

Avoid concomitant use; if concomitant use cannot be avoided, reduce encorafenib dosage to one-half of dose given prior to initiating diltiazem (e.g., dose of 450 mg reduced to 225 mg)1

Grapefruit or grapefruit juice

Possible increased peak plasma concentrations and systemic exposure of encorafenib1

Avoid concomitant use1

Hormonal contraceptives

Possible decreased systemic exposure of hormonal contraceptive and reduced contraceptive efficacy1

Avoid concomitant use1

Advise women of childbearing potential to use alternative nonhormonal contraception during and for 2 weeks after the last dose of encorafenib1

Posaconazole

Posaconazole increased peak plasma concentrations and AUC of encorafenib by 1.7- and 2.8-fold, respectively1 5

Avoid concomitant use; if concomitant use cannot be avoided, reduce encorafenib dosage to one-third of dose given prior to initiating posaconazole (e.g., dose of 450 mg reduced to 150 mg)1

Rabeprazole

No substantial effect on peak plasma concentration and systemic exposure of encorafenib1

Encorafenib Pharmacokinetics

Absorption

Bioavailability

≥86% absorbed following oral administration.1

Following oral administration, peak plasma concentrations attained in 2 hours.1

Systemic exposure increases in a proportional manner following single administration of encorafenib 50–700 mg, but increases in a less than proportional manner following repeated administration of encorafenib 50–800 mg once daily.1

Steady-state concentrations are achieved within 15 days.1

Food

Administration with high-fat, high-calorie meal decreased mean peak plasma concentration by 36%, but did not substantially affect extent of absorption.1

Special Populations

In patients with mild hepatic impairment (Child-Pugh class A), systemic exposure of encorafenib was similar to that in patients with normal hepatic function.1 5

In patients with mild or moderate renal impairment (Clcr of 30–89 mL/minute), systemic exposure of encorafenib was similar to that in patients with normal renal function.1 5

Distribution

Extent

Distributed into fetal plasma of rats and rabbits at concentrations up to 1.7 and 0.8%, respectively, of maternal plasma concentrations.1

Not known whether encorafenib is distributed into human milk.1

Plasma Protein Binding

86%.1

Elimination

Metabolism

Metabolized mainly by CYP3A4 and, to a lesser extent, by CYP2C19 and CYP2D6.1

Elimination Route

Eliminated in feces (47%) and urine (47%), mainly as metabolites.1

Half-life

3.5 hours.1

Special Populations

Age (19–89 years), gender, and body weight do not substantially affect pharmacokinetics of encorafenib.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1 Store in original container, tightly closed, with desiccant.1

Actions

  • Inhibitor of BRAF V600E or V600K mutation.1 2

  • Approximately 40–60% of cutaneous melanomas carry a BRAF mutation.2 3 8 11 Substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E) is the most common BRAF mutation;8 9 11 substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.8 9 11

  • Mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).7 8 9

  • Inhibits MAPK/ERK signal transduction pathway resulting in tumor regression in xenograft models of tumor cells with BRAF V600E mutation.1

  • Inhibits tumor growth in cell lines testing positive for BRAF V600E, V600D, and V600K mutations.1

  • Combination therapy with a BRAF inhibitor (i.e., encorafenib, dabrafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.3 11 14

  • Combination therapy with encorafenib and binimetinib resulted in increased antiproliferative activity in cell lines testing positive for BRAF V600 mutation compared with either drug alone.1

  • Combination therapy with encorafenib and binimetinib resulted in increased inhibition of tumor growth and delayed emergence of resistance compared with either drug alone in xenograft models of melanoma harboring BRAF V600E mutation in mice.1

  • Inhibits wild-type b-Raf, c-Raf, JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36.1

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • If a dose of encorafenib is missed by >12 hours or vomited, importance of administering the next dose at the regularly scheduled time.1 A replacement dose should not be administered.1

  • Risk of new primary cutaneous malignancies.1 Importance of contacting a clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, mole that changes in size or color).1

  • Risk of hemorrhage.1 Importance of contacting a clinician promptly and seeking immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., headache, dizziness, weakness, blood in stool, coughing up blood, vomiting blood) occur.1

  • Risk of QT-interval prolongation.1 Importance of contacting a clinician promptly if syncope, abnormal heartbeat, or feelings of dizziness or faintness occur.1

  • Risk of uveitis.1 Importance of contacting a clinician promptly if ocular pain, swelling, redness, changes in vision, or blurred vision occurs.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use an effective nonhormonal method of contraception while receiving the drug and for 2 weeks after the last dose.1 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise patient of potential fetal hazard if used during pregnancy.1

  • Importance of advising women to avoid breast-feeding while receiving encorafenib and for 2 weeks after the last dose.1

  • Importance of advising men of reproductive potential that encorafenib may reduce male fertility.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of encorafenib is restricted.27 (See Restricted Distribution Program under Dosage and Administration.)

Encorafenib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Braftovi

Array BioPharma

75 mg

Braftovi

Array BioPharma

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 27, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Array BioPharma, Inc. Braftovi (encorafenib) capsules prescribing information. Boulder, CO; 2018 Jun.

2. Dummer R, Ascierto PA, Gogas HJ et al. 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; 19:603-15.

3. Dummer R, Ascierto PA, Gogas HJ et al. 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. Lancet Oncol. 2018, Sept 12;

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 Oct 20. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210496Orig1s000: Multi-discipline review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210496Orig1s000MultidisciplineR.pdf

7. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med. 2011; 364:2547-8. http://www.ncbi.nlm.nih.gov/pubmed/21639809?dopt=AbstractPlus

8. Liu Y, Sheikh MS. Melanoma: Molecular Pathogenesis and Therapeutic Management. Mol Cell Pharmacol. 2014; 6:228. http://www.ncbi.nlm.nih.gov/pubmed/25745537?dopt=AbstractPlus

9. Ascierto PA, Kirkwood JM, Grob JJ et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012; 10:85. http://www.ncbi.nlm.nih.gov/pubmed/22554099?dopt=AbstractPlus

10. Array BioPharma, Inc. Boulder, CO: Personal communication.

11. Rauschenberg R, Garzarolli M, Dietrich U et al. Systemic therapy of metastatic melanoma. J Dtsch Dermatol Ges. 2015; 13:1223-37. http://www.ncbi.nlm.nih.gov/pubmed/26612791?dopt=AbstractPlus

14. Sanlorenzo M, Choudhry A, Vujic I et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma. J Am Acad Dermatol. 2014; 71:1102-1109.e1. http://www.ncbi.nlm.nih.gov/pubmed/25440439?dopt=AbstractPlus

15. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 2012; 18:263-72. http://www.ncbi.nlm.nih.gov/pubmed/22096025?dopt=AbstractPlus

16. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464:427-30. http://www.ncbi.nlm.nih.gov/pubmed/20179705?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3178447&blobtype=pdf

17. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366:207-15. http://www.ncbi.nlm.nih.gov/pubmed/22256804?dopt=AbstractPlus

18. Weeraratna AT. RAF around the edges--the paradox of BRAF inhibitors. N Engl J Med. 2012; 366:271-3. http://www.ncbi.nlm.nih.gov/pubmed/22256810?dopt=AbstractPlus

19. Ribas A, Gonzalez R, Pavlick A et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014; 15:954-65. http://www.ncbi.nlm.nih.gov/pubmed/25037139?dopt=AbstractPlus

20. Peng L, Wang Y, Hong Y et al. Incidence and relative risk of cutaneous squamous cell carcinoma with single-agent BRAF inhibitor and dual BRAF/MEK inhibitors in cancer patients: a meta-analysis. Oncotarget. 2017; 8:83280-83291. http://www.ncbi.nlm.nih.gov/pubmed/29137342?dopt=AbstractPlus

21. Ernstoff MS. Been there, not done that--melanoma in the age of molecular therapy. N Engl J Med. 2011; 364:2547-8. http://www.ncbi.nlm.nih.gov/pubmed/21639809?dopt=AbstractPlus

22. Arnault JP, Mateus C, Escudier B et al. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 2012; 18:263-72. http://www.ncbi.nlm.nih.gov/pubmed/22096025?dopt=AbstractPlus

23. Poulikakos PI, Zhang C, Bollag G et al. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010; 464:427-30. http://www.ncbi.nlm.nih.gov/pubmed/20179705?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3178447&blobtype=pdf

24. Sosman JA, Kim KB, Schuchter L et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366:707-14. http://www.ncbi.nlm.nih.gov/pubmed/22356324?dopt=AbstractPlus

25. Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012; 366:207-15. http://www.ncbi.nlm.nih.gov/pubmed/22256804?dopt=AbstractPlus

26. Array BioPharma, Inc. Mektovi (binimetinib) tablets prescribing information. Boulder, CO; 2018 Jun.

27. Array BioPharma, Inc. Braftovi (encorafenib) capsules and Mektovi (binimetinib) tablets fact sheet. From Braftovi Mektovi for Healthcare Professionals website. https://www.braftovimektovi.com/wp-content/uploads/Ordering_fact-sheet.pdf

Frequently asked questions