1 INDICATIONS AND USAGE BRAFTOVI is a kinase inhibitor indicated: Melanoma • in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test.

( 1.1 , 2.1 ) Colorectal Cancer (CRC) • in combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA‑authorized test.

( 1.2 , 2.1 ) • in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy.

( 1.2 , 2.1 ) Non-Small Cell Lung Cancer (NSCLC) • in combination with binimetinib, for the treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test.

( 1.3 , 2.1 ) Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC.

( 1.4 , 5.2 ) 1.1 BRAF V600E or V600K Mutation–Positive Unresectable or Metastatic Melanoma BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1) ] .

1.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) • BRAFTOVI is indicated, in combination with cetuximab and fluorouracil-based chemotherapy , for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA- authorized test [see Dosage and Administration (2.1) ].

• BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA- authorized test, after prior therapy [see Dosage and Administration (2.1) ].

1.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1) ] .

1.4 Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC [see Warnings and Precautions (5.2)] .

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) ] • Melanoma : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia.

( 6.1 ) • CRC : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab and mFOLFOX6, are peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation.

( 6.1 ) • Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab and FOLFIRI are nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash.

( 6.1 ) • Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab, are fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

( 6.1 ) • NSCLC : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.

at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

Adverse Reaction BRAFTOVI with binimetinib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm.

(%) All Grades (%) Grades 3 and 4 (%) General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms.

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 Laboratory Abnormality BRAFTOVI with binimetinib Grades per National Cancer Institute CTCAE v4.03.

N=192 Vemurafenib N=186 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/m 2 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/m 2 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.

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 Represents a subset of the control arm (mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab).

All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Nervous System Disorders Peripheral neuropathy Represents multiple related terms.

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.

Laboratory Abnormality 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.

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 Represents a subset of the control arm (mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab).

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.

Adverse Reaction BRAFTOVI with cetuximab and FOLFIRI N=71 FOLFIRI with or without bevacizumab N=68 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Gastrointestinal Disorders Nausea 61 2.8 57 1.5 Diarrhea Represents multiple related terms.

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.

Laboratory Abnormality 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.

BRAFTOVI with cetuximab and FOLFIRI FOLFIRI with or without bevacizumab 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/m 2 initial dose, followed by 250 mg/m 2 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.

Adverse Reaction BRAFTOVI with cetuximab N=216 Irinotecan with cetuximab or FOLFIRI with cetuximab N=193 All Grades (%) ≥Grade 3 Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade 5 hemorrhage (n=1).

(%) All Grades (%) ≥Grade 3 (%) General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms.

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.

Laboratory Abnormality Based on the number of patients with available baseline and at least one on-treatment laboratory test.

BRAFTOVI with cetuximab Irinotecan with cetuximab or FOLFIRI with cetuximab 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.

Adverse Reaction BRAFTOVI with binimetinib N=98 All Grades (%) Grades 3 and 4 One Grade 5 adverse reaction of hemorrhage occurred.

(%) General Disorders and Administration Site Conditions Fatigue Fatigue includes fatigue, asthenia.

61 8 Edema Edema includes edema peripheral, generalized edema, swelling, localized edema, face edema.

23 1 Pyrexia 22 0 Gastrointestinal Disorders Nausea 58 3.1 Diarrhea Diarrhea includes diarrhea, colitis.

52 7 Vomiting 37 1 Abdominal pain Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort.

32 1 Constipation 27 0 Eye Disorders Visual impairment Visual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia.

29 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck pain.

48 4.1 Skin and Subcutaneous Tissue Disorders Rash Rash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation.

27 3.1 Pruritis Pruritis includes pruritus, pruritus genital.

16 0 Dry skin 13 0 Alopecia 12 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional.

27 8 Cough Cough includes cough, productive cough.

26 0 Nervous System Disorders Dizziness Dizziness includes dizziness, balance disorder.

17 1 Headache 11 0 Metabolism and Nutrition Disorders Decreased appetite 14 1 Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage.

12 4.1 Hypertension 10 5 Cardiac Disorders Left ventricular dysfunction/cardiomyopathy Left ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive.

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.

Laboratory Abnormality Based on the number of patients with available baseline and at least one on-treatment laboratory test.

BRAFTOVI with binimetinib 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