Binimetinib

Melanoma, Non-Small Cell Lung Cancer

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 The recommended dose is 45 mg orally twice daily in combination with encorafenib. Non-Small Cell Lung Cancer (NSCLC) Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating encorafenib. The recommended dose is 45 mg orally twice daily in combination with encorafenib.

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

No overall differences in the safety or effectiveness of Binimetinib plus encorafenib were observed in older patients as compared to younger patients

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

Take with or without food.

New Primary Malignancies, Cutaneous and Non-cutaneous: Can occur when Binimetinib is used in combination with encorafenib. Cardiomyopathy: The safety of Binimetinib has not been established in patients with LVEF below 50%. Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur. Ocular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Interstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Hepatotoxicity: Monitor liver function tests before and during treatment with Binimetinib and encorafenib and as clinically indicated. Rhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. Hemorrhage: Major hemorrhagic events can occur in patients receiving Binimetinib and encorafenib. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. MONITORING PARAMETERS Monitor patients for new malignancies prior to initiation of treatment, during treatment, and after discontinuation of treatment. Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every 2 to 3 months thereafter. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Monitor liver function tests before and during treatment with Binimetinib and encorafenib and as clinically indicated. Monitor creatine phosphokinase and creatinine periodically and as clinically indicated.

Not Classi 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

ADRs in combination with encorafenib >50% All grades Increased creatinine (91-93%) Fatigue (43-61%) Increased creatine kinase (41-58%) Nausea (41-58%) Diarrhea (36-52%) >10-50% All grades Musculoskeletal pain (48%) Hyperglycemia (48%) Anemia (36-47%) Increased gamma glutamyl transferase (GGT) (45%) Lipase increased (40%) Vomiting (30-37%) Increased ALT (29-34%) Hypoalbuminemia (32%) Abdominal pain (28-32%) Hyperkalemia (31%) Increased AST (27-31%) Increased alkaline phosphatase (21-31%) Visual impairment (20-29%) Dyspnea (27%) Rash (22-27%) Constipation (22-27%) Cough (26%) Hyponatremia (18-26%) Lymphopenia (13-24%) Edema (23%) Serum amylase increased (22%) Pyrexia (18-22%) Thrombocytopenia (20%) Retinopathy, serious (20%) Hemorrhage (12-19%) Dizziness (15-17%) Pruritus (16%) Decreased appetite (14%) Peripheral edema (13%) Dry skin (13%) Leukopenia (12-13%) Neutropenia (12-13%) Hypocalcemia (12%) Alopecia (12%) Weight increased (11%) Headache (11%) Hypertension (10-11%) Left ventricular dysfunction (LVD)/cardiomyopathy (7-11%) Grade 3 or 4 Lipase increased (14%) Increased GGT (11%) Anemia (3.6-11%) Hyponatremia (3.6-11%) 1-10% All grades Insomnia (10%) Retinal detachment (8%) Venous thromboembolism (6-7%) Macular edema (6%) Uveitis (1-4%) Cutaneous squamous cell carcinoma (2%) Skin papilloma (2%) Pneumonitis (1%) Grade 3 or 4 Increased AST (2.6-10%) Increased ALT (6-9%) Dyspnea (8%) Fatigue (3-8%) Diarrhea (3-7%) Hyperglycemia (6%) Hypertension (5-6%) Lymphopenia (2.1-6%) Increased creatine kinase (3.3-5%) Musculoskeletal pain (4.1%) Hemorrhage (3-4.1%) Pyrexia (≤4%) Abdominal pain (1-4%) Increased creatinine (3.2-3.6%) Increased alkaline phosphatase (≤3.2%) Nausea (2-3.1%) Neutropenia (1.1-3.1%) Rash (1-3.1%) Pulmonary embolism (1-3.1%) Retinopathy, serious (3%) Dizziness (1-3%) Hyperkalemia (2.1%) Hypocalcemia (2.1%) Visual impairment (≤2%) Vomiting (1-2%) LVD/cardiomyopathy (1-1.6%) Serum amylase increased (1.1%) Thrombocytopenia (1.1%) Edema (1%) Decreased

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