BRAFTOVI® (encorafenib) 6 ADVERSE REACTIONS

(encorafenib)

Prescribing Information

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 fluorouracil-based chemotherapy

The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every 2 weeks) and mFOLFOX6 was evaluated in 232 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)]. In a separate cohort of BREAKWATER (Cohort 3), 139 patients with BRAF V600E mutation-positive mCRC were evaluated; of which 71 patients received BRAFTOVI in combination with cetuximab (500 mg/m2 every 2 weeks) and FOLFIRI. 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 were excluded.

BRAFTOVI in combination with cetuximab and mFOLFOX6

Among patients who received BRAFTOVI, 73% were exposed for 6 months or longer and 48% were exposed for one year or longer.

Serious adverse reactions occurred in 46% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (4.7%), pyrexia (3.9%), sepsis (3.4%), and abdominal pain (3.4%).

Fatal intestinal obstruction occurred in 0.9%, and fatal large intestinal perforation and gastrointestinal perforation occurred in 0.4% (each) of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.

Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 14% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included increased lipase and sepsis.

Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 68% of patients. Adverse reactions which required dosage interruption in ≥5% included neutropenia, anemia, pyrexia, COVID-19, and diarrhea.

Dose reductions of BRAFTOVI due to an adverse reaction occurred in 25% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included fatigue, anemia, arthralgia, increased lipase, nausea, neurotoxicity, and vomiting.

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

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 patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 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 a subset of the control arm (mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab). ‡ Represents multiple related terms.
Adverse Reaction	BRAFTOVI with cetuximab and mFOLFOX6 N=232		mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab N=229		mFOLFOX6 with or without bevacizumab N=115†
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Nervous System Disorders
Peripheral neuropathy‡	64	19	53	9	57	10
Headache‡	15	0.4	9	0	12	0
Dysgeusia	15	0	14	0	19	0
Neurotoxicity	11	6	8	0	12	0
Gastrointestinal Disorders
Nausea	54	3	50	3.9	44	2.6
Diarrhea	42	1.3	50	4.8	44	2.6
Vomiting	36	3.9	22	2.2	17	1.7
Abdominal pain‡	32	5	31	1.7	30	1.7
Constipation	27	0.4	23	0.4	25	0.9
Stomatitis‡	17	2.2	16	1.3	19	1.7
General Disorders and Administration Site Conditions
Fatigue‡	53	7	41	4.8	45	7
Pyrexia‡	29	2.2	16	0.4	17	0.9
Metabolism and Nutrition Disorders
Decreased appetite	38	2.2	27	1.3	30	2.6
Skin and Subcutaneous Tissue Disorders
Rash‡	36	1.3	6	0	5	0
Alopecia	23	0	11	0	12	0
Dry skin‡	22	0.4	6	0	5	0
Dermatitis acneiform‡	20	0.9	1.3	0	0.9	0
Skin hyperpigmentation	19	0	3.1	0	1.7	0
Pruritus‡	14	0	3.9	0.4	5	0.9
Vascular Disorders
Hemorrhage‡	34	2.6	21	1.3	15	1.7
Edema‡	11	0	4.4	0	6	0
Musculoskeletal and Connective Tissue Disorders
Arthralgia‡	32	2.6	6	0.4	7	0.9
Myopathy‡	19	0	4.8	0.4	6	0.9
Musculoskeletal pain‡	14	0.9	10	1.3	13	1.7
Infections and Infestations
COVID-19‡	16	0.9	17	0.4	16	0.9
Respiratory tract infection‡	11	0.9	11	0.4	9	0.9
Psychiatric Disorders
Insomnia‡	13	0	9	0	5	0

Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6 were:

Immune system disorders: Drug hypersensitivity

Skin and subcutaneous tissue disorders: Hyperkeratosis

Gastrointestinal disorders: Pancreatitis

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. ‡ Represents a subset of the control arm (mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab).
Laboratory Abnormality†	BRAFTOVI with cetuximab and mFOLFOX6		mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab		mFOLFOX6 with or without bevacizumab‡
Laboratory Abnormality†	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
Hemoglobin decreased	68	19	50	6	45	7
Activated partial thromboplastin time prolonged	67	5	43	1	50	2
Neutrophil count decreased	66	37	63	35	62	33
White blood cell decreased	66	12	59	8	56	6
Platelet count decreased	65	1	57	3	61	4
INR increased	47	1	23	1	24	2
Chemistry
Lipase increased	85	53	57	28	53	23
Creatinine increased	70	1	72	1	75	0
Glucose increased	56	11	40	2	39	1
Alanine aminotransferase increased	43	1	44	3	46	4
Albumin decreased	42	1	27	1	25	1
Aspartate aminotransferase increased	40	1	41	2	37	3
Alkaline phosphatase increased	40	3	35	1	32	3
Potassium decreased	38	5	23	5	17	3
Calcium decreased	33	4	22	2	19	2
Magnesium decreased	27	1	12	1	9	0
Sodium decreased	23	3	17	4	16	5

BRAFTOVI in combination with cetuximab and FOLFIRI

Among patients who received BRAFTOVI, 81% were exposed for 6 months or longer and 17% were exposed for one year or longer.

Serious adverse reactions occurred in 39% of patients who received BRAFTOVI in combination with cetuximab and FOLFIRI. Serious adverse reactions in >3% of patients included febrile neutropenia (5.6%) and infusion related reaction (4.2%).

Fatal gastrointestinal perforation occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab and FOLFIRI.

Permanent discontinuation of BRAFTOVI due to an adverse reaction occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of BRAFTOVI in ≥1% of patients included completed suicide, diarrhea, dyspnea, gastrointestinal perforation, infusion related reaction and pyrexia.

Dosage interruptions of BRAFTOVI due to an adverse reaction occurred in 55% of patients. Adverse reactions which required dosage interruption in ≥5% included neutropenia, diarrhea, and febrile neutropenia.

Dose reductions of BRAFTOVI due to an adverse reaction occurred in 20% of patients. Adverse reactions leading to dose reductions of BRAFTOVI in ≥2% of patients included nausea, vomiting, decreased appetite, fatigue, and diarrhea.

The most common (≥25%) adverse reactions of BRAFTOVI when used in combination with cetuximab and FOLFIRI were nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.

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

Table 9 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI in Cohort 3 of BREAKWATER.

Table 9: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and FOLFIRI (Cohort 3) in BREAKWATER*
* Grades per National Cancer Institute CTCAE v4.03. † Represents multiple related terms.
Adverse Reaction	BRAFTOVI with cetuximab and FOLFIRI N=71		FOLFIRI with or without bevacizumab N=68
Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal Disorders
Nausea	61	2.8	57	1.5
Diarrhea†	55	10	49	9
Vomiting	47	2.8	31	0
Constipation	31	1.4	29	1.5
Abdominal pain†	30	0	22	1.5
General Disorders and Administration Site Conditions
Fatigue†	47	4.2	50	6
Pyrexia†	17	0	4.4	1.5
Skin and Subcutaneous Tissue Disorders
Alopecia	35	1.4	22	0
Rash†	27	0	1.5	0
Dry skin†	24	0	6	0
Skin hyperpigmentation	24	0	2.9	0
Palmar-plantar erythrodysaesthesia syndrome	17	0	7	0
Dermatitis acneiform†	11	0	0	0
Pruritus†	11	0	4.4	0
Metabolism and Nutrition Disorders
Decreased appetite	30	4.2	32	2.9
Musculoskeletal and Connective Tissue Disorders
Arthralgia†	24	0	4.4	0
Myopathy†	13	0	9	0
Vascular Disorders
Hemorrhage†	21	0	22	0
Nervous System Disorders
Dysgeusia	14	0	4.4	0
Headache†	13	0	13	0
Psychiatric Disorders
Insomnia†	13	0	13	0
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps)
Melanocytic nevus	11	0	0	0
Cardiac Disorders
Arrhythmia†	11	0	1.5	0

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

Immune system disorders: Drug hypersensitivity

Skin and subcutaneous tissue disorders: Hyperkeratosis

Gastrointestinal disorders: Pancreatitis

Nervous system disorders: Peripheral neuropathy

Table 10: Laboratory Abnormalities Occurring in ≥20% (All Grades) of Patients Receiving BRAFTOVI in Combination with Cetuximab and FOLFIRI in BREAKWATER*
* Grades per National Cancer Institute CTCAE v4.03. † The denominator used to calculate the rate varied from 65 to 68 based on the number of patients with a baseline and at least one post‑treatment value.
Laboratory Abnormality†	BRAFTOVI with cetuximab and FOLFIRI		FOLFIRI with or without bevacizumab
Laboratory Abnormality†	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Hematology
White blood cell decreased	72	20	67	6
Neutrophil count decreased	69	30	62	32
Hemoglobin decreased	61	10	58	3
INR increased	43	0	21	0
Activated partial thromboplastin time prolonged	33	2	43	0
Platelet count decreased	21	0	26	0
Chemistry
Creatinine increased	59	2	82	3
Lipase increased	46	22	32	12
Glucose increased	43	8	35	3
Alanine aminotransferase increased	34	2	33	3
Albumin decreased	34	2	26	0
Potassium decreased	34	6	18	6
Calcium decreased	27	2	24	5
Alkaline phosphatase increased	22	0	36	5

BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with Cetuximab

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

Table 11: 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 12: 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 (14.3)] 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 13 and Table 14 present adverse drug reactions and laboratory abnormalities, respectively, identified in PHAROS.

Table 13: 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 14: 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

Medication Guide

MEDICATION GUIDE

MEDICATION GUIDE BRAFTOVI® (braf-TOE-vee) (encorafenib) capsules
Important information: BRAFTOVI is used in combination with other medicines, including binimetinib, cetuximab, or cetuximab and fluorouracil-based chemotherapy. Read the Medication Guide that comes with binimetinib if BRAFTOVI is used with binimetinib. Talk to your healthcare provider about cetuximab, or cetuximab and mFOLFOX6 or FOLFIRI if used with BRAFTOVI.
What is the most important information I should know about BRAFTOVI? BRAFTOVI can cause serious side effects, including: Risk of new skin cancers. BRAFTOVI can cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma. Talk to your healthcare provider about your risk for these cancers. Check your skin and tell your healthcare provider right away about any skin changes, including a: • new wart • skin sore or reddish bump that bleeds or does not heal • change in size or color of a mole Your healthcare provider should check your skin before treatment with BRAFTOVI, every 2 months during treatment, and for up to 6 months after you stop treatment with BRAFTOVI to look for any new skin cancers. Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with BRAFTOVI. See "What are the possible side effects of BRAFTOVI?" for more information about side effects.
What is BRAFTOVI? BRAFTOVI is a prescription medicine used: • in combination with a medicine called binimetinib to treat people with a type of skin cancer called melanoma: o that has spread to other parts of the body or cannot be removed by surgery, and o that has a certain type of abnormal "BRAF" gene • in combination with medicines called cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin, and irinotecan) to treat adults with cancer of the colon or rectum (colorectal cancer): o that has spread to other parts of the body, and o that has a certain type of abnormal "BRAF" gene • in combination with a medicine called cetuximab to treat adults with cancer of the colon or rectum (colorectal cancer) after past treatment: o that has spread to other parts of the body, and o that has a certain type of abnormal "BRAF" gene • in combination with a medicine called binimetinib to treat adults with a type of lung cancer called non‑small‑cell lung cancer (NSCLC): o that has spread to other parts of the body, and o that has a certain type of abnormal "BRAF" gene BRAFTOVI should not be used to treat people with wild-type‑BRAF melanoma, wild-type‑BRAF colorectal cancer, or wild-type‑BRAF NSCLC. Your healthcare provider will perform a test to make sure that BRAFTOVI is right for you. It is not known if BRAFTOVI is safe and effective in children.
Before taking BRAFTOVI, tell your healthcare provider about all of your medical conditions, including if you: • have had bleeding problems • have eye problems • have heart problems, including a condition called long QT syndrome • have been told that you have low blood levels of potassium, calcium, or magnesium • have liver or kidney problems • are pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby. Females who are able to become pregnant: o Use effective nonhormonal birth control (contraception) during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. Birth control methods that contain hormones (such as birth control pills, injections or transdermal systems) may not work as well during treatment with BRAFTOVI. o Talk to your healthcare provider about birth control methods that may be right for you during this time. o Your healthcare provider will do a pregnancy test before you start taking BRAFTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with BRAFTOVI. • are breastfeeding or plan to breastfeed. It is not known if BRAFTOVI passes into your breast milk. Do not breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose of BRAFTOVI. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRAFTOVI and certain other medicines can affect each other, causing side effects or affecting how BRAFTOVI or the other medicines work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take BRAFTOVI? • Take BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking BRAFTOVI unless your healthcare provider tells you to. • Take BRAFTOVI by mouth 1 time each day. • BRAFTOVI may be taken with or without food. • Avoid grapefruit and grapefruit juice during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in your body. • If you miss a dose of BRAFTOVI, take it as soon as you remember. If it is within 12 hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose. • Do not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time. • If you stop treatment with binimetinib or cetuximab, talk to your healthcare provider about your BRAFTOVI treatment. Your BRAFTOVI dose may need to be changed or stopped.
What are the possible side effects of BRAFTOVI? BRAFTOVI can cause serious side effects, including: • See "What is the most important information I should know about BRAFTOVI?" • Heart problems, including heart failure. BRAFTOVI can cause heart problems. Your healthcare provider will check your heart function before and during treatment with BRAFTOVI. Tell your healthcare provider right away if you get any of the following signs and symptoms of a heart problem: o feeling like your heart is pounding or racing o shortness of breath o swelling in your hands, ankles legs or feet o feeling faint or lightheaded • Liver problems. BRAFTOVI can cause liver problems. Your healthcare provider will perform blood tests to check your liver function before and during treatment with BRAFTOVI. Tell your healthcare provider if you get any of the following signs and symptoms of a liver problem:
	o yellowing of your skin or your eyes o dark or brown (tea-colored) urine o nausea or vomiting o loss of appetite o tiredness o bruising o bleeding
• Bleeding problems. BRAFTOVI can cause serious bleeding problems, including in your stomach or brain, that can lead to death. Tell your healthcare provider and get medical help right away if you develop any signs of bleeding, including: o headaches, dizziness, or feeling weak o cough up blood or blood clots o vomit blood or your vomit looks like “coffee grounds” o red or black stools that look like tar o nose bleeds • Eye problems. BRAFTOVI can cause eye problems. Your healthcare provider should perform an eye exam regularly. Tell your healthcare provider right away if you develop any new or worsening symptoms of eye problems, including: o blurred vision, loss of vision, or other vision changes o see colored dots o see halos (blurred outline around objects) o eye pain, swelling, or redness • Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider should do tests before you start treatment with BRAFTOVI during your treatment to check your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or if you feel your heart beating irregularly or fast during treatment with BRAFTOVI. These symptoms may be related to QT prolongation. Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with BRAFTOVI if you have certain side effects. The most common side effects of BRAFTOVI when taken in combination with binimetinib for melanoma include: • fatigue • nausea • vomiting • abdominal pain • pain or swelling of your joints (arthralgia) The most common side effects of BRAFTOVI when taken in combination with cetuximab and mFOLFOX6 for colorectal cancer include:
• numbness, tingling or burning in your hands or feet (peripheral neuropathy) • nausea • fatigue • diarrhea • decreased appetite • rash		• vomiting • bleeding (hemorrhage) • stomach-area (abdominal) pain • pain or swelling of your joints (arthralgia) • fever • constipation
The most common side effects of BRAFTOVI when taken in combination with cetuximab and FOLFIRI for colorectal cancer include:
• nausea • diarrhea • fatigue • vomiting • hair loss (alopecia)		• constipation • stomach-area (abdominal) pain • decreased appetite • rash
The most common side effects of BRAFTOVI when taken in combination with cetuximab for colorectal cancer include:
• fatigue • nausea • diarrhea • acne-like rash (dermatitis acneiform)		• stomach-area (abdominal) pain • decreased appetite • pain or swelling of your joints (arthralgia) • rash
The most common side effects of BRAFTOVI when taken in combination with binimetinib for NSCLC include:
• fatigue • nausea • diarrhea • muscle or joint pain • vomiting • stomach-area (abdominal) pain		• blurred vision, loss of vision, or other vision changes • constipation • shortness of breath • rash • cough
BRAFTOVI may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you. These are not all of the possible side effects of BRAFTOVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer Inc. at 1-800-438-1985.
How should I store BRAFTOVI? • Store BRAFTOVI at room temperature between 68°F to 77°F (20°C to 25°C). • Store BRAFTOVI in the original bottle. • Keep the BRAFTOVI bottle tightly closed and protect it from moisture. • BRAFTOVI comes with a desiccant packet in the bottle to help protect your medicine from moisture. Do not remove the desiccant packet from the bottle. Keep BRAFTOVI and all medicines out of the reach of children.
General information about the safe and effective use of BRAFTOVI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRAFTOVI for a condition for which it was not prescribed. Do not give BRAFTOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about BRAFTOVI that is written for health professionals.
What are the ingredients in BRAFTOVI? Active ingredient: encorafenib Inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, and magnesium stearate of vegetable origin Capsule shell: gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol) Distributed by: Array BioPharma Inc., a wholly owned subsidiary of Pfizer Inc. Boulder, Colorado 80301. BRAFTOVI® is a registered trademark of Array BioPharma Inc. in the United States and various other countries. LAB-1429-5.0 For more information, go to www.braftovi.com or call 1-844-792-7729. © 2024 Array BioPharma Inc. All rights reserved.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 02/2026

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