daily) in COLUMBUS.

The COLUMBUS trial [see Clinical Studies (14)] excluded patients with a history of Gilbert’s syndrome,abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and

history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months forpatients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with

vemurafenib.

The most common (≥ 25%) adverse reactions in patients receiving MEKTOVI in combination withencorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain.

Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receivingMEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and

serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% ofpatients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular

dysfunction (3%), serous retinopathy (3%), and colitis (2%). 

Five percent (5%) of patients receivingMEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanentdiscontinuation of MEKTOVI. 

The most common adverse reactions resulting in permanent discontinuationof MEKTOVI were hemorrhage in 2% and headache in 1% of patients.

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified inCOLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference

in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, forany specific adverse reaction listed in Table 3. 

Table 3: Adverse Reactions Occurring in ≥ 10% of Patients Receiving MEKTOVI in Combination

with Encorafenib in COLUMBUSa

Adverse Reaction

MEKTOVI

with encorafenib

N=192

Vemurafenib

N=186

All

Grades

(%)

Grades

3 and 4b

(%)

All

Grades

(%)

Grades

3 and 4b

(%)

General Disorders and Administration Site Conditions

 Fatiguec

 43 3 46 6

 Pyrexiac

 18 4 30 0

 Peripheral edemac 13 1 15 1

Gastrointestinal Disorders

 Nausea 41 2 34 2

 Diarrhea 36 3 34 2

 Vomitingc 30 2 16 1

 Abdominal painc

 28 4 16 1

Constipation 22 0 6 1

Skin and Subcutaneous Tissue Disorders

Rashc

 22 1 53 13

Nervous System Disorders

 Dizzinessc

 15 3 4 0

Visual Disorders

 Visual impairmentc

 20 0 4 0

 Serous retinopathy/RPEDc

 20 3 2 0

Vascular Disorders

 Hemorrhagec

 19 3 9 2

 Hypertensionc

 11 6 11 3

a Grades per National Cancer Institute CTCAE v4.03. b Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in

the vemurafenib arm. c Represents a composite of multiple, related preferred terms.

Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI incombination with encorafenib were: