Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. Inmice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions

associated with RAF/MEK/ERK pathway suppression.

Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Comparedwith either drug alone, co-administration of encorafenib and binimetinib resulted in greater anti-proliferative

activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumorgrowth 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 mutanthuman melanoma xenografts in mice compared to either drug alone.

12.2 Pharmacodynamics

Cardiac Electrophysiology

A dedicated study to eva luate the QT prolongation potential of BRAFTOVI has not been conducted.

BRAFTOVI is associated with dose-dependent QTc interval prolongation. Following administration of therecommended dose of BRAFTOVI in combination with binimetinib, based on a central tendency analysis of

QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline(ΔQTcF) was 18 (14 to 22) ms [see Warnings and Precautions (5.5)].

12.3 Pharmacokinetics

The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors,including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or

V600K mutation. After a single dose, systemic exposure of encorafenib was dose proportional over the doserange of 50 mg to 700 mg. After once-daily dosing, systemic exposure of encorafenib was less than dose

proportional over the dose range of 50 mg to 800 mg. Steady-state was reached within 15 days, withexposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to

69%.

Absorption

After oral administration, the median Tmax of encorafenib is 2 hours. At least 86% of the dose is absorbed.

Effect of Food

Administration of a single dose of BRAFTOVI 100 mg (0.2 times the recommended dose) with a high-fat,high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates,

and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with noeffect on AUC. 

 

Distribution

Encorafenib is 86% bound to human plasma proteins in vitro. The blood-to-plasma concentration ratio is0.58. The geometric mean (CV%) of apparent volume of distribution is 164 L (70%).

Elimination

The mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state.

Metabolism

The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to totaloxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and

CYP2D6 (1%).

Excretion

Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administereddose was recovered in the feces and 47% (2% unchanged) was recovered in the urine.