Cobimetinib – Uses, Dosage, Side Effects, Interaction

Cobimetinib fumarate is a fumarate salt prepared from cobimetinib by a reaction of one molecule of fumaric acid for every two molecules of cobimetinib. An inhibitor of mitogen-activated protein kinase that is used in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma. It has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor and an antineoplastic agent. It is a fumarate salt and an organoammonium salt. It contains a cobimetinib(1+).

Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine–tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors become BRAF-inhibitor resistant due to reactivation of MAPK signaling. BRAF-inhibitor-resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK.

Use in Cancer

Cobimetinib fumarate is approved to be used with vemurafenib to treat:

• Melanoma that cannot be removed by surgery or has spread to other parts of the body. It is used in patients whose cancer has a certain mutation in the BRAF gene.

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

Contraindications

• diabetic retinopathy, a type of damage to the eye from diabetes
• detachment of the retina of the eye
• a blockage of blood vessels in the retina of the eye
• chronic heart failure
• bleeding
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• muscle pain or tenderness with increase creatine kinase
• retinal eye changes caused by high blood pressure

Dosage

Strengths: 20 mg

Melanoma – Metastatic

• 60 mg orally once a day for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity
• The presence of BRAF V600E or V600K mutation in tumor specimens should be confirmed with an FDA-approved test prior to therapy initiation; information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics.

Renal Dose Adjustments

• Mild (CrCl 60 to 89 mL/min) to moderate (CrCl 30 to 59 mL/min) renal impairment: No adjustment recommended.
• Severe (CrCl less than 30 mL/min) renal impairment or end-stage renal disease: Data not available

Liver Dose Adjustments

• Mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment: No adjustment in the starting dose is recommended.

Liver Laboratory Abnormalities and Hepatotoxicity Occur During Treatment:
First Occurrence Grade 4:

• Withhold treatment for up to 4 weeks.
• Resume at next lower dose if improved to Grade 0 or 1; permanently discontinue drug if not improved to Grade 0 or 1 within 4 weeks.
• Permanently discontinue the drug for recurrent Grade 4 abnormalities/hepatotoxicity.
• First Dose Reduction: 40 mg orally once a day
• Second Dose Reduction: 20 mg orally once a day
• Permanently discontinue the drug if the patient is unable to tolerate 20 mg orally once a day.

Dose Adjustments

MODERATE OR STRONG CYP450 3A INHIBITORS:

• Do not take moderate or strong CYP450 3A inhibitors while taking this drug.
• If concurrent short-term (14 days or less) use of moderate CYP450 3A inhibitors is unavoidable for patients who are taking this drug at 60 mg, reduce the dose of this drug to 20 mg. After discontinuation of a moderate CYP450 3A inhibitor, resume the previous dose of this drug at 60 mg.
• Use an alternative to a moderate or strong CYP450 3A inhibitor in patients who are taking a reduced dose of this drug (20 or 40 mg daily).

RECOMMENDED DOSE REDUCTIONS:

• First dose reduction: 40 mg orally once a day
• Second dose reduction: 20 mg orally once a day
• Permanently discontinue this drug if the patient is unable to tolerate 20 mg orally once a day.

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
PRIMARY MALIGNANCIES (cutaneous and non-cutaneous):

• No adjustment is recommended.

HEMORRHAGE:

• Grade 3: Withhold this drug for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• Grade 4: Permanently discontinue therapy.

CARDIOMYOPATHY:

• Asymptomatic, absolute decrease in left ventricular ejection fraction (LVEF) from baseline of greater than 10% AND less than the institutional lower limit of normal (LLN): Withhold therapy for 2 weeks; repeat LVEF. Resume at next lower dose if LVEF at or above LLN AND absolute decrease from baseline LVEF 10% or less. Permanently discontinue therapy if LVEF is less than LLN OR an absolute decrease from baseline LVEF is more than 10%.
• Symptomatic LVEF decrease from baseline: Withhold therapy for up to 4 weeks; repeat LVEF. Resume at the next lower dose if symptoms resolve, LVEF at or above LLN, AND absolute decrease from baseline LVEF 10% or less. Permanently discontinue therapy if symptoms persist, LVEF is less than LLN, OR absolute decrease from baseline LVEF of more than 10%.

DERMATOLOGIC REACTIONS:

• Intolerable Grade 2 or Grade 3 or 4: Reduce dose or withhold therapy.

SEROUS RETINOPATHY OR RETINAL VEIN OCCLUSION:

• Serious retinopathy: Withhold therapy for up to 4 weeks; if improved resume at the next lower dose level; if not improved or symptoms recur at the lower dose within 4 weeks, permanently discontinue therapy.
• Retinal vein occlusion: Permanently discontinue therapy.

LIVER LABORATORY ABNORMALITIES AND HEPATOTOXICITY:

• First occurrence Grade 4: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved to Grade 0 or 1 within 4 weeks, permanently discontinue therapy.
• Recurrent Grade 4: Permanently discontinue therapy.

RHABDOMYOLYSIS AND CREATINE PHOSPHOKINASE (CPK) ELEVATIONS:

• Grade 4 CPK elevation/any CPK elevation and myalgia: Withhold therapy for up to 4 weeks; if improved to Grade 3 or lower, resume at the next lower dose level: if not improved within 4 weeks, permanently discontinue therapy.

PHOTOSENSITIVITY:

• Intolerable Grade 2 or Grade 3 or 4: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.

OTHER:

• Intolerable Grade 2 adverse reactions: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• Any Grade 3 adverse reactions: Withhold therapy for up to 4 weeks; if improved to Grade 0 or 1, resume at the next lower dose level; if not improved within 4 weeks, permanently discontinue therapy.
• First occurrence of any Grade 4 adverse reaction: Withhold therapy until adverse reaction improves to Grade 0 or 1; resume at the next lower dose level, OR permanently discontinue therapy.
• Recurrent Grade 4 adverse reaction: Permanently discontinue therapy.

Administration advice:

• This drug may be taken with or without food.
• If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-daily regimen.
• In case of vomiting after administration of a dose, the patient should not take an additional dose on that day and therapy should be continued the following day.

Side Effects

The Most Common

• mouth ulcers
• hair loss
• diarrhea
• rash that covers a large area of your body, blisters, or peeling skin
• changes in skin appearance
• new wart
• skin sore or red bump that bleeds or does not heal
• change in size or color of a mole
• unusual bleeding or bruising
• tarry or black stools
• blood in the urine
• unusual vaginal bleeding
• headache
• dizziness
• rapid, irregular, or pounding heartbeat
• coughing or wheezing
• shortness of breath
• swelling of the face, arms, legs, ankles, or feet
• tiredness
• muscle pain or weakness
• change in vision, including seeing halos (blurred outline around objects)
• yellowing of the skin or eyes
• dark-colored (tea-colored) urine
• pain in upper right part of the stomach
• nausea
• vomiting
• loss of appetite

More Common

• vision changes, partial vision loss, seeing halos around lights;
• unexplained muscle pain, tenderness, or weakness (especially if you also have fever and dark-colored urine);
• easy bruising or bleeding (nosebleeds, bleeding gums);
• signs of bleeding inside the body–weakness, dizziness, headache, red or pink urine, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds;
• signs of a heart problem–cough, wheezing, shortness of breath (even with mild exertion), chest pain, fast heartbeats, swelling in your feet or ankles;
• low levels of sodium in the body–headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• liver problems–nausea, upper stomach pain, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or
• severe skin reaction–skin pain, itching, redness, bumps or pimples, thickened or wrinkled skin, skin rash that spreads and causes blistering and peeling.
• nausea, vomiting, diarrhea;
• fever;
• sunburn or increased sensitivity to sunlight;
• low sodium levels; or
• abnormal laboratory tests.

Rare

• acne-like skin rash
• hives
• increased blood pressure
• increased sensitivity to sunlight (e.g., sunburn, rash)
• new skin cancer (e.g., new skin sore, wart, or bump on the skin that bleeds or does not heal)
• signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
• signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
• signs of dehydration (e.g., decreased urine, dry skin, dry and sticky mouth, sleepiness, dizziness, headache, thirst, confusion)
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
• signs of muscle damage (e.g., unexplained muscle pain, tenderness, or weakness, or brown or discoloured urine)
• swelling ankles or feet
• swelling, pain, and redness of the palms of the hands and soles of the feet
• symptoms of heart problems (e.g., persistent cough, wheezing, shortness of breath, tiredness)
• symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odour)
• symptoms of irregular heartbeat (e.g., fast heartbeat, weakness, tiredness, dizziness, lightheadedness, confusion, chest pain, trouble breathing)
• symptoms of lung inflammation (e.g., trouble breathing, cough, fever or chills)
• tender red bumps under the skin
• vision problems (e.g., blurred vision, halos, missing parts of vision)
• signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
• signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
• signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

The proposed labeling states that cobimetinib can cause fetal harm when administered to a pregnant woman based on findings in animal studies, and lists cobimetinib under the pregnancy category. It is not known whether cobimetinib is excreted in human milk.

Lactation

No information is available on the clinical use of cobimetinib during breastfeeding. Because cobimetinib is 90% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 44 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during cobimetinib therapy and for 2 weeks after the last dose.

References