6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

•: New Primary Malignancies [see Warnings and Precautions (5.1)]
•: Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]
•: Cardiomyopathy [see Warnings and Precautions (5.3)]
•: Hepatotoxicity [see Warnings and Precautions (5.4)]
•: Hemorrhage [see Warnings and Precautions (5.5)]
•: Uveitis [see Warnings and Precautions (5.6)]
•: QT Prolongation [see Warnings and Precautions (5.7)]
•: Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)]
•: Risks Associated with BRAFTOVI as a Single Agent [see Warnings and Precautions (5.9)]
•: Risks Associated with Combination Treatment [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical 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.

BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma

The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-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 (14.1)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history 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 with vemurafenib.

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

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI 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 patients receiving 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 most common were hemorrhage in 2% and headache in 1% of patients.

Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 5.

Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS*
* Grades per National Cancer Institute CTCAE v4.03. † Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm. ‡ Represents a composite of multiple, related preferred terms.
Adverse Reaction	BRAFTOVI with binimetinib N=192		Vemurafenib N=186
Adverse Reaction	All Grades (%)	Grades 3 and 4† (%)	All Grades (%)	Grades 3 and 4 (%)
General Disorders and Administration Site Conditions
Fatigue‡	43	3	46	6
Pyrexia‡	18	4	30	0
Gastrointestinal Disorders
Nausea	41	2	34	2
Vomiting‡	30	2	16	1
Abdominal pain‡	28	4	16	1
Constipation	22	0	6	1
Musculoskeletal and Connective Tissue Disorders
Arthralgia‡	26	1	46	6
Myopathy‡	23	0	22	1
Pain in extremity	11	1	13	1
Skin and Subcutaneous Tissue Disorders
Hyperkeratosis‡	23	1	49	1
Rash‡	22	1	53	13
Dry skin‡	16	0	26	0
Alopecia‡	14	0	38	0
Pruritus‡	13	1	21	1
Nervous System Disorders
Headache‡	22	2	20	1
Dizziness‡	15	3	4	0
Peripheral neuropathy‡	12	1	13	2
Vascular Disorders
Hemorrhage‡	19	3	9	2

BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%).

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:

Nervous system disorders: Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity

Immune system disorders: Drug hypersensitivity

Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS*
* Grades per National Cancer Institute CTCAE v4.03.
Laboratory Abnormality	BRAFTOVI with binimetinib* N=192		Vemurafenib* N=186
Laboratory Abnormality	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 Gamma Glutamyl Transferase	45	11	34	4.8
Increased ALT	29	6	27	2.2
Increased AST	27	2.6	24	1.6
Hyperglycemia	28	5	20	2.7
Increased Alkaline Phosphatase	21	0.5	35	2.2
Hyponatremia	18	3.6	15	0.5
Hypermagnesemia	10	1.0	26	0.5

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in combination with Cetuximab and mFOLFOX6

The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every 2 weeks) and mFOLFOX6 was evaluated in 231 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)]. BREAKWATER excluded patients with pancreatitis, leptomeningeal disease, chronic inflammatory bowel disease requiring medical intervention, as well as clinically significant cardiovascular diseases [e.g., myocardial infarction, acute coronary syndromes, NYHA Class ≥II congestive heart failure, prolonged QTcF interval (≥480 ms), history of prolonged QT syndrome] and active infectious conditions.

Among patients who received BRAFTOVI, 54% were exposed for 6 months or longer and 18% were exposed for one year or longer.

Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction and pyrexia (3.5% each).

Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.

Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 12% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included increased lipase.

Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 57% of patients. Adverse reactions which required dosage interruption in ≥5% included decreased neutrophil count, pyrexia, and anemia.

Dose reductions of BRAFTOVI due to an adverse reaction occurred in 22% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included increased lipase, nausea, and vomiting.

The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and mFOLFOX6 were peripheral neuropathy, nausea, fatigue, rash, diarrhea, decreased appetite, vomiting, hemorrhage, abdominal pain, and pyrexia.

The most common Grade 3 or 4 laboratory abnormalities (≥10%) of BRAFTOVI when used in combination with cetuximab and mFOLFOX6 were increased lipase, decreased neutrophil count, decreased hemoglobin, decreased white blood cell count, and increased glucose.

Table 7 and Table 8 present adverse drug reactions and laboratory abnormalities, respectively, identified in BREAKWATER.

Table 7: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATER*
* Grades per National Cancer Institute CTCAE v4.03. † Represents multiple related terms.
Adverse Reaction	BRAFTOVI with cetuximab and mFOLFOX6 N=231		mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab N=228
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Nervous System Disorders
Peripheral neuropathy†	62	15	53	6
Headache	13	<1	7	0
Dysgeusia	12	0	14	0
Neurotoxicity	11	5	8	0
Gastrointestinal Disorders
Nausea	51	3	48	3
Diarrhea	34	1	47	4
Vomiting	33	4	21	2
Abdominal pain†	26	4	27	1
Constipation	20	<1	19	<1
General Disorders and Administration Site Conditions
Fatigue†	49	7	38	4
Pyrexia†	26	2	14	<1
Metabolism and Nutrition Disorders
Decreased appetite	33	2	25	1
Musculoskeletal and Connective Tissue Disorders
Arthralgia†	23	1	4	0
Myopathy†	14	0	7	<1
Skin and Subcutaneous Tissue Disorders
Rash†	31	1	4	0
Alopecia	21	0	10	0
Dry skin†	17	0	4	0
Dermatitis acneiform†	17	1	1	0
Skin hyperpigmentation	17	0	2	0
Pruritus	11	0	3	<1
Vascular Disorders
Hemorrhage†	30	3	18	1
Psychiatric Disorder
Insomnia†	11	0	7	0

Table 8: Laboratory Abnormalities Occurring in ≥20% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab and mFOLFOX6 in BREAKWATER*
* Grades per National Cancer Institute CTCAE v4.03. † The denominator used to calculate the rate varied from 220 to 227 based on the number of patients with a baseline and at least one post-treatment value.
Laboratory Abnormality†	BRAFTOVI with cetuximab and mFOLFOX6		mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab
Laboratory Abnormality†	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Neutrophil count decreased	63	36	60	34
White blood cell decreased	62	12	54	7
Hemoglobin decreased	60	13	47	5
Platelet count decreased	60	1	50	2
Activated partial thromboplastin time prolonged	57	3	38	1
INR increased	39	1	20	1
Chemistry
Lipase increased	82	51	54	25
Creatinine increased	64	1	67	1
Glucose increased	49	11	35	2
Alanine aminotransferase increased	38	1	40	2
Albumin decreased	36	0	24	1
Aspartate aminotransferase increased	36	1	35	2
Potassium decreased	33	4	19	4
Alkaline phosphatase increased	31	2	31	1
Calcium decreased	24	4	16	2
Magnesium decreased	23	1	11	1

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)

The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (400 mg/m2 initial dose, followed by 250 mg/m2 weekly) was evaluated in 216 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.3)] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 4.4 months for patients treated with BRAFTOVI in combination with cetuximab and 1.6 months for patients treated with either irinotecan or infusional 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI) in combination with cetuximab.

The most common (≥25%) adverse reactions in patients receiving BRAFTOVI in combination with cetuximab were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 33% of patients receiving BRAFTOVI in combination with cetuximab; the most common were vomiting (4%), fatigue (4%), nausea (4%), pyrexia (3%), and diarrhea (3%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 9% of patients receiving BRAFTOVI in combination with cetuximab; the most common were fatigue (2%), arthralgia (2%), and peripheral neuropathy (2%). Ten percent (10%) of patients receiving BRAFTOVI in combination with cetuximab experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI. None of the adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than one patient (>0.5%).

Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in BEACON CRC.

Table 9: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC*
* Grades per National Cancer Institute CTCAE v4.03. † Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1). ‡ Represents a composite of multiple, related preferred terms.
Adverse Reaction	BRAFTOVI with cetuximab N=216		Irinotecan with cetuximab or FOLFIRI with cetuximab N=193
Adverse Reaction	All Grades (%)	≥ Grade 3† (%)	All Grades (%)	≥ Grade 3 (%)
General Disorders and Administration Site Conditions
Fatigue‡	51	7	50	8
Pyrexia‡	17	1	15	1
Gastrointestinal Disorders
Nausea	34	1	41	1
Diarrhea‡	33	2	48	10
Abdominal pain‡	30	4	32	5
Vomiting	21	1	29	3
Constipation	15	0	18	1
Metabolism and Nutrition Disorders
Decreased appetite	27	1	27	3
Musculoskeletal and Connective Tissue Disorders
Arthralgia‡	27	1	3	0
Myopathy‡	15	1	4	0
Pain in extremity	10	0	1	0
Skin and Subcutaneous Tissue Disorders
Dermatitis acneiform‡	32	1	43	3
Rash‡	26	0	26	2
Pruritus‡	14	0	6	0
Melanocytic nevus	14	0	0	0
Dry skin‡	13	0	12	1
Nervous System Disorders
Headache‡	20	0	3	0
Peripheral neuropathy‡	12	1	6	0
Vascular Disorders
Hemorrhage‡	19	2	9	0
Psychiatric Disorders
Insomnia‡	13	0	6	0

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab were:

Gastrointestinal disorders: Pancreatitis

Table 10: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab in BEACON CRC*
* Grades per National Cancer Institute CTCAE v4.03. † Based on the number of patients with available baseline and at least one on-treatment laboratory test.
Laboratory Abnormality†	BRAFTOVI with cetuximab		Irinotecan with cetuximab or FOLFIRI with cetuximab
Laboratory Abnormality†	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Hematology
Anemia	34	4	48	5
Lymphopenia	24	7	35	5
Increased Activated Partial Thromboplastin Time	13	1	7	1
Chemistry
Hypomagnesemia	19	0	22	1
Increased Alkaline Phosphatase	18	4	30	7
Increased ALT	17	0	29	3
Increased AST	15	1	22	2
Hypokalemia	12	3	32	5
Hyponatremia	11	2	13	2

BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

The safety of BRAFTOVI in combination with binimetinib was evaluated in 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in an open-label, single-arm trial (PHAROS).

The PHAROS trial [see Clinical Studies (14.4)] excluded patients with abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of treatment for BRAFTOVI and binimetinib was 9.2 and 8.4 months, respectively.

The most common (≥25%) adverse reactions in patients receiving BRAFTOVI were fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 59% of patients receiving BRAFTOVI; the most common (≥5%) were diarrhea (17%); nausea (13%); musculoskeletal pain, fatigue (8% each); AST increased (7%); ALT increased, anemia, hemorrhage, vomiting (6% each); and acute kidney injury (5%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI; the most common (≥5%) were diarrhea, nausea (8% each); AST increased and fatigue (5% each). A total of 16% of patients receiving BRAFTOVI experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common (≥2%) were diarrhea, musculoskeletal pain (3.1% each); fatigue, rash, nausea, visual impairment, and vomiting (2% each). None of the other adverse reactions leading to permanent discontinuation of BRAFTOVI occurred in more than 1 patient.

Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with binimetinib. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%); diarrhea (4.1%); anemia, dyspnea, pneumonia (3.1% each); arrhythmia, device related infection, edema, myocardial infarction, and pleural effusion (2% each). Fatal adverse reactions occurred in 2% of patients who received BRAFTOVI (450 mg once daily) in combination with binimetinib, including intracranial hemorrhage and myocardial infarction (1% each).

Table 11 and Table 12 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.

Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in PHAROS*
* Grades per National Cancer Institute CTCAE v4.03. † One Grade 5 adverse reaction of hemorrhage occurred. ‡ Fatigue includes fatigue, asthenia. § Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema. ¶ Diarrhea includes diarrhea, colitis. # Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. Þ Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. ß Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck pain. à Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. è Pruritis includes pruritus, pruritus genital. ð Dyspnea includes dyspnea, dyspnea exertional. ø Cough includes cough, productive cough. ý Dizziness includes dizziness, balance disorder. £ Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. ¥ Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive.
Adverse Reaction	BRAFTOVI with binimetinib N=98
Adverse Reaction	All Grades (%)	Grades 3 and 4† (%)
General Disorders and Administration Site Conditions
Fatigue‡	61	8
Edema§	23	1
Pyrexia	22	0
Gastrointestinal Disorders
Nausea	58	3.1
Diarrhea¶	52	7
Vomiting	37	1
Abdominal pain#	32	1
Constipation	27	0
Eye Disorders
Visual impairmentÞ	29	2
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal painß	48	4.1
Skin and Subcutaneous Tissue Disorders
Rashà	27	3.1
Pruritisè	16	0
Dry skin	13	0
Alopecia	12	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspneað	27	8
Coughø	26	0
Nervous System Disorders
Dizzinessý	17	1
Headache	11	0
Metabolism and Nutrition Disorders
Decreased appetite	14	1
Vascular Disorders
Hemorrhage†£	12	4.1
Hypertension	10	5
Cardiac Disorders
Left ventricular dysfunction/cardiomyopathy¥	11	1
Investigations
Weight increased	11	1
Psychiatric Disorders
Insomnia	10	0

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were:

Nervous system disorders: Peripheral neuropathy, Dysgeusia, Facial paresis

Gastrointestinal disorders: Pancreatitis

Skin and subcutaneous tissue disorders: Hyperkeratosis, Erythema, Photosensitivity

Immune system disorders: Drug hypersensitivity

Table 12: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI with Binimetinib*
* Grades per National Cancer Institute CTCAE v4.03. † Based on the number of patients with available baseline and at least one on-treatment laboratory test.
Laboratory Abnormality†	BRAFTOVI with binimetinib
Laboratory Abnormality†	All Grades (%)	Grades 3 and 4 (%)
Hematology
Anemia	47	11
Lymphopenia	24	6
Thrombocytopenia	20	1.1
Leukopenia	12	0
Neutropenia	12	1.1
Chemistry
Increased creatinine	91	3.2
Hyperglycemia	48	6
Increased creatine kinase	41	3.3
Lipase increased	40	14
Increased ALT	34	9
Hypoalbuminemia	32	0
Increased AST	31	10
Increased alkaline phosphatase	31	3.2
Hyperkalemia	31	2.1
Hyponatremia	26	11
Serum amylase increased	22	1.1
Hypocalcemia	12	2.1