encorafenib

Encorafenib is an anticancer (antineoplastic) medication used in the treatment of certain types of cancers in adults. Encorafenib is approved by the FDA for use in combination with either binimetinib or cetuximab, depending on the type of cancer, to treat metastatic skin, colon, and lung cancers with BRAF V600E or V600K gene mutations, as confirmed by an FDA-approved test. The combination treatment is more effective than any of the drugs alone in controlling cancer growth as well as emergence of resistance to treatment.

Encorafenib is a small molecule drug that enters into the cells and changes specific cell mechanisms. Encorafenib targets the BRAF V600E gene mutation, as well as BRAF and CRAF normal (wild-type) genes and inhibits their expression and signaling. BRAF enzymes (kinases) encoded by the BRAF gene promote cell proliferation, and BRAF mutations result in uncontrolled cell growth and proliferation. In lab studies encorafenib inhibited BRAF V600E, D and K mutations. Encorafenib also binds to other kinases including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and inhibits their activation.

When encorafenib is used with binimetinib in the treatment of skin and non-small cell lung cancers, the two drugs target two different kinases in the signaling cascade activated by the BRAF mutations. Lab and animal studies on BRAF mutation-positive melanoma cells lines and non-small lung cancer cell lines showed that the combination of encorafenib and binimetinib exhibited greater antitumor activity as well as delay in emergence of resistance in the cancer cells, compared to either drug alone.

Encorafenib is also used effectively to treat colorectal cancer with cetuximab, a humanized monoclonal antibody produced in the lab using DNA recombinant technology. In BRAF-mutant colorectal cancers, cancer cells develop resistance to encorafenib treatment by inducing another signaling pathway (MAPK) mediated by epidermal growth factor (EGF), a protein that promotes cell growth and differentiation. As a combination treatment, encorafenib targets BRAF mutation and cetuximab inhibits the EGF receptors, to overcome the resistance.

The FDA-approved indications of encorafenib currently are treatment of adult patients with:

• Unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test, in combination with binimetinib.
• Metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy, in combination with cetuximab.
• Metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test, in combination with binimetinib.

• Encorafenib treatment has been associated with the development of new primary malignancies, both skin (cutaneous) and non-cutaneous.
  • Perform dermatologic examinations before initiation of encorafenib, every 2 months during, and for up to 6 months after discontinuation of treatment. Evaluate suspicious skin lesions and manage with excisions. Dose modification is not recommended for primary cutaneous malignancies.
  • Encorafenib can promote non-cutaneous primary malignancies by the activation of RAS proteins, another protein involved in cell growth, proliferation, and migration. Monitor patients and discontinue encorafenib treatment if the patient develops RAS mutation-positive non-cutaneous malignancies.
• Evidence of BRAF V600E or V600K mutation must be confirmed with the FDA-approved test before initiating encorafenib. Lab experiments show encorafenib can cause paradoxical activation of MAP-kinase signaling and increase cell proliferation in BRAF wild-type cells.
• Encorafenib/binimetinib combination treatment can cause heart muscle disease (cardiomyopathy), which can reduce the left ventricular ejection fraction (LVEF).
  • Evaluate LVEF in patients before starting treatment, and monitor 1 month after treatment initiation, and every 2 to 3 months during treatment.
  • Safety of encorafenib/binimetinib therapy in patients with baseline LVEF below 50% or the institutional lower limit of normal (LLN) is not established.
  • Closely monitor patients with cardiovascular risks during treatment.
  • Withhold, reduce dose, or permanently discontinue treatment, based on severity of adverse reactions.
• Encorafenib/binimetinib treatment can be toxic to the liver.
  • Evaluate liver function before initiating treatment, and once a month or as clinically required during treatment.
  • Withhold, reduce dose or permanently discontinue based on severity of reaction.
• Encorafenib/binimetinib treatment can cause hemorrhage, including gastrointestinal and intracranial hemorrhage. Depending on severity, withhold, reduce or permanently discontinue treatment.
• Encorafenib/binimetinib can cause inflammation in the uvea, the middle layer of the eye (uveitis) including in the iris (iritis) and the ciliary body (iridocyclitis).
  • Assess patient’s ocular health and vision status regularly during treatment, to monitor for and follow new onset or worsening of visual disturbances.
  • Withhold, reduce dose or permanently discontinue treatment, based on severity of ocular adverse reactions.
• Encorafenib/binimetinib treatment is associated with dose-related heart rhythm disturbance (QTc interval prolongation).
  • Monitor patients who already have or who are at a significant risk for developing QTc prolongation including patients:
    • With long QT syndrome
    • With severe or uncontrolled heart failure
    • With slow irregular heart rhythm (bradyarrhythmia)
    • Taking other medications that can prolong QTc interval
    • Monitor electrolyte levels and correct low potassium (hypokalemia) or low magnesium (hypomagnesemia) before and during treatment.
    • Withhold, reduce dose, or permanently discontinue for QTc above 500 ms.
• Encorafenib can cause fetal harm if used during pregnancy. Verify pregnancy status of women of pregnancy potential before initiating encorafenib. Inform women who may get pregnant of the hazard to the fetus and advise them to use effective non-hormonal contraception for the recommended period during and after treatment.
• If used as a single agent, encorafenib can increase the risk for certain adverse reactions, compared with use in combination with binimetinib, including dermatologic reactions. If binimetinib is withheld temporarily or discontinued permanently, reduce encorafenib dosage as recommended.
• Encorafenib is used in combination with binimetinib or cetuximab. Refer to the binimetinib and cetuximab prescribing information for additional risk information pertaining to those drugs.

Common side effects of encorafenib in combination with binimetinib or cetuximab include:

• Fatigue
• Joint pain (arthralgia)
• Muscle disease (myopathy)
• Fever (pyrexia)
• Headache
• Peripheral nerve disease (neuropathy)
• Pain in extremity
• Nausea
• Vomiting
• Abdominal pain
• Constipation
• Bleeding (hemorrhage)
• Rash
• Dry skin
• Itching (pruritus)
• Increase in liver enzymes ALT and AST
• Increase in alkaline phosphatase (ALK)
• Low blood sodium level (hyponatremia)
• Blood disorders including:
  • Low red cell count (anemia)
  • Low lymphocyte count (lymphopenia)

Additional side effects specific to melanoma treatment in combination with binimetinib:

• Dizziness
• Back pain
• Taste disorder (dysgeusia)
• Thickening of skin (hyperkeratosis)
• Redness of skin (erythema)
• Acneiform dermatitis
• Hair loss (alopecia)
• Increased creatinine
• Increase in gamma-glutamyl transferase (GGT)
• Increase in blood sugar levels (hyperglycemia)
• High blood magnesium (hypermagnesemia)
• Blood disorders including:
  • Low white cell count (leukopenia)
  • Low neutrophil count (neutropenia)
• Weakness of facial muscles (facial paresis)
• Inflammation of the pancreas (pancreatitis)
• Inflammation of the fat tissue beneath the skin (panniculitis)
• Drug hypersensitivity

Additional side effects specific to non-small cell lung cancer treatment in combination with binimetinib:

• Swelling (edema)
• Diarrhea
• Musculoskeletal pain
• Visual impairment
• Shortness of breath
• Cough
• Dizziness
• Decreased appetite
• High blood pressure (hypertension)
• Increased weight
• Insomnia
• Left ventricular dysfunction
• Heart muscle disease (cardiomyopathy)
• Hair loss (alopecia)
• Blood disorders including:
  • Low white cell count (leukopenia)
  • Low neutrophil count (neutropenia)
  • Low platelet count (thrombocytopenia)
• Increased creatinine
• Increase in blood sugar levels (hyperglycemia)
• Increase in creatine kinase
• Increase in lipase enzyme
• Increase in serum amylase
• Low albumin in blood (hypoalbuminemia)
• High blood potassium level (hyperkalemia)
• Low blood calcium (hypocalcemia)

Additional side effects specific to colorectal cancer treatment in combination with cetuximab:

• Diarrhea
• Decreased appetite
• Insomnia
• Acneiform dermatitis
• Proliferation of pigment-producing skin cells (melanocytic nevus)
• Increased activated partial thromboplastin time
• Low blood magnesium (hypomagnesemia)
• Low blood potassium (hypokalemia)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 75 mg

Adult:

Melanoma

• Indicated in combination with binimetinib for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, as detected by an FDA-approved test
• 450 mg orally once daily in combination with binimetinib
• Continue until disease progression or unacceptable toxicity
• See binimetinib drug monograph for recommended dosing information

Non-Small Cell Lung Cancer

• Indicated in combination with binimetinib for unresectable or metastatic non-small cell lung cancer (NSCLC) in patients with a BRAF V600E mutation, as detected by an FDA-approved test
• 450 mg orally once daily in combination with binimetinib
• Continue until disease progression or unacceptable toxicity
• See binimetinib drug monograph for recommended dosing information

Metastatic Colorectal Cancer

• Indicated in combination with cetuximab for metastatic colorectal cancer (CRC) in patients with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy
• 300 mg orally once daily in combination with cetuximab
• Continue until disease progression or unacceptable toxicity
• See cetuximab drug monograph for recommended dosing information

Dosage Modifications

Recommended dose reductions for encorafenib for adverse reactions

• Melanoma or NSCLC
  • If binimetinib is withheld, reduce encorafenib to a maximum dose of 300 mg/day until binimetinib is resumed
  • First dose reduction: 300 mg orally once daily
  • Second dose reduction: 225 mg orally once daily
  • Unable to tolerate 225 mg orally once daily: Permanently discontinue
• Metastatic colorectal cancer
  • If cetuximab is discontinued, discontinue encorafenib
  • First dose reduction: 225 mg orally once daily
  • Second dose reduction: 150 mg orally once daily
  • Unable to tolerate 150 mg orally once daily: Permanently discontinue

New primary malignancies

• Noncutaneous RAS mutation-positive malignancies: Permanently discontinue

Uveitis

• Grade 1 or 2 (no response to specific ocular therapy), or Grade 3 uveitis: Withhold for up to 6 weeks; if uveitis resolves, resume at same or reduced dose; permanently discontinue if uveitis does not improve
• Grade 4: Permanently discontinue

Cardiomyopathy

• Symptomatic congestive heart failure or absolute decrease in left ventricular ejection fraction (LVEF) more than 20% from baseline that is also below lower limit of normal (LLN)
• Reduce by 1 dose level if
  • LVEF improves to at least institutional LLN and absolute decrease to 10% or lower compared to baseline, continue encorafenib at reduced dose
  • No improvement, withhold until improves to at least institutional LLN and absolute decrease to 10% or lower compared to baseline and then resume at reduced dose or reduce dose an additional dose level

QT prolongation

• QTcF above 500 ms and ≤60 ms increase from baseline: Withhold until QTcF 500 ms or lower, then resume at reduced dose; if there are more than 1 recurrence, permanently discontinue
• QTcF above 500 ms and above 60 ms increase from baseline: Permanently discontinue

Hepatotoxicity

• Grade 2 AST or ALT increased: Maintain dose; if no improvement within 4 weeks, withhold until improves to below Grade 1 or baseline and then resume at same dose
• Grade 3 or 4 AST or ALT increased
• First occurrence Grade 3: Withhold for up to 4 weeks; if improves to below Grade 1 or baseline, resume at reduced dose; if no improvement, permanently discontinue
• First occurrence Grade 4: Permanently discontinue or withhold for up to 4 weeks; if improves to below Grade 1 or to baseline, resume at reduced dose; if no improvement, permanently discontinue
• Recurrent Grade 3: Consider permanently discontinuing
• Recurrent Grade 4: Permanently discontinue

Dermatologic

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

Other adverse reactions, including hemorrhage

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

Coadministered strong or moderate CYP3A4 inhibitors

• Avoid concurrent use of strong or moderate CYP3A4 inhibitors during treatment
• Planned dose is based on the recommendations for dose reductions for adverse effects
• After discontinuing the inhibitor for 3-5 elimination half-lives, resume previous encorafenib dose
• Moderate CYP3A4 inhibitors
  • Planned dose (encorafenib 450 mg/day): Reduce to 225 mg/day
  • Planned dose (encorafenib 300 mg/day): Reduce to 150 mg/day
  • Planned dose (encorafenib 150 mg or 225 mg/day): Reduce to 75 mg/day
• Strong CYP3A4 inhibitors
  • Planned dose (encorafenib 450 mg/day): Reduce to 150 mg/day
  • Planned dose (encorafenib 150, 225, or 300 mg/day): Reduce to 75 mg/day

Hepatic impairment

• Mild (Child-Pugh A): No dose adjustment required
• Moderate-to-severe (Child-Pugh B or C): No recommended dose established

Renal impairment

• Mild-to-moderate (creatinine clearance [CrCl] 30 to below 90 mL/minute): No dose adjustment required
• Severe (CrCl below 30 mL/minute): A recommended dose has not been established

Dosing Considerations

• Melanoma: Confirm presence of a BRAF V600E or V600K mutation in tumor specimens before initiating
• NSCLC or CRC: Confirm presence of a BRAF V600E mutation in tumor specimens before initiating
• NSCLC: If no mutation is detected in a plasma specimen, test tumor tissue
• Information on FDA-approved tests for the detection of BRAF V600E or V600K mutations is available at: https://www.fda.gov/CompanionDiagnostics

Limitations of use

• Not indicated for melanoma in patients with wild-type BRAF melanoma or wild-type BRAF CRC

Pediatric:

• Safety and efficacy not established

Overdose

In one reported case of encorafenib overdose for 16 days, the patient experienced nausea, vomiting, upset stomach, bloating and muscle pain, and was found to have elevated liver values and prolonged QTc interval. There are no specific treatment recommendations for encorafenib. Hemodialysis is unlikely to be effective in the treatment of overdose. Encorafenib overdose may be treated with symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of encorafenib include:
  • doravirine
  • dronedarone
  • elagolix
  • isavuconazonium sulfate
  • lonafarnib
  • mavacamten
  • pacritinib
  • voriconazole
• Encorafenib has serious interactions with at least 229 different drugs.
• Encorafenib has moderate interactions with at least 347 different drugs.
• Mild interactions of encorafenib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • erdafitinib
  • larotrectinib
  • nitrofurantoin

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Encorafenib can cause fetal harm, based on its mechanism of action and animal reproductive studies. There is no clinical data available on the use of encorafenib in pregnant women.
• Women of reproductive potential must use effective contraception during treatment with encorafenib and for at least 2 weeks after the final dose. The contraception method should be non-hormonal, because encorafenib has the potential to render hormonal contraceptives ineffective.
• Encorafenib may adversely affect male fertility.
• There is no information on the presence of encorafenib or its metabolites in breastmilk, or its effects on milk production or the breastfed infant.
• Nursing mothers should avoid breastfeeding during treatment and for 2 weeks after the final dose, because of the potential for serious adverse reactions in the breastfed infant.

• Take encorafenib exactly as prescribed.
• You will need medical tests before starting encorafenib and periodically thereafter. Follow up with your physician and do not miss your appointments.
• Avoid taking grapefruit and grapefruit juice, over-the-counter drugs, vitamins and herbal products, and prescription drugs as instructed by your treating physician to avoid.
• Report to your physician immediately if you notice any new warts, bumps or sores, or changes in color or size of a mole.
• Report to your physician immediately if you develop:
  • Any heart-related symptoms such as fainting, shortness of breath with activity, fatigue, and weakness
  • Symptoms of unusual bleeding
  • Liver-related symptoms such as jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding
  • Changes in vision
• Store encorafenib safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.