Encorafenib (Monograph)

Brand name: Braftovi
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jul 27, 2023. Written by ASHP.

[Web]

Introduction

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

Uses for Encorafenib

Melanoma

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

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.

Not indicated for use in patients with wild-type BRAF melanoma.

Colorectal Cancer

In combination with cetuximab for the treatment of metastatic colorectal cancer in adults with BRAF V600E mutation after prior therapy.

FDA-approved diagnostic test (e.g., Qiagen therascreen BRAF V600E RGQ polymerase chain reaction [PCR] kit) required to confirm presence of BRAF V600E mutation prior to initiation of therapy.

Not indicated for use in patients with wild-type BRAF colorectal cancer.

Encorafenib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of BRAF V600E or V600K mutation using an FDA-approved diagnostic test prior to initiation of combination therapy with encorafenib and binimetinib for melanoma.

• Confirm presence of the BRAF V600E mutation using an FDA-approved diagnostic test prior to initiation of combination therapy with encorafenib and cetuximab for metastatic colorectal cancer.

• Perform a dermatologic evaluation prior to initiation of therapy.

• Measure and correct any hypokalemia or hypomagnesemia prior to initiation of therapy.

Patient Monitoring

• Perform dermatologic evaluations every 2 months during therapy, and for up to 6 months following discontinuance of combination therapy. Monitor for signs and symptoms of new noncutaneous malignancies.

• Perform ophthalmologic examinations at regular intervals and as clinically indicated for visual disturbances.

• Monitor patients who have or are at significant risk for corrected QT (QTc) prolongation; correct any hypokalemia or hypomagnesemia during therapy.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Dosage

Adults

Melanoma

Oral

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

If concomitant use with moderate or strong inhibitors of CYP3A4 cannot be avoided, reduce dosage of encorafenib.

Colorectal Cancer

Oral

300 mg once daily; use in combination with cetuximab. Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate or strong inhibitors of CYP3A4 cannot be avoided, reduce dosage of encorafenib.

Dosage Modification for Toxicity

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

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

Melanoma Dose Modifications

If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once daily until binimetinib is resumed.

If dosage reduction from 450 mg once daily is necessary, reduce dosage to 300 mg once daily. If further dosage reduction necessary, reduce dosage to 225 mg once daily. Dosages <225 mg once daily not recommended; permanently discontinue drug if 225 mg daily dosage is not tolerated.

Colorectal Cancer Dose Modifications

If concomitant therapy with cetuximab is discontinued, discontinue encorafenib.

If dosage reduction from 300 mg once daily is necessary, reduce dosage to 225 mg once daily. If further dosage reduction necessary, reduce dosage to 150 mg once daily. Dosages <150 mg once daily not recommended; permanently discontinue drug if 150-mg daily dosage is not tolerated.

Development of New Primary Malignancies

If new primary cutaneous malignancies develop during combination therapy with encorafenib and binimetinib, no dosage adjustment required.

If new primary RAS mutation-positive, noncutaneous malignancies develop, permanently discontinue encorafenib.

Ocular Effects

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. If toxicity does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.

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. If toxicity does not improve within 6 weeks of interrupting therapy, permanently discontinue drug.

If grade 4 uveitis occurs, permanently discontinue drug.

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

Prolongation of QT Interval

If the QT interval (corrected for heart rate using Fridericia's formula) [QT_cF] >500 msec and increase ≤60 msec from baseline, interrupt encorafenib therapy. When QT_c interval improves to ≤500 msec, resume therapy at a reduced dosage. If there is more than one recurrence, permanently discontinue encorafenib therapy.

If QT_c F >500 msec and increase >60 msec from baseline, permanently discontinue drug.

Hepatotoxicity

For grade 2 elevations of serum ALT or AST, continue therapy at same dosage for up to 4 weeks. 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.

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. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. For recurrent grade 3 elevations of serum ALT or AST, consider permanent discontinuance of encorafenib.

For first occurrence of grade 4 elevations of serum ALT or AST, permanently discontinue drug or temporarily interrupt therapy. 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. If toxicity does not improve within 4 weeks of interrupting therapy, permanently discontinue drug. For recurrent grade 4 elevations of serum ALT or AST, permanently discontinue drug.

Dermatologic Effects

If grade 2 dermatologic reactions occur (other than hand-foot skin reactions), continue therapy at same dosage for up to 2 weeks. If toxicity persists, interrupt encorafenib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage.

For first occurrence of grade 3 dermatologic reactions (other than hand-foot skin reactions), interrupt encorafenib therapy until toxicity improves to grade 1 or less, and then resume therapy at same dosage. 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.

If grade 4 dermatologic reactions occur (other than hand-foot skin reactions), permanently discontinue drug.

Other Toxicities Including Hemorrhage and Hand-Foot Skin Reaction

For recurrent grade 2 adverse reactions, withhold encorafenib therapy for up to 4 weeks; may resume therapy at a reduced dosage when toxicity improves to grade 1 or less or to baseline. If the toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, permanently discontinue the drug.

For the first occurrence of any grade 3 adverse reaction, withhold encorafenib therapy for up to 4 weeks; may resume therapy at a reduced dosage when toxicity improves to grade 1 or less or to baseline. If toxicity does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, permanetly discontinue the drug. If any grade 3 adverse reaction recurs, consider permanent discontinuance of encorafenib.

For the first occurrence of any grade 4 adverse reaction, permanently discontinue encorafenib therapy or temporarily interrupt therapy. If encorafenib therapy is temporarily interrupted, withhold drug for up to 4 weeks; may resume therapy at a reduced dosage when toxicity improves to grade 1 or less or to baseline. If the grade 4 adverse reaction does not improve to grade 1 or less or to baseline within 4 weeks of withholding therapy, permanently discontinue the drug. For recurrent grade 4 adverse reactions, permanently discontinue encorafenib therapy.

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Avoid concomitant use of moderate or strong CYP3A4 inhibitors; however, if such concomitant use cannot be avoided, reduce dosage of encorafenib. (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

If concomitant use of the strong or moderate CYP3A4 inhibitor is discontinued, return the encorafenib dosage (after 3–5 terminal half-lives of the CYP3A4 inhibitor) to the dosage used prior to initiation of the strong or moderate CYP3A4 inhibitor.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment required.

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

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30 to <90 mL/minute): No dosage adjustment required.

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

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Encorafenib

Contraindications

• None.

Warnings/Precautions

Combination Therapy

When used in combination with binimetinib or cetuximab, consider cautions, precautions, and contraindications of binimetinib or cetuximab, respectively.

Development of New Primary Malignancies

Cutaneous and noncutaneous malignancies reported.

Cutaneous squamous cell carcinoma (including keratoacanthoma), basal cell carcinoma, and new primary melanoma reported in clinical trials evaluating encorafenib in combination with binimetinib or cetuximab in patients with melanoma or colorectal cancer, respectively. In melanoma clinical trials, median time to first appearance of such skin lesions was 5.8 months in patients receiving combination therapy with encorafenib and binimetinib.

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

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.

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

Hemorrhage

Hemorrhage reported.

Most common hemorrhagic events include GI hemorrhage (e.g., rectal hemorrhage, hematochezia, hemorrhoidal hemorrhage) in patients receiving encorafenib in combination with binimetinib to treat melanoma in the COLUMBUS study; fatal intracranial hemorrhage also reported.

Most common hemorrhagic events include epistaxis, hematochezia, and rectal hemorrhage in patients receiving encorafenib in combination with cetuximab to treat colorectal cancer in the BEACON CRC study; fatal GI hemorrhage also reported.

If hemorrhagic events occur, temporary interruption followed by dosage reduction or discontinuance of therapy may be necessary.

Ocular Effects

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

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

Prolongation of QT Interval

Prolongation of QT interval reported.

Monitor patients with increased risk for QT_c-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). Correct hypokalemia and hypomagnesemia prior to administration of encorafenib and as clinically indicated during therapy.

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

If prolongation of QT interval occurs, therapy interruption followed by dosage reduction or discontinuance of drug may be necessary.

Fetal/Neonatal Morbidity and Mortality

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

Encorafenib crosses the placenta in animals.

Confirm pregnancy status prior to initiating therapy. Avoid pregnancy during therapy. Women of childbearing potential should use effective nonhormonal contraception while receiving encorafenib and for 2 weeks after the last dose.

Apprise patients of potential fetal hazard.

Use as a Single Agent

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

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

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

Females and Males of Reproductive Potential

May reduce male fertility.

For women of childbearing potential, use an effective nonhormonal method of contraception while receiving encorafenib and for 2 weeks after the last dose. Advise use of a nonhormonal method as encorafenib can interact with hormonal contraceptives and render them ineffective.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

Hepatic Impairment

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

Not studied in patients with moderate or severe hepatic impairment.

Renal Impairment

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

Not studied in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (≥25%) in patients with melanoma, in combination with binimetinib: fatigue, nausea, vomiting, abdominal pain, arthralgia.

Most common adverse reactions (≥25%) in patients with colorectal cancer, in combination with cetuximab: fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, rash.

Drug Interactions

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

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

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

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.

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

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. Avoid concomitant use; if concomitant therapy cannot be avoided, reduce encorafenib dosage per recommendations in Table 1 prior to initiating the moderate CYP3A4 inhibitor.

Strong CYP3A4 inhibitors: Possible increased peak plasma concentrations and AUC of encorafenib and increased incidence of adverse effects. Avoid concomitant use; if concomitant therapy cannot be avoided, reduce encorafenib dosage per recommendations in Table 1 prior to initiating the strong CYP3A4 inhibitor.

When coadministered with a strong CYP3A4 inhibitor, exposure to encorafenib at the 75-mg dosage is expected to be higher than the 150-mg dosage without concomitant CYP3A4 inhibitor and similar to the 225-mg dosage without concomitant CYP3A4 inhibitor. Closely monitor for adverse reactions and use clinical judgement when encorafenib 150 mg is used in combination with a strong CYP3A4 inhibitor.

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

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP3A4 substrates: Possible increased incidence of adverse effects or reduced efficacy of substrate drug.

Drugs that Prolong QT Interval

Risk of prolonged QT interval. Avoid concomitant use.

Specific Drugs and Foods

Encorafenib Pharmacokinetics

Absorption

Bioavailability

≥86% absorbed following oral administration.

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

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.

Steady-state concentrations are achieved within 15 days.

Food

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

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.

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

Distribution

Extent

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

Not known whether encorafenib is distributed into human milk.

Plasma Protein Binding

86%.

Elimination

Metabolism

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

Elimination Route

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

Half-life

3.5 hours.

Special Populations

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

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C). Store in original container, tightly closed, with desiccant.

Actions

• Inhibitor of BRAF V600E or V600K mutation.

• Approximately 40–60% of cutaneous melanomas and 12% of metastatic colorectal cancers carry a BRAF mutation. Substitution of glutamic acid for valine at codon 600 in exon 15 (BRAF V600E) is the most common BRAF mutation; substitution of lysine for valine at codon 600 in exon 15 (BRAF V600K) occurs less frequently.

• 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).

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

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

• Combination therapy with a BRAF inhibitor (i.e., encorafenib, dabrafenib, vemurafenib) and a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor (i.e., binimetinib, cobimetinib, trametinib) results in complete inhibition of the MAPK/ERK pathway.

• 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.

• 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.

• Combination therapy with BRAF and epidermal growth factor receptor (EGFR) inhibitors resulted in synergistic inhibition of tumor growth and improved activity in xenograft models and clinical studies.

• Inhibits wild-type b-Raf, c-Raf, c-Jun NH(2)-terminal protein kinase (JNK)1, JNK2, JNK3, LIM domains kinase (LIMK)1, LIMK2, MEK4, and serine/threonine kinase (STK)36.

Advice to Patients

• Importance of reading the manufacturer's patient information.

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

• Risk of new primary cutaneous malignancies. 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).

• Risk of hemorrhage. 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.

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

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

• Risk of fetal harm. 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. Importance of women informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.

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

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

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses. Advise patients to avoid grapefruit or grapefruit juice while receiving encorafenib.

• Inform patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Encorafenib can only be obtained through select specialty pharmacies. Contact the manufacturer or consult the Braftovi and Mektovi website for specific availability information ([Web]).

Reload page with references included

Frequently asked questions

• What is Braftovi used to treat?
• What is Mektovi used to treat?

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