cobimetinib

Cobimetinib is used in the treatment of melanoma, a type of skin cancer, and histiocytic neoplasms, a rare group of tumors that are caused by uncontrolled proliferation of certain types of immune cells known as histiocytes, which include monocytes, macrophages, and dendritic cells. Cobimetinib is FDA-approved, in combination with vemurafenib, to treat adults with unresectable or metastatic melanoma with BRAF V600E or V600K gene mutation, identified by FDA-approved tests, and as a monotherapy in adults with histiocytic neoplasms.

Cobimetinib is a small molecule drug that enters into the cancer cell, changes a specific cell mechanism that causes the proliferation of these cancer cells, and leads to their destruction. Cobimetinib is a 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 that promote cell proliferation. Mutations in BRAF V600E or V600K genes activate MEK1 and MEK2, which results in uncontrolled cell growth and proliferation.

Animal studies with implanted tumor cell lines that had BRAF 600 E mutation showed that cobimetinib reduced tumor growth. Cobimetinib is used concurrently with vemurafenib, because the two drugs target two different enzymes (kinases) in the signaling cascade activated by the BRAF mutations. The combination increased the programmed cell death (apoptosis) of tumor cells in animal studies.

• Cobimetinib/vemurafenib treatment can cause new primary skin or non-skin malignancies.
  • Evaluate patients for skin cancers before initiating therapy, and perform tests every 2 months during therapy. Evaluate and treat any suspicious skin lesions. Continue monitoring for 6 months after discontinuation of treatment, when both cobimetinib and vemurafenib are administered.
  • Monitor patients for signs and symptoms of non-skin cancers, particularly those taking both drugs.
• Cobimetinib can cause bleeding, including major hemorrhage in critical organs. Monitor patients for signs and symptoms of hemorrhage and:
  • Withhold cobimetinib for Grade 3 hemorrhagic events and resume at a lower dose, if condition improves to Grade 0 or 1 within 4 weeks.
  • Discontinue permanently in case of Grade 4 hemorrhage, and Grade 3 hemorrhagic events that do not improve.
• Cobimetinib treatment is associated with heart muscle disease (cardiomyopathy) that can reduce the left ventricular ejection fraction (LVEF).
  • Evaluate LVEF in patients before starting treatment, and monitor 1 month after treatment initiation, and every 3 months thereafter.
  • Manage cardiomyopathy with interruption, dose reduction or discontinuation of cobimetinib treatment, as appropriate.
  • In patients who restart treatment after interruption or dose reduction, monitor LVEF at approximately 2 weeks, 4 weeks, 10 weeks, 16 weeks, and then as required based on the patient's clinical condition.
• Cobimetinib can cause severe rash and other skin reactions. Interrupt, reduce dose or discontinue cobimetinib as recommended, based on the patient's condition.
• Cobimetinib can be toxic to the eye, causing ocular conditions including fluid accumulation under the retinal layers (serous retinopathy) which can affect vision. 
  • Monitor the patient’s eye health regularly, and if the patient has new onset or worsening of visual disturbances, evaluate patient for serous retinopathy.
  • If serous retinopathy is confirmed, interrupt cobimetinib until visual symptoms improve. Manage the condition further with interruption, dose reduction or discontinuation of cobimetinib, as needed.
• Cobimetinib may cause liver toxicity. Evaluate liver function in patients before starting cobimetinib, and continue monitoring once a month, or more often if required, during treatment. Manage Grade 3 and 4 liver toxicity with interruption, dose reduction or discontinuation of cobimetinib, as necessary.
• Cobimetinib has been associated with muscle breakdown (rhabdomyolysis).
  • Evaluate the patient’s baseline creatine phosphokinase (CPK) and creatinine levels before starting cobimetinib and periodically during treatment.
  • If CPK levels are elevated, evaluate for rhabdomyolysis and other causes.
  • Depending on the severity of symptoms and CPK elevation, Interrupt, reduce dose or discontinue cobimetinib as needed.
• Cobimetinib can cause severe light sensitivity of the skin.
  • Manage Grade 2 or higher photosensitivity with dose reduction.
  • Advise patients to avoid direct sun exposure, and wear protective clothing and use effective sunscreen when outdoors.
• Cobimetinib can cause fetal harm. Advise women of pregnancy potential to use effective contraception during treatment and for 2 weeks after treatment completion.

Common side effects of cobimetinib include:

• Diarrhea
• Nausea
• Vomiting
• Indigestion (dyspepsia)
• Oral inflammation (stomatitis)
• Dry mouth (xerostomia)
• Oral pain
• Increase in serum creatinine
• Increase in creatine phosphokinase (CPK)
• Muscle breakdown (rhabdomyolysis)
• Liver toxicity
• Increase in liver enzymes AST and ALT
• Increase in alkaline phosphatase (ALK)
• Increase in gamma-glutamyl transferase (GGT)
• Low albumin in blood (hypoalbuminemia)
• Abnormal bilirubin levels
• Electrolyte disturbances including:
  • Low phosphate level in blood (hypophosphatemia)
  • Low sodium levels (hyponatremia)
  • Low calcium levels (hypocalcemia)
  • Low or high blood potassium (hypokalemia or hyperkalemia)
• Blood disorders including:
  • Low count of lymphocyte immune cells (lymphopenia)
  • Low red blood cell count (anemia)
  • Low platelet count (thrombocytopenia)
  • Low count of leukocyte immune cells (leukopenia)
  • Low count of neutrophil immune cells (neutropenia)
• Light sensitivity (photosensitivity) of skin
• Acneiform dermatitis
• Dry skin
• Rash with flat and raised lesions (maculopapular rash)
• Itching (pruritus)
• Infections
• Urinary tract infection
• Pulmonary infection
• Shortness of breath (dyspnea)
• Cough 
• Lung inflammation (pneumonitis)
• Fluid in lungs (pulmonary edema)
• Respiratory failure
• Low oxygen saturation in tissue (hypoxia)
• Fever (pyrexia)
• Chills
• Headache
• Decreased left ventricular ejection fraction
• High blood pressure (hypertension)
• Bleeding (hemorrhage) including:
  • Gastrointestinal hemorrhage
  • Genitourinary tract hemorrhage
  • Cerebral hemorrhage
  • Nasal bleeding (epistaxis)
  • Nail bed bleeding
  • Ocular hemorrhage including retinal bleeding
• Eye disorders including:
  • Impaired vision
  • Blurred vision
  • Serous retinopathy
  • Retinal vein occlusion
  • Retinal vascular disorder
  • Retinopathy
  • Chorioretinopathy
  • Retinal detachment
• Acute kidney injury
• Fall
• New primary skin malignancies including:
  • Cutaneous squamous cell carcinoma
  • Basal cell carcinoma
  • Keratocanthoma
  • Second primary melanoma
• Non-cutaneous 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

• 20 mg

Adult:

Melanoma

• Indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib
• 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity
• Vemurafenib: 960 mg orally twice daily on days 1-28 of an every 28-day cycle

Histiocytic Neoplasms

• Indicated as a single agent for adults with histiocytic neoplasms
• 60 mg orally once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity

Dosage Modifications

• New primary malignancies (cutaneous and non-cutaneous): No dosage modification required
• Avoid concurrent use of cobimetinib and strong or moderate CYP3A inducers including but not limited to carbamazepine, efavirenz, phenytoin, rifampin, and St. John’s Wort

Hepatic impairment

• Mild-to-severe (Child-Pugh A to C): No dosage adjustment necessary

Renal impairment

• Mild-to-moderate (creatinine clearance [CrCl] 30-89 mL/minute): No dosage adjustment necessary
• Severe (CrCl below 30 mL/minute): Safety and efficacy not established

Coadministration with CYP3A inhibitors

• Do not take strong or moderate CYP3A inhibitors while taking cobimetinib
• If concurrent short-term (14 or fewer days) use of moderate CYP3A inhibitors is unavoidable for patients taking cobimetinib 60 mg, reduce dose to 20 mg; after the moderate CYP3A inhibitor is discontinued, resume previous cobimetinib dose
• Use an alternative to a strong or moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily)

Dose reductions

• First dose reduction: 40 mg orally once daily
• Second dose reduction: 20 mg orally once daily
• Subsequent modification: Permanently discontinue cobimetinib if unable to tolerate 20-mg dose

Hemorrhage

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

Cardiomyopathy

• Asymptomatic
  • Definition: Absolute decrease in left ventricle ejection fraction (LVEF) from baseline of above 10% and less than institutional lower limit of normal (LLN); Withhold cobimetinib for 2 weeks; repeat LVEF
  • Resume at next lower dose if all of the following are present: LVEF is LLN or above and absolute decrease from baseline LVEF is 10% or less
  • Permanently discontinue if any of the following are present: LVEF is 10%
• Symptomatic LVEF decrease from baseline
  • Withhold cobimetinib for 4 weeks; repeat LVEF
  • Resume at next lower dose if all of the following are present:
  • Symptoms resolve and LVEF is LLN or above and absolute decrease from baseline LVEF is 10% or less
  • Permanently discontinue if any of the following are present:
  • Symptoms persist, or LVEF is 10%
• Dermatologic reactions
  • Grade 2 (intolerable) or grades 3 or 4: Withhold or reduce dose

Retinopathy or retinal vein occlusion

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

Hepatoxicity

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

Rhabdomyolysis and elevated CPK

• Grade 4 creatine phosphokinase (CPK) elevation or any CPK elevation plus myalgia: Withhold for up to 4 weeks; if improved to grade 3 or less, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks

Photosensitivity

• Grade 2 (intolerable), grades 3 or 4: Withhold for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks

Other adverse events

• Grade 2 (intolerable) adverse reactions or any grade 3
  • Withhold for up to 4 weeks; if improved to grade 0 or 1, resume at the next lower dose level; permanently discontinue if not improved within 4 weeks
• First occurrence of any grade 4 adverse reaction
  • Withhold until adverse reaction improves to grade 0 or 1 and then resume at the next lower dose level, OR
  • Permanently discontinue
• Recurrent grade 4 adverse reaction
  • Permanently discontinue

Dosage Considerations

Melanoma

• Confirm presence of BRAF V600E or V600K mutation in tumor specimens before initiating cobimetinib with vemurafenib
• See information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma

Pediatric:

• Safety and efficacy not established

Overdose

There is no information on cobimetinib overdose. Overdose will likely intensify the drug’s adverse effects. 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.

• Cobimetinib has severe interactions with at least 46 different drugs.
• Cobimetinib has serious interactions with at least 46 different drugs.
• Moderate interactions of cobimetinib include:
  • belzutifan
  • cenobamate
  • cholera vaccine
  • dengue vaccine
  • duvelisib
  • elagolix
  • encorafenib
  • fedratinib
  • istradefylline
  • lenacapavir
  • mifepristone
  • ponesimod
  • rucaparib
  • siponimod
  • stiripentol
  • tazemetostat
  • tecovirimat
• Mild interactions of cobimetinib include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

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.

• There is no data on the safety of cobimetinib use in pregnant women, however, animal reproductive studies show it can cause fetal harm.
• Women of pregnancy potential must use effective contraception during treatment and for two weeks following the final dose of cobimetinib.
• Cobimetinib may reduce fertility in both males and females of reproductive potential.
• There is no information on the presence of cobimetinib in breastmilk, or its effects on milk production or the breastfed infant. Nursing mothers should not breastfeed during treatment and for two weeks following the final dose of cobimetinib, because of the potential for serious adverse reactions in the breastfed infant.

• Take cobimetinib exactly as directed.
• You will periodically need blood count and other tests. Do not miss your appointments.
• Report to your treating physician immediately if you:
  • Notice any new skin lesions
  • Experience any unusual or severe bleeding, or symptoms of internal bleeding such as blood in stool or urine
  • Develop heart-related symptoms such as palpitations, fatigue, shortness of breath
  • Experience any skin reactions
  • Develop light sensitivity of skin. Protect your skin from direct sunlight with protective clothing and effective sunscreen
  • Experience new onset or worsening of visual symptoms
  • Develop muscle pain and weakness, and dark urine
• Store cobimetinib safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.