Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in practice.

The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in

combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial(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, andhistory or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for

patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated withvemurafenib.

The most common (> 25%) adverse reactions in patients receiving BRAFTOVI in combination withbinimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia.

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receivingBRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%) and

pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patientsreceiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue(2%) and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib

experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the mostcommon 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 differencein adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for

any specific adverse reaction listed in Table 3. 

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

with Binimetinib in COLUMBUSa

Adverse Reaction

BRAFTOVI

with binimetinib

N=192

Vemurafenib

N=186

All

Grades

(%)

Grades

3 and 4b

(%)

All

Grades

(%)

Grades

3 and 4

(%)

General Disorders and Administration Site Conditions

 Fatiguec

 43 3 46 6

 Pyrexiac

 18 4 30 0

Gastrointestinal Disorders

 Nausea 41 2 34 2

 Vomitingc 30 2 16 1

 Abdominal painc

 28 4 16 1

 Constipation 22 0 6 1

Musculoskeletal and Connective Tissue Disorders

 Arthralgiac

 26 1 46 6

 Myopathyc

 23 0 22 1

 Pain in extremity 11 1 13 1

Skin and Subcutaneous Tissue Disorders

 Hyperkeratosisc

 23 1 49 1

 Rashc

 22 1 53 13

 Dry skinc

 16 0 26 0

 Alopeciac

 14 0 38 0

 Pruritusc

 13 1 21 1

Nervous System Disorders

 Headachec