Binimetinib

Indications

Binimetinib is used for: Melanoma

Adult Dose

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 PO BID in combination with encorafenib until disease progression or unacceptable toxicity Hepatic impairment Moderate (total bilirubin >1.5 to ?3 x ULN and any AST): 30 mg PO BID Severe (total bilirubin >3 x ULN and any AST): 30 mg PO BID

Child Dose

Renal Dose

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

Administration

Contra Indications

Precautions

In the COLUMBUS trial, venous thromboembolism (VTE) occurred in 6% of patients receiving binimetinib in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism Hepatotoxicity can occur when binimetinib concomitantly used with encorafenib; monitor liver laboratory tests before initiating, monthly during treatment, and as clinically indicated Rhabdomyolysis can occur when binimetinib is administered in combination with encorafenib; monitor CPK and creatinine levels prior to initiating treatment, periodically during treatment, and as clinically indicated; withhold, reduce dose, or permanently discontinue based on severity of adverse reaction Hemorrhage can occur when encorafenib is administered in combination with binimetinib; hemorrhagic events include GI, hemorrhoidal, rectal, and intracranial hemorrhage, and hematochezia; withhold, reduce dose, or discontinue drug

Pregnancy-Lactation

Pregnancy Based on animal reproduction studies and its mechanism of action, fetal harm may occur when binimetinib is administered to a pregnant woman There are no available clinical data on the use of binimetinib during pregnancy Advise pregnant women of the potential risk to a fetus Animal data In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures ~5 times the human exposure at the clinical dose of 45 mg PO BID Contraception Verify pregnancy status of females of reproductive potential prior to initiating treatment Advise females of reproductive potential to use effective contraception during treatment with binimetinib and for at least 30 days after the final dose Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking encorafenib and binimetinib Lactation There are no data on the presence of binimetinib or its active metabolite in human milk, the effects of binimetinib on the breastfed infant, or on milk production Because of the potential for serous adverse reactions from binimetinib in breastfed infants, advise women not to breastfeed during treatment with binimetinib and for 3 days after the final dose

Interactions

Adverse Effects

Side effects of Binimetinib : >10% Increased creatinine (93%) Increased creatine phosphokinase (58%) Increased gamma glutamyl transferase (GGT) (45%) Fatigue (43%) Nausea (41%) Diarrhea (36%) Anemia (36%) Vomiting (30%) Increased AST/ALT (27-29%) Abdominal pain (28%) Constipation (22%) Rash (22%) Increased alkaline phosphatase (21%) Visual impairment (20%) Serous retinopathy/retinal pigment epithelial dystrophy (RPED) (20%) Hemorrhage (19%) Hyponatremia (18%) Pyrexia (18%) Dizziness (15%) Leukopenia (13%) Lymphopenia (13%) Neutropenia (13%) Peripheral edema (13%) Increased GGT, Grades 3 and 4 (11%) Hypertension (11%) 1-10% Colitis (<10%) Panniculitis (<10%) Drug hypersensitivity (<10%) Hypertension, Grades 3 and 4 (6%) Increased AST/ALT (2.6-6%) Increased creatine phosphokinase, Grades 3 and 4 (5%) Pyrexia, Grades 3 and 4 (4%) Anemia, Grades 3 and 4 (3.6%) Increased creatinine, Grades 3 and 4 (3.6%) Hyponatremia, Grades 3 and 4 (3.6%) Neutropenia, Grades 3 or 4 (3.1%) Fatigue, Grades 3 and 4 (3%) Dizziness, Grades 3 and 4 (3%) Peripheral edema, Grades 3 and 4 (3%) Hemorrhage, Grades 3 and 4 (3%) Diarrhea, Grades 3 and 4 (3%) Serous retinopathy/RPED, Grades 3 and 4 (3%) Lymphopenia, Grades 3 or 4 (2.1%) Nausea, Grades 3 and 4 (2%) Vomiting, Grades 3 and 4 (2%) Abdominal pain, Grades 3 and 4 (2%) Rash, Grades 3 and 4 (1%)

Mechanism of Action

Inhibits mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK 2 MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)-related phosphorylation and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines Encorafenib and binimetinib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in greater antiproliferative activity in vitro in BRAF mutation-positive cell lines and greater antitumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with either drug alone