Brand Name: Mektovi

Drug Name: Binimetinib

Primary Indications: Metastatic or unresectable melanoma

Manufacturer: Array Biopharma

FDA Approval date: 27 June 2018

Mektovi (Binimetinib) is a drug that blocks the effects of two important kinases, MEK-1 and MEK-2. MEK or mitogen-activated extracellular signal-regulated kinases are proteins that regulate ERK (Extracellular signal-related kinases). Mektovi inhibits tumor growth by inhibiting phosphorylation of mutant cells that have developed BRAF mutations. 

Mektovi FDA-Approved uses:

Mektovi (Binimetinib), when given in combination with Encorafenib (Braftovi), is indicated for the treatment of melanoma that has:

1. BRAF V600E or V600K mutations
2. That can not be resected, or that has spread (Metastasized)

Mektovi (Binimetinib) Dosage and Administration:

Who may receive the treatment?

• Patients with confirmed BRAF V600E or V600K mutations positive metastatic/ unresectable melanoma

Recommended Dosage:

• 45 mg taken orally twice daily (12 hours apart) with or without meals.
• It is given with Braftovi (Encorafenib).
• Do not take an extra dose if you vomit or miss your dose. You can take the missed dose within 6 hours. If 6 hours have passed, wait for the next scheduled dose.

Dosage Modifications for Adverse Reactions

• If you can not take Braftovi (encorafenib) or have to discontinue Braaftove because of side effects or any contraindications, you should also not take Mektovi then. Mektovi is only indicated when used with Braftovi.
• Dose reductions for adverse reactions associated with MEKTOVI are given below:
  • The first dose reduction is to 30 mg orally two times a day.
  • If subsequent modifications are needed and the patient is unable to tolerate MEKTOVI even at 30 mg twice daily, then MEKTOVI should be permanently discontinued.

Recommended Dosage Modifications for MEKTOVI for Adverse Reactions

Adverse Reaction	Severity	Dose Modification for MEKTOVI
Cardiomyopathy	Asymptomatic, but >10% decrease in LVEF from baseline	Stop the treatment temporarily the treatment for up to 4 weeks, and evaluate LVEF every 2 weeks. Resume at a reduced dose if LVEF is normal, the decrease is <10% & patient is asymptomatic. Discontinue the treatment if no improvement in LVEF is noted after 4 weeks
	Symptomatic or >20% decrease	Permanently discontinue MEKTOVI.
Venous Thromboembolism	Uncomplicated DVT or PE	Stop MEKTOVI treatment temporarily and resume at a reduced dose if improved to Grade 0-1 is noted, otherwise, discontinue the treatment permanently.
	Life-threatening PE	Discontinue MEKTOVI treatment permanently.
Serous Retinopathy	Symptomatic	Stop the treatment temporarily for up to 10 days. Resume at the recommended dose if improvement is noted or in cases of severe retinopathy, restart at a lower dose or consider permanent discontinuation.
Retinal Vein Occlusion (RVO)	Any Grade	Permanently stop the treatment.
Uveitis	Grade 1-3	Stop the treatment temporarily for up to 6 weeks. Resume at the same or reduced dose if clinical improvement is noted. If no improvement is noted, permanently discontinue it.
	Grade 4	Stop MEKTOVI treatment permanently.
Interstitial Lung Disease	Grade 2	Stop the treatment temporarily for up to 4 weeks and then restart at a lower dose if the improvement is noted (to Grade 0-1). Stop the treatment if no improvement is noted at all.
	Grade 3 or 4	Permanently stop the treatment.
Hepatotoxicity	Increase in AST/ALT of Grade 2 severity	Continue the same MEKTOVI dose and see if the AST and ALT improve within 2 weeks spontaneously or not. If no improvement is noted, stop the treatment temporarily until improved to Grade 0-1 or pre-treatment/baseline levels, then resume at the same dose.
	Increase in AST/ALT of Grade 3 or 4 severity	See Other Adverse Reactions.
Rhabdomyolysis or CPK elevations	Grade 4 asymptomatic	Stop the treatment temporarily for up to 4 weeks. Restart at a lower dose if improved to Grade 0-1, otherwise, stop the treatment.
	Any Grade with symptoms or renal impairment	Stop the treatment temporarily for up to 4 weeks. Restart at a lower dose if improved to Grade 0-1, otherwise, permanently discontinue it.
Dermatologic	Grade 2	Stop the treatment temporarily until improved to Grades 0-1. Resume at the same dose if this was the first time, if recurrent, then use a lower dose.
	Grade 3	Stop the treatment temporarily until improved to Grades 0-1. Restart at the same dose if this was the first time, and reduce it if it's recurrent.
	Grade 4	Permanently stop the treatment.
Other Adverse Reactions (including Hemorrhage)	Recurrent Grade 2 or first occurrence of any Grade 3	Stop the treatment temporarily for up to 4 weeks. Restart at a lower dose if improved to Grade 0-1 or pre-treatment/baseline levels, permanently discontinue otherwise.
	The first occurrence of any Grade 4	Permanently discontinue MEKTOVI or Stop the treatment temporarily for up to 4 weeks, then resume at a reduced dose if improved to Grade 0-1

Criteria for Hepatic Impairment and Recommended Dosage:

Liver Impairment	Criteria	Recommended Dosage
Moderate	Total bilirubin > 1.5 to ≤ 3 times ULN and any AST	30 mg orally twice daily
Severe	Total bilirubin > 3 times ULN and any AST	30 mg orally twice daily

This dosage modification helps to ensure that the patient receives the appropriate treatment while avoiding potential harm due to hepatic impairment.

MEKTOVI Contraindications:

No contraindication is given in the FDA prescribing information.

Warning & Precautions:

• Cardiomyopathy

Patients on Mektovi/ Braftovi are at risk of developing cardiac dysfunction. The severity of left ventricular dysfunction determines the patient's symptoms, however, some patients with mildly reduced LVEF may become greatly symptomatic.

Cardiomyopathy was observed in about 7% of the participants in the COLUMBUS trial. Severe left ventricular dysfunction of Grade 3 or more severity was observed in 1.6% of the patients. These patients developed cardiac dysfunction within about 3.6 months of using Mektovi/Braftovi.

Cardiomyopathy resolved in 87% of patients when the treatment was discontinued. All patients should have echocardiography or a MUGA scan done before the start of the treatment and should be repeated at about 2 to 3-month intervals.

It is essential to screen for left ventricular dysfunction and all patients with a baseline EF of less than 50% should be excluded from Mektovi/ Braftovi treatment. Treatment may need to be stopped temporarily or even permanently depending on the degree of left ventricular dysfunction.

• Venous Thromboembolism

Venous thromboembolism (VTE) was observed in about 6% of the participants who received Mektovi/ Braftovi in the Columbus trial. 3.1% of these patients developed pulmonary embolism.

If the patient develops VTE, the treatment with MEKTOVI plus encorafenib may be stopped, withheld temporarily, or the dose reduced depending on the severity of the condition.

• Ocular Toxicities

Eyes-related side effects may include retinopathy, retinal vein occlusion, or uveitis.

• Serous Retinopathy

Retinopathy was observed in about 20% of the patients in the clinical trial including 8% of the participants developing retinal detachment, and 6% of the patients developing macular edema.

Symptomatic retinopathy without blindness was observed in 8%. The median time of eye-related events, especially retinopathy was about 1.2 months.

Assess for visual symptoms at each visit and perform an ophthalmologic examination at regular intervals to detect new or worsening visual disturbances.

Withhold, reduce dose, or permanently discontinue based on the severity of the adverse reaction.

• Retinal Vein Occlusion

RVO is a well-known side effect of all MEK inhibitors. However, it is not known if Mektovi/Braftovi combination is safe or not in patients with a history of or risk factors of retinal vein occlusion such as hypercoagulability, hyperviscosity, and glaucoma.

Patients who report visual loss or those who report a change in vision should be evaluated within 24 hours of the onset of symptoms and managed accordingly. Mektovi treatment, in such cases, should be permanently stopped.

• Uveitis

Uveitis, including iritis and iridocyclitis, has been observed in about 4% of the participants in the clinical trials with Mektovi/ Braftovi combination therapy.

The eye examination should be performed periodically and when patients complain of eye-related side effects such as impaired vision or blurred vision and eye redness. The treatment should be discontinued permanently in severe cases. In mild to moderate cases, the treatment may be stopped only temporarily or the dose may need to be reduced.

• Interstitial Lung Disease (ILD)

0.3% of patients on Mektovi developed ILD during the clinical trials. All patients should be asked to report symptoms of progressive or new onset shortness of breath, cough, or chest pain.

The treatment should be discontinued permanently in severe cases. In mild to moderate cases, the treatment may be stopped only temporarily or the dose may need to be reduced.

• Hepatotoxicity

Severe liver impairment, as observed by an elevation of liver enzymes of grade 3 or 4 was observed in 6% of the participants in the clinical trial.

All patients should undergo liver functions done at monthly intervals and when clinically indicated. The treatment may be discontinued temporarily, or permanently, or the dose reduced based on the severity of impaired liver functions.

• Rhabdomyolysis

Elevated muscle enzymes were observed in 58% of patients with one patient developing rhabdomyolysis during the trial. It is essential to check CPK levels and then perform this test at regular intervals or when clinically indicated.

The severity of the disease or elevation in muscle enzyme will determine whether to continue the treatment at a lower dose or discotnue it.

• Hemorrhage

Bleeding may occur as was seen in 19% of patients receiving Mektovi/ Braftovi treatment. 3.2% of the participants developed severe bleeding of grade 3 or more severity.

Most patients who developed bleeding had GI bleeding and 1.6% had fatal bleeding into the brain. Patients should be monitored for bleeding and the dose adjusted or treatment discontinued based on the severity of the symptoms.

Mektovi Side effects:

Frequency	Side Effect
Common	Increase in liver enzyme levels (ALT, AST)
	Nausea
	Vomiting
	Diarrhea
	Swelling in hands, feet, or face
Less Common	Rhabdomyolysis
	Interstitial lung disease (ILD)
	Hemorrhage
Severe	Intracranial hemorrhage
	Hepatotoxicity

Side effects of Mektovi as reported in clinical trials:

Topic	Summary
Common side effects	Fatigue, nausea, diarrhea, vomiting, and abdominal pain
Side effects that led to treatment interruptions	left ventricular dysfunction serous retinopathy
Side effects that led to dose reduction	left ventricular dysfunction, serous retinopathy, and colitis
Side effects that led to permanent discontinuation	Hemorrhage and headache

Common side effects >10% as reported in the clinical trial:

 

Common Side effects >10%	Side Effect
General	Fatigue Fever Peripheral edema
GI side effects	Nausea Diarrhea Vomiting Abdominal pain Constipation
Skin	Rash
CNS	Dizziness
Vision	Visual impairment Serous retinopathy
Vascular	Bleeding Hypertension

Drug Interactions:

No Significant Interactions were observed with MEKTOVI

Use Of Mektovi In Specific Populations

Pregnancy

• MEKTOVI may cause harm to a developing fetus in pregnant women. Effective contraception should be used during treatment with MEKTOVI and for at least 30 days after the final dose in females of reproductive potential.

Lactation

• Breastfeeding should be avoided during treatment with MEKTOVI and for 3 days after the final dose.

Pediatric Use

• The safety and effectiveness of MEKTOVI have not been established in children.

Geriatric Use

• Elderly patients aged 65 years and older with BRAF mutation-positive melanoma can use MEKTOVI plus encorafenib safely and effectively.

Hepatic Impairment

• Patients with moderate or severe hepatic impairment may need a reduced dose of MEKTOVI, while no dose adjustment is recommended for patients with mild hepatic impairment.

• Mektovi Mechanism of action:

Binimetinib is a reversible inhibitor of MEK1 and MEK2 activity resulting in the inhibition of ERK pathways. This pathway is involved in the proliferation and growth of melanoma cells that have BRAF mutations.

Binimetinib and encorafenib target different kinases in the RAS/RAF/MEK/ERK pathway. When administered together, they exhibit greater anti-proliferative and anti-tumor activity in BRAF mutation-positive cell lines and human melanoma xenograft studies in mice

The combination of Mektovi and Braftovi delays the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone.

Effect on QT Interval:

• The use of MEKTOVI 45 mg twice daily did not result in any meaningful prolongation of QT interval in studies on cardiac electrophysiology.

Pharmacokinetics
Absorption	At least half of the drug is absorbed when taken orally with a median time for maximal absorption is 1.6 hours.
Effect of food (High-fat, high-calorie meal)	No effect
Plasma protein binding	97%
Terminal half-life (t1/2)	Mean of 3.5 hours (28.5%)
Primary metabolic pathway	Glucuronidation, with UGT1A1 contributing up to 61% of metabolism
Other pathways	N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain
Active metabolite	M3 produced by CYP1A2 and CYP2C19 represents 8.6% of exposure
Excretion	62% (32% unchanged) recovered in feces and 31% (6.5% unchanged) recovered in urine following a single oral dose of 45 mg in healthy subjects

How Supplied:

MEKTOVI (binimetinib) is available in the form of film-coated tablets that are unscored, biconvex, and oval-shaped. They are yellow or dark yellow in color and are imprinted with a stylized “A” on one side and “15” on the other side. These tablets are packaged in bottles containing 180 tablets, and the National Drug Code (NDC) for the same is 70255-010-02.

Storage and Handling:

The storage conditions for MEKTOVI (binimetinib) are as follows:

• The tablets must be stored at a temperature between 20°C and 25°C (68°F and 77°F).
• Short excursions between 15°C and 30°C (59°F and 86°F) are permitted.
• The tablets must be stored at a USP Controlled Room Temperature.