binimetinib

Binimetinib is an anticancer (antineoplastic) medication used in the treatment of adults with melanoma, a type of skin cancer and non-small cell lung cancer (NSCLC). Binimetinib is approved by the FDA to be used in combination with encorafenib, another antineoplastic drug, to treat melanoma with BRAF V600E or V600K gene mutations and NSCLC with BRAF V600E mutations, as confirmed by an FDA-approved test. The combination treatment is more effective than either drug alone in inhibiting cancer growth and emergence of resistance to treatment.

Binimetinib is a small molecule drug that can enter into a cell, and change specific cell mechanisms that cause proliferation of cancer cells, and inhibit tumor growth. Binimetinib is an MEK inhibitor that inhibits the activity of mitogen-activated extracellular kinase 1 and 2 (MEK1 and MEK2), two enzymes that are part of the BRAF signaling pathway which promotes cell proliferation. Mutations in BRAF V600E or V600K genes activate MEK1 and MEK2, which results in uncontrolled cell growth and proliferation.

Binimetinib and encorafenib target two different enzymes (kinases) in the signaling cascade activated by the BRAF mutations. Lab and animal studies on BRAF mutation-positive melanoma and BRAF V600E mutation-positive NSCLC cells lines showed that the combination of binimetinib and encorafenib exhibited greater antitumor activity as well as delay in emergence of resistance in the cancer cells, compared to either drug alone.

The FDA-approved indications of binimetinib 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 encorafenib.
• Metastatic non-small cell lung cancer with a BRAF V600E mutation, as detected by an FDA-approved test, in combination with encorafenib.

• Binimetinib, when administered in combination with encorafenib, has been associated with the development of new primary malignancies, both skin (cutaneous) and non-cutaneous. Evaluate patients for new malignancies prior to, during, and after discontinuation of treatment.
• Binimetinib/encorafenib 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 binimetinib/encorafenib 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.
• Venous thromboembolism and/or pulmonary embolism developed in some patients treated with binimetinib/encorafenib. Monitor patients and withhold, reduce dose or permanently discontinue treatment, based on severity of adverse reactions.
• Binimetinib/encorafenib treatment can be toxic to the eye, resulting in ocular conditions including uvea inflammation (uveitis) and retinal vein occlusion (RVO), and fluid accumulation under the retinal layers (serous retinopathy) that can affect vision.
  • Monitor the patient’s ocular health regularly, and if the patient has new onset or worsening of visual disturbances or acute vision loss, immediately evaluate the patient for ocular toxicities.
  • Withhold, reduce dose or permanently discontinue treatment, based on severity, in case of uveitis or serous retinopathy.
  • The safety of binimetinib is not established in patients with a history of RVO or current risk factors for RVO, including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. If the patient develops retinal vein occlusion, permanently discontinue binimetinib.
• Assess unexplained new or progressive pulmonary symptoms for possible interstitial lung disease. Withhold, reduce dose or permanently discontinue binimetinib/encorafenib treatment, based on the severity of pulmonary disease.
• Binimetinib/encorafenib 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.
• Binimetinib/encorafenib treatment may cause muscle breakdown (rhabdomyolysis).
  • Evaluate the patient’s baseline creatine phosphokinase (CPK) and creatinine levels before initiating treatment and periodically thereafter, as clinically indicated.
  • If CPK levels are elevated, evaluate for rhabdomyolysis.
  • Depending on the severity of symptoms and CPK elevation, withhold, reduce dose or permanently discontinue treatment.
• Binimetinib/encorafenib treatment can cause hemorrhage, including gastrointestinal and intracranial hemorrhage. Depending on severity, withhold, reduce or permanently discontinue treatment.
• Binimetinib can cause fetal harm if used during pregnancy. Verify pregnancy status in women of pregnancy potential before initiating binimetinib. Apprise women who can get pregnant of the potential fetal risk and advise them to use effective contraception for the recommended period during and following treatment.
• Binimetinib is used in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information pertaining to encorafenib.

Common side effects of binimetinib used in combination with encorafenib include:

• Fatigue
• Fever (pyrexia)
• Swelling of extremities (peripheral edema)
• Musculoskeletal pain
• Generalized edema
• Localized edema
• Facial edema
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Constipation
• Decreased appetite
• Taste disorder (dysgeusia)
• Shortness of breath (dyspnea)
• Cough
• Pneumonia
• Fluid around the lungs (pleural effusion)
• Interstitial lung disease
• Liver toxicity (hepatotoxicity)
• Muscle breakdown (rhabdomyolysis)
• Increase in creatinine levels
• Increase in creatine phosphokinase (CPK)
• Increase in gamma-glutamyl transferase (GGT) enzyme
• Increase in liver enzyme alanine aminotransferase (ALT)
• Increase in liver enzyme aspartate aminotransferase (AST)
• Increase in alkaline phosphatase (ALK)
• Low blood sodium (hyponatremia)
• High blood potassium (hyperkalemia)
• Low calcium in blood (hypocalcemia)
• High blood sugar levels (hyperglycemia)
• Increase in lipase enzyme
• Increase in serum amylase
• Low albumin level in blood (hypoalbuminemia)
• Blood disorders including:
  • Low red blood cell count (anemia)
  • Low count of leukocyte immune cell (leukopenia)
  • Low lymphocyte immune cell count (lymphopenia)
  • Low count of neutrophil immune cell (neutropenia)
  • Low platelet count (thrombocytopenia)
• Eye toxicities including:
  • Fluid buildup beneath the retina (serous retinopathy)
  • Macular edema
  • Retinal detachment
  • Retinal pigment epithelial dystrophy
  • Retinal vein occlusion
  • Inflammation of uvea (uveitis)
  • Visual impairment
• Rash
• Itching (pruritus)
• Dry skin
• Thickening of skin (hyperkeratosis)
• Redness of skin (erythema)
• Hair loss (alopecia)
• Bleeding (hemorrhage)
• High blood pressure (hypertension)
• Left ventricular dysfunction
• Heart muscle disease (cardiomyopathy)
• Irregular heart rhythm (arrhythmia)
• Heart attack (myocardial infarction)
• Dizziness
• Headache
• Acute kidney injury
• Inflammation of the fat tissue beneath the skin (panniculitis)
• Drug hypersensitivity reactions
• Colon inflammation (colitis)
• Inflammation of the pancreas (pancreatitis)
• Increase in weight
• Insomnia
• Peripheral nerve disease (neuropathy)
• Weakness of facial muscles (facial paresis)
• Blood clot block in vein (venous thromboembolism)
• Blood clot in lungs (thromboembolism)
• New primary malignancies

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.

Tablet

• 15 mg

Adult:

Melanoma

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

Non-Small Cell Lung Cancer (NSCLC)

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

Dosage Modifications

• If encorafenib is permanently discontinued, discontinue binimetinib

Recommended dose reductions for binimetinib for adverse reactions

• First dose reduction: 30 mg orally twice daily
• Subsequent modifications: Permanently discontinue if unable to tolerate 30 mg/day

Cardiomyopathy

• Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) of above 10% from baseline that is also below lower limit of normal (LLN): Withhold for up to 4 weeks, evaluate LVEF once every 2 weeks
• Resume at a reduced dose if the following are present
  • LVEF is at or above the LLN and
  • Absolute decrease from baseline is 10% or below and
  • Patient is asymptomatic
  • If the LVEF does not recover within 4 weeks permanently discontinue
• Symptomatic congestive heart failure or absolute decrease in LVEF of above 20% from baseline that is also below LLN: Permanently discontinue

Venous thromboembolism

• Uncomplicated deep vein thrombosis (DVT) or pulmonary embolism (PE)
  • Withhold drug; if improves to Grade 0-1, resume at a reduced dose
  • If no improvement, permanently discontinue
• Life-threatening PE: Permanently discontinue

Serous retinopathy

• Symptomatic serous retinopathy/retinal pigment epithelial detachments
• Withhold drug for up to 10 days
  • If improves and becomes asymptomatic, resume at same dose
  • If not improved, resume at a lower dose or permanently discontinue

Retinal vein occlusion

• Any grade: Permanently discontinue

Uveitis

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

Interstitial lung disease

• Grade 2
  • Withhold for up to 4 weeks; if improved to Grade 0-1, resume at a reduced dose
  • If not resolved within 4 weeks, permanently discontinue
• Grades 3 or 4: Permanently discontinue

Hepatotoxicity

• Grade 2 aspartate aminotransferase/alanine aminotransferase (AST/ALT) increased
  • Maintain binimetinib dose; if no improvement within 2 weeks, withhold dose until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose
• Recurrent Grade 2 or first occurrence of any Grade 3 AST/ALT increased
  • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose
  • If no improvement, permanently discontinue
• First occurrence of any Grade 4 AST/ALT increased
  • Permanently discontinue OR
  • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose; if no improvement, permanently discontinue
• Recurrent Grade 3 AST/ALT increased
• Consider permanently discontinuing
• Recurrent Grade 4 AST/ALT increased
  • Permanently discontinue

Rhabdomyolysis or CPK elevations

• Grade 4 asymptomatic CPK elevation OR any Grade CPK elevation with symptoms or with renal impairment
• Withhold dose for up to 4 weeks; if improved to Grade 0-1 resume at a reduced dose
• If not resolved within 4 weeks, permanently discontinue

Dermatologic

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

Other adverse reactions, including hemorrhage

• Dose modification when administered with encorafenib is NOT recommended for palmar plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation
• Recurrent Grade 2 or first occurrence of any Grade 3
  • Withhold for up to 4 weeks; if improves to Grade 0-1 or to pretreatment/baseline level, 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 Grade 0-1 or to pretreatment/baseline level, resume at reduced dose; if no improvement, permanently discontinue
• Recurrent Grade 3
  • Consider permanently discontinuing
• Recurrent Grade 4
  • Permanently discontinue

Hepatic impairment

• Moderate (total bilirubin above 1.5 to 3 or fewer times upper limit normal (ULN) and any AST): 30 mg orally twice daily
• Severe (total bilirubin above 3 times ULN and any AST): 30 mg orally twice daily

Renal impairment

• No clinically important changes in binimetinib exposure were observed with severe renal impairment as compared with patients with normal renal function

Dosing Considerations

Limitations of use:

• Not indicated for patients with wild-type BRAF melanoma

Patient selection:

• Melanoma: Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens before initiating
• NSCLC: Confirm the presence of a BRAF V600E mutation in tumor specimens before initiating
• Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma and BRAF V600E mutations in NSCLC are available at: https://www.fda.gov/CompanionDiagnostics

Pediatric:

• Safety and efficacy not established

Overdose

Binimetinib overdose will likely intensify its adverse effects. Hemodialysis is unlikely to be effective in the treatment of overdose. 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.

• Binimetinib has no listed severe, serious, moderate, or mild interactions with other drugs.

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.

• Binimetinib can cause fetal harm, based on its mechanism of action and animal reproductive studies. There is no clinical data available on the use of binimetinib in pregnant women.
• Women of reproductive potential must use effective contraception during treatment with binimetinib and for at least 30 days after the final dose.
• There is no information on the presence of binimetinib or its active metabolite in breastmilk, or its effects on milk production or the breastfed infant.
• Nursing mothers should avoid breastfeeding during treatment and for 3 days after the final dose, because of the potential for serious adverse reactions in the breastfed infant.

• Take binimetinib along with encorafenib exactly as instructed.
• You will periodically need medical tests. Follow up with your physician and do not miss your appointments.
• 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 treating physician immediately if you experience:
  • Symptoms of heart failure such as swelling in extremities, fatigue, rapid or irregular heartbeat and shortness of breath
  • Symptoms of blood clots in veins or lungs, which may include sudden onset of leg pain, swelling and difficulty breathing
  • Changes in vision
  • New or worsening respiratory symptoms such as shortness of breath or coughing
  • Symptoms of liver damage such as jaundice, nausea, vomiting, loss of appetite, dark urine, fatigue, bruising or bleeding
  • Muscle breakdown symptoms such as unusual or new onset of muscle pain and weakness, and dark urine
  • Unusual or severe bleeding, or symptoms of internal bleeding such as blood in stool or urine
• Store binimetinib safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.