encorafenib (Rx)

>10% (Melanoma)

All grades

• Fatigue (43%)
• Nausea (41%)
• Vomiting (30%)
• Abdominal pain (28%)
• Arthralgia (26%)
• Myopathy (23%)
• Hyperkeratosis (23%)
• Constipation (22%)
• Rash (22%)
• Headache (22%)
• Hemorrhage (19%)
• Pyrexia (18%)
• Dry skin (16%)
• Dizziness (15%)
• Alopecia (14%)
• Pruritus (13%)
• Peripheral neuropathy (12%)
• Pain in extremity (11%)

>10% (mCRC)

All grades

• Fatigue (51%)
• Anemia (34%)
• Nausea (34%)
• Diarrhea (33%)
• Dermatitis acneiform (32%)
• Abdominal pain (30%)
• Decreased appetite (27%)
• Arthralgia (27%)
• Rash (26%)
• Lymphopenia (24%)
• Vomiting (21%)
• Headache (20%)
• Hypomagnesemia (19%)
• Hemorrhage (19%)
• Peripheral neuropathy (19%)
• Increased alkaline phosphatase (18%)
• Pyrexia (17%)
• Increased AST/ALT (15-17%)
• Constipation (15%)
• Myopathy (15%)
• Melanocytic nevus (14%)
• Pruritus (14%)
• Increased aPTT (13%)
• Insomnia (13%)
• Dry skin (13%)
• Hypokalemia (12%)
• Hyponatremia (11%)

1-10% (Melanoma)

All grades

• Facial paresis (<10%)
• Pancreatitis (<10%)
• Panniculitis (<10%)
• Drug hypersensitivity (<10%)

Grade 3 or 4

• Abdominal pain (4%)
• Pyrexia (4%)
• Fatigue (3%)
• Hemorrhage (3%)
• Dizziness (3%)
• Vomiting (2%)
• Nausea (2%)
• Headache (2%)
• Pruritus (1%)
• Rash (1%)
• Hyperkeratosis (1%)
• Peripheral neuropathy (1%)
• Pain in extremity (1%)
• Arthralgia (1%)

1-10% (mCRC)

All grades

• Pancreatitis (<10%)
• Pain in extremity (10%)

Grade 3 or 4

• Fatigue (7%)
• Increased alkaline phosphatase (4%)
• Abdominal pain (4%)
• Hypokalemia (3%)
• Diarrhea (2%)
• Hyponatremia (2%)
• Hemorrhage (2%)
• Peripheral neuropathy (1%)
• Increased AST (1%)
• Dermatitis acneiform (1%)
• Arthralgia (1%)
• Myopathy (1%)
• Decreased appetite (1%)
• Vomiting (1%)
• Nausea (1%)
• Pyrexia (1%)

Contraindications

None

Cautions

Confirm evidence of BRAF V600E or V600K mutation prior to initiating treatment; in vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors; not indicated for wild-type BRAF melanoma

Hemorrhage can occur; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage and hematochezia

Uveitis (eg, iritis, iridocyclitis) reported; assess for visual symptoms at each visit; perform an ophthalmologic evaluation regularly and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings

Dose-dependent QTc interval prolongation reported; monitor patients who already have or who are at significant risk of developing QTc prolongation (eg, patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, those taking medications associated with QT prolongation); correct hypokalemia and hypomagnesemia prior to and during administration

Based on its mechanism of action, fetal harm may occur when administered to a pregnant woman

Grade 3 or 4 dermatologic reactions occurred in 21% of patients treated with encorafenib as a single agent compared with 2% of patients treated with encorafenib in combination with binimetinib

Refer to the binimetinib or cetuximab prescribing information for additional risk information that applies to combination use treatment

New primary malignancies

• New primary malignancies, cutaneous and noncutaneous, observed

• Cutaneous squamous cell carcinoma

  • In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA) and basal cell carcinoma occurred in patients who received encorafenib in combination with binimetinib
  • Perform dermatologic evaluations before initiating treatment, q2months 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

• Noncutaneous malignancies

  • Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms
  • Monitor for signs and symptoms of noncutaneous malignancies
  • Discontinue treatment for RAS mutation-positive noncutaneous malignancies

Drug interaction overview

• Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations
• Encorafenib induces CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations
• Encorafenib is a CYP3A4 and P-glycoprotein (P-gp) substrate

• Strong or moderate CYP3A4 inhibitors

  • Coadministration with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions
  • Avoid use with strong or moderate CYP3A4 inhibitors (eg, grapefruit juice)
  • If coadministration of strong or moderate CYP3A4 inhibitors is unavoidable, modify dose as recommended

• Strong or moderate CYP3A4 inducers

  • Coadministration with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy
  • Avoid use with strong or moderate CYP3A4 inducers

• Sensitive CYP3A4 substrates

  • Coadministration with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents
  • Concomitant use of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy; avoid hormonal contraceptives

• Drugs that prolong the QT interval

  • Encorafenib is associated with dose-dependent QTc interval prolongation
  • Avoid use with drugs known to prolong QT/QTc

Pregnancy

Based on its mechanism of action, fetal harm may occur when administered to pregnant women

There are no available clinical data on the use of encorafenib during pregnancy

Advise pregnant women of the potential risk to a fetus

Animal data

• In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures ~26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses

Contraception

• Verify the pregnancy status of females of reproductive potential prior to initiating treatment
• Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose
• Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking encorafenib and binimetinib (see Drug Interactions)

Infertility

• Based on findings in male rats at doses ~13 times the human exposure at the 450-mg clinical dose, use of encorafenib may impact fertility in males

Lactation

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Kinase inhibitor that targets BRAF V600E

This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma

Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in greater antiproliferative 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

Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone

Absorption

Peak plasma time: 2 hr

At least 86% of the dose is absorbed

Effect of Food

• Administration of a single dose of encorafenib 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (composed of ~150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean peak plasma concentration by 36% with no effect on AUC

Distribution

Protein bound: 86%

Vd: 164 L

Metabolism

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%)

Elimination

Half-life: 3.5 hr

Clearance: 14 L/hr (day 1); 32 L/hr (steady-state)

Excretion, single 100-mg dose: Feces 47% (5% unchanged); urine 47% (2% unchanged)

Oral Administration

May take with or without food

Missed dose: Do not take a missed dose within 12 hr of the next scheduled dose

Vomiting: Do not take an additional dose if vomiting occurs following administration, but continue with the next scheduled dose

Storage

Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

Dispense in original bottle and protect from moisture

Capsules are moisture sensitive; advise patients to store encorafenib in the original bottle with desiccant and to keep the cap of the bottle tightly closed

Do not remove the desiccants from the bottle