Renal Impairment: In subjects with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), no clinicallyimportant changes in binimetinib exposure were observed as compared to subjects with normal renal

function.

Drug Interaction Studies

Clinical Studies

Effect of UGT1A1 Inducers or Inhibitors on Binimetinib: UGT1A1 genotype and smoking (UGT1A1inducer) do not have a clinically important effect on binimetinib exposure. Simulations predict similar Cmax

of binimetinib 45 mg in the presence or absence of atazanavir 400 mg (UGT1A1 inhibitor).

No differences in binimetinib exposure have been observed when MEKTOVI is coadministered withencorafenib.

Effect of Binimetinib on CYP Substrates: Binimetinib did not alter the exposure of a sensitive CYP3A4substrate (midazolam).

Effect of Acid Reducing Agents on Binimetinib: The extent of binimetinib exposure (AUC) was not altered inthe presence of a gastric acid reducing agent (rabeprazole).

In Vitro Studies

Effect of Binimetinib on CYP Substrates: Binimetinib is not a time-dependent inhibitor of CYP1A2,CYP2C9, CYP2D6 or CYP3A.

Effect of Transporters on Binimetinib: Binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancerresistance protein (BCRP). Binimetinib is not a substrate of organic anion transporting polypeptide

(OATP1B1, OATP1B3, OATP2B1) or organic cation transporter 1 (OCT1). 

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with binimetinib have not been conducted. Binimetinib was not genotoxic in studieseva luating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in

bone marrow of rats.

No dedicated fertility studies have been conducted with binimetinib in animals. In general toxicology studiesin rats and monkeys, there were no remarkable findings in male or female reproductive organs.

14 CLINICAL STUDIES

MEKTOVI in combination with encorafenib was eva luated in a randomized, active-controlled, open-label,multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or

V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux

THxID™BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting andone prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAFinhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on

Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group(ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease

(yes versus no).

Patients were randomized (1:1:1) to receive MEKTOVI 45 mg twice daily in combination with encorafenib450 mg once daily (MEKTOVI in combination with encorafenib), encorafenib 300 mg once daily, or

vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

Only the results of the approved dosing (MEKTOVI 45 mg in combination with encorafenib 450 mg) aredescribed below.