Table 4: Laboratory Abnormalities Occurring in ≥ 10% (All grades) of Patients Receiving

MEKTOVI in Combination with Encorafenib in COLUMBUSa

Laboratory Abnormality

MEKTOVI

with encorafenib

N=192

Vemurafenib

N=186

All

Grades

(%)

Grades

3 and 4

(%)

All

Grades

(%)

Grades

3 and 4

(%)

Hematology

 Anemia 36 3.6 34 2.2

Leukopenia 13 0 10 0.5

 Lymphopenia 13 2.1 30 7

 Neutropenia 13 3.1 4.8 0.5

Chemistry

 Increased Creatinine 93 3.6 92 1.1

 Increased Creatine Phosphokinase 58 5 3.8 0

 Increased Gamma Glutamyl Transferase 45 11 34 4.8

 Increased ALT 29 6 27 2.2

 Increased AST 27 2.6 24 1.6

Increased Alkaline Phosphatase 21 0.5 35 2.2

 Hyponatremia 18 3.6 15 0.5

a Grades per National Cancer Institute CTCAE v4.03.

7 DRUG INTERACTIONS

No clinically important drug interactions have been observed with MEKTOVI.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal reproduction studies and its mechanism of action, MEKTOVI can cause fetalharm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available

clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administrationof binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses

greater than or equal to those resulting in exposures approximately 5 times the human exposure at theclinical dose of 45 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesisresulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses≥ 30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical

dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period oforganogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and

increased post-implantation loss, including total loss of pregnancy at doses ≥ 10 mg/kg/day (approximately5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). Therewas a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/dayof binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice

daily).

8.2 Lactation

Risk Summary

There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects ofbinimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse

reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment withMEKTOVI and for 3 days after the final dose.