MEKTOVI

Small Molecule Antineoplastic Mitogen-Activated Protein Kinase (MEK) Inhibitors

Binimetinib may be taken with or without food.
Space doses approximately 12 hours apart.
If a dose is missed, it may be taken up to 6 hours prior to the next dose. If there is less than 6 hours until the next scheduled dose, skip the dose and take the next dose at the scheduled time.
If vomiting occurs after a dose, do not take an additional dose; take the next dose at the regularly scheduled time.

retinopathy / Delayed / 0-20.0
visual impairment / Early / 20.0-20.0
retinal detachment / Delayed / 8.0-8.0
cardiomyopathy / Delayed / 7.0-7.0
heart failure / Delayed / 0-7.0
thromboembolism / Delayed / 6.0-6.0
thrombosis / Delayed / 0-6.0
macular edema / Delayed / 6.0-6.0
hypertension / Early / 6.0-6.0
GI bleeding / Delayed / 1.0-4.2
uveitis / Delayed / 4.0-4.0
fever / Early / 4.0-4.0
abdominal pain / Early / 4.0-4.0
anemia / Delayed / 3.6-3.6
nephrotoxicity / Delayed / 3.6-3.6
hyponatremia / Delayed / 3.6-3.6
bleeding / Early / 3.2-3.2
pulmonary embolism / Delayed / 3.1-3.1
neutropenia / Delayed / 3.1-3.1
fatigue / Early / 3.0-3.0
diarrhea / Early / 3.0-3.0
dizziness / Early / 3.0-3.0
lymphopenia / Delayed / 2.1-2.1
vomiting / Early / 2.0-2.0
nausea / Early / 2.0-2.0
intracranial bleeding / Delayed / 0-1.6
peripheral edema / Delayed / 1.0-1.0
rash / Early / 1.0-1.0
elevated hepatic enzymes / Delayed / 0-0.5
rhabdomyolysis / Delayed / 0.3-0.3

constipation / Delayed / 20.0-20.0
leukopenia / Delayed / 13.0-13.0
colitis / Delayed / 0-10.0
iritis / Delayed / 0-4.0
interstitial lung disease / Delayed / 0.3-0.3
pneumonitis / Delayed / 0-0.3

panniculitis / Delayed / Incidence not known

MEKTOVI

Rx

MEK inhibitor
Used for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with encorafenib
Cardiomyopathy, venous thromboembolism, interstitial lung disease, and rhabdomyolysis have been reported

45 mg orally twice daily in combination with encorafenib 450 mg orally once daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[63318] At a median follow-up time of 40.8 months, combination therapy with encorafenib plus binimetinib resulted in a significantly longer median progression-free survival (PFS) time (primary endpoint) compared with single-agent vemurafenib (14.9 months vs. 7.3 months; hazard ratio (HR) = 0.51; 95% CI, 0.4 to 0.67) in patients with locally advanced stage IIIB, IIIC, or IV melanoma, unresectable or metastatic cutaneous melanoma, or unknown primary melanoma and BRAF V600E and/or V600K mutations in a multinational, randomized, 3-arm, phase 3 study (n = 577; the COLUMBUS study). Additionally, the median overall survival (OS) time was significantly improved in the combination therapy arm compared with vemurafenib (33.6 months vs. 16.9 months; HR = 0.65; 95% CI, 0.5 to 0.81) at a median follow-up time of 70.4 months. The median PFS (14.9 months vs. 9.6 months; HR = 0.79; 95% CI, 0.61 to 1.02) and OS (33.6 months vs. 23.5 months; HR = 0.93; 95% CI, 0.72 to 1.19) times were not significantly longer in the combination therapy arm compared with single-agent encorafenib. The 5-year PFS rates were 23%, 10%, and 19% in the encorafenib plus binimetinib, single-agent vemurafenib, and single-agent encorafenib arms, respectively; the 5-year OS rates were 35%, 21%, and 35%, respectively. Most patients in this study had extensive disease (stage IV M1c disease, 64%; 3 or more organs involved, 45%); 30% of patients had progressed on or after immunotherapy.[63319]

Mild hepatic impairment (total bilirubin greater than 1 and 1.5-times the upper limit of normal (ULN) and any AST level OR total bilirubin level at the ULN or less and AST level greater than the ULN) at baseline: No dosage adjustment is necessary.
Moderate (total bilirubin level greater than 1.5- to and 3-times the ULN and any AST level) or severe (total bilirubin level greater than 3-times the ULN and any AST level) hepatic impairment at baseline: 30 mg PO twice daily.
Treatment-Related Toxicity
Grade 2 elevated hepatic enzymes (AST or ALT levels): Continue current binimetinib dose. If the toxicity does not improve within 4 weeks, hold therapy until toxicity improves to grade 1 or less or to baseline levels. Therapy may be resumed at the same dose.
Recurrent grade 2 toxicity or first occurrence of grade 3 toxicity: Hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. If the toxicity does not improve within 4 weeks, permanently discontinue binimetinib.
Recurrent grade 3 toxicity: Consider permanently discontinuing binimetinib.
Grade 4 toxicity: Consider permanently discontinuing binimetinib or hold binimetinib for up to 4 weeks. If toxicity improves to grade 1 or less or to baseline level, resume binimetinib at a reduced dose. Permanently discontinue binimetinib if the toxicity does not improve within 4 weeks or for recurrent grade 4 toxicity.

No binimetinib dosage adjustment is recommended for renal impairment. Binimetinib exposure was similar in subjects with severe renal impairment (defined as an estimated glomerular filtration rate 29 mL/min/1.73 m2 or less) compared with subjects who had normal renal function.

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

MEKTOVI Oral Tab: 15mg

90 mg/day PO.

90 mg/day PO.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

Binimetinib is a reversible protein kinase inhibitor that targets mitogen-activated extracellular signal-related kinase (MEK)-1 and MEK-2. MEK kinases are upstream regulators of the extracellular signal-related kinase (ERK) pathway; activation of this pathway stimulates tumor cell growth. In vitro, binimetinib inhibits MEK-dependent phosphorylation of BRAF-mutant human melanoma cells. In animal studies in mice implanted with BRAF-mutant expressing tumors, binimetinib inhibited ERK phosphorylation and tumor growth. Additionally, combination therapy with binimetinib and encorafenib, a BRAF inhibitor, led to greater anti-tumor activity and delayed resistance in BRAF V600-mutant human melanoma xenografts in mice compared with either drug alone.

Binimetinib is administered orally. It is 97% bound to plasma proteins, has a blood-to-plasma ratio of 0.72, and has an apparent volume of distribution of 92 L (coefficient of variation (CV), 45%). Binimetinib is metabolized mostly by glucuronidation via UGT1A1 (61%) but also by N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The active metabolite M3 is produced via CYP1A2 and CYP2C19 and represents 8.6% of binimetinib exposure. The mean terminal half-life is 3.5 hours (CV, 28.5%) and the apparent clearance is 20.2 L/hour (CV, 24%). Following a radioactive binimetinib 45-mg dose, 62% of the dose was recovered in the feces and 31% of the total reactivity was recovered in the urine; unchanged drug excretion was 32% and 6.5%, respectively.
 
Affected cytochrome P450 isoenzymes and drug transporters: none
Binimetinib has no clinically important drug interactions. In vitro, binimetinib is a substrate of P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP).

Following oral administration, 50% or more of the dose is absorbed and the median time to peak plasma concentration (Tmax) is 1.6 hours. Binimetinib exhibits approximately dose proportional exposure. The accumulation was 1.5-fold at steady-state following twice-daily dosing in healthy subjects and patients with solid tumors. The AUC inter-subject variability (CV%) was less than 40%.
Effects of Food: Administering a single-dose of binimetinib 45 mg orally with a high-fat (500 calories from fat), high-calorie (150 calories from protein; 350 calories from carbohydrates) meal had no effect on the AUC when compared to the fasted state. Binimetinib may be taken with or without food.

Binimetinib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and data from animal studies. Advise females of reproductive potential to avoid pregnancy while taking binimetinib. Discuss the potential hazard to the fetus if binimetinib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weights and an increased rate of pregnancy loss and malformations were observed in the offspring of pregnant rabbits who received binimetinib doses that resulted in drug exposures that were about 5-times the recommended human exposure.

It is not known if binimetinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during binimetinib therapy and for 3 days after the last dose.