Encorafenib – Uses, Dosage, Side Effects, Interaction

Use in Cancer

Encorafenib is approved to be used with other drugs to treat patients whose cancer has a certain mutation in the BRAF gene, including:

• Colorectal cancer has spread to other parts of the body. It is used with cetuximab in adults who have received previous treatment.
• Melanoma. It is used with binimetinib in patients whose cancer cannot be removed by surgery or has spread to other parts of the body.

Encorafenib is also being studied in the treatment of other types of cancer.

Contraindications

• have untreated low potassium or low magnesium in your blood
• anemia
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• fluid in the covering of the heart or pericardium
• chronic heart failure
• escape of fluid into the lungs
• fluid in the lungs
• liver problems
• fluid retention in the legs, feet, arms or hands
• high amount of bilirubin in the blood
• excessive diarrhea
• abnormal liver function tests
• pregnancy

Dosage

Strengths: 50 mg; 75 mg

Melanoma – Metastatic

• 450 mg orally once a day in combination with binimetinib until disease progression or unacceptable toxicity
• If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg once a day until binimetinib is resumed.
• Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating therapy
• Refer to the binimetinib prescribing information for recommended dosing information.

Colorectal Cancer

• 300 mg orally once a day in combination with cetuximab until disease progression or unacceptable toxicity
• Confirm the presence of a BRAF V600E mutation in tumor specimens prior to initiating therapy.
• Refer to the cetuximab prescribing information for recommended dosing information.

Dose Adjustments

BRAF V600E OR V600K MUTATION-POSITIVE UNRESECTABLE OR METASTATIC MELANOMA:

• If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 orally mg once a day until binimetinib is resumed.
• If cetuximab is discontinued, discontinue binimetinib.

RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma:

• First dose reduction: 300 mg orally once a day
• Second dose reduction: 225 mg orally once a day
• Subsequent modification: Permanently discontinue this drug if unable tolerate 225 mg once a day.

BRAF V600E MUTATION-POSITIVE METASTATIC COLORECTAL CANCER (CRC):

• If cetuximab is discontinued, discontinue binimetinib.

RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS for BRAF V600E MUTATION-POSITIVE METASTATIC CRC:

• First dose reduction: 225 mg orally once a day
• Second dose reduction: 150 mg orally once a day
• Subsequent modification: Permanently discontinue this drug if unable tolerate 150 mg once a day.

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC):
NEW PRIMARY MALIGNANCIES:

• Non-cutaneous RAS mutation-positive malignancies: Discontinue this drug.

UVEITIS:

• Grade 1 through 3: If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold this drug for up to 6 weeks; if improved, resume at same or reduced dose; if not improved, permanently discontinue this drug.
• Grade 4: Permanently discontinue therapy.

QTc PROLONGATION:

• QTcF greater than 500 milliseconds (ms) and less than or equal to 60 ms increase from baseline: Withhold this drug until QTcF is less than or equal to 500 ms; resume at reduced dose; if more than one recurrence, permanently discontinue this drug.
• QTcF greater than 500 ms and greater than 60 ms increase from baseline: Permanently discontinue this drug.

HEPATOTOXICITY:

• Grade 2 AST or ALT increased: Maintain the dose; if no improvement within 4 weeks, withhold this drug until improvement to Grade 0 or 1 or to pretreatment/baseline levels and then resume at same dose.
• Recurrent Grade 2 or first occurrence of any Grade 3 AST or ALT increased: Withhold this drug for up to 4 weeks; if improvement to Grade 0 or 1 or to pretreatment/baseline level, resume at reduced dose; if no improvement, permanently discontinue this drug.
• First occurrence of any Grade 4 AST or ALT increase: Permanently discontinue this drug OR withhold this drug for up to 4 weeks; if improves to Grade 0 or 1 or to pretreatment/baseline level, then resume at reduced dose; if no improvement, permanently discontinue this drug.
• Recurrent Grade 3 AST or ALT increased: Consider permanently discontinuing this drug.
• Recurrent Grade 4 AST or ALT increased: Permanently discontinue this drug.

DERMATOLOGIC:

• Grade 2: If no improvement within 2 weeks, withhold this drug until Grade 0 or 1; resume at same dose.
• Grade 3: Withhold this drug until Grade 0 or 1; resume at same dose if first occurrence or reduce dose if recurrent.
• Grade 4: Permanently discontinue this drug.

OTHER ADVERSE REACTIONS (INCLUDING HEMORRHAGE):

• Recurrent Grade 2 or first occurrence of any Grade 3: Withhold this drug for up to 4 weeks; if improves to Grade 0 or 1 or to pretreatment/baseline level, then resume at reduced dose; if no improvement, permanently discontinue this drug.
• First occurrence of any Grade 4: Permanently discontinue this drug OR withhold for up to 4 weeks; if improves to Grade 0 or 1 or to pretreatment/baseline level, then resume at reduced dose; if no improvement, permanently discontinue this drug.
• Recurrent Grade 3: Consider permanently discontinuing this drug.
• Recurrent Grade 4: Permanently discontinue this drug.

DOSE MODIFICATIONS FOR COADMINISTRATION OF STRONG OR MODERATE CYP450 3A4 INHIBITORS:
Avoid concurrent use of strong or moderate CYP450 3A4 inhibitors during therapy with this drug. If concomitant use of a strong or moderate CYP450 3A4 inhibitor is unavoidable, reduce the dose of this drug as follows:
Current daily dose 450 mg:

• Dose for coadministration with moderate CYP450 3A4 inhibitor: 225 mg
• Dose for coadministration with strong CYP450 3A4 inhibitor: 150 mg

Current daily dose 300 mg:

• Dose for coadministration with moderate CYP450 3A4 inhibitor: 150 mg
• Dose for coadministration with strong CYP450 3A4 inhibitor: 75 mg

Current daily dose 225 mg:

• Dose for coadministration with moderate CYP450 3A4 inhibitor: 75 mg
• Dose for coadministration with strong CYP450 3A4 inhibitor: 75 mg

Current daily dose 150 mg:

• Dose for coadministration with moderate CYP450 3A4 inhibitor: 75 mg
• Dose for coadministration with strong CYP450 3A4 inhibitor: 75 mg

*NOTE: Encorafenib exposure at the 75 mg daily dose when coadministered with a strong CYP450 3A4 inhibitor is expected to be higher than at the 150 mg daily dose in the absence of a CYP450 3A4 inhibitor and similar to exposure at the 225 mg daily dose in the absence of a CYP450 3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgement when using encorafenib with strong CYP450 3A4 inhibitors at the 150 mg dose level.

Side Effects

The Most Common

• fatigue
• fever
• nausea
• vomiting
• stomach pain
• constipation
• decreased appetite
• headache
• dizziness
• skin thickening
• rash
• dry or itchy skin
• hair loss
• joint or muscle pain
• change in taste
• back, arm, or leg pain
• acne
• numbness, burning or tingling in the arms, hands, feet, or legs
• difficulty falling asleep or staying asleep
• dizziness, fainting or feeling faint
• vision changes
• skin changes such as a new wart, a sore or reddish bump that does not heal, a change in the size or color of a mole
• unusual bleeding or bruising
• black, tarry, or bloody stools
• coughing up blood
• nose bleeding
• redness, swelling, numbness, and skin peeling of hands and soles of feet

More Common

• eye pain or swelling, vision changes, seeing halos around lights, seeing color “dots” in your vision;
• severe skin rash, skin pain or swelling, redness, and peeling skin on your hands or feet;
• fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness (like you might pass out); or
• signs of bleeding–weakness, dizziness, headache, nosebleeds, rectal bleeding, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.
• nausea, vomiting, stomach pain;
• tiredness; or
• joint pain or swelling.

Rare

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• eye pain,
• swelling of the eye,
• vision changes,
• seeing halos around lights,
• seeing color “dots” in your vision,
• severe skin rash,
• skin pain or swelling,
• redness and peeling skin on your hands or feet,
• fast or pounding heartbeats,
• fluttering in your chest,
• shortness of breath,
• sudden dizziness,
• weakness,
• dizziness,
• headache,
• nosebleeds,
• rectal bleeding,
• bloody or tarry stools,
• coughing up blood, and
• vomit that looks like coffee grounds

Drug Interaction

Pregnancy and Lactation

TGA pregnancy category D:

US FDA pregnancy category Not Assigned

Pregnancy

Drugs that have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

Lactation

The effects in the nursing infant are unknown. Women should be advised not to breastfeed during therapy with this drug and for 2 weeks after the final dose.

References