ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described elsewhere in the labeling:oNew Primary Malignancies [see Warnings and Precautions (5.1)]oTumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]oCardiomyopathy [see Warnings and Precautions (5.3)]oHepatotoxicity [see Warnings and Precautions (5.4)]oHemorrhage [see Warnings and Precautions (5.5)]oUveitis [see Warnings and Precautions (5.6)]oQT Prolongation [see Warnings and Precautions (5.7)]oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.8)]oRisks Associated with BRAFTOVI as Single Agent [see Warnings and Precautions (5.9)]oRisks Associated with Combination Treatment [see Warnings and Precautions (5.10)]. oNew Primary Malignancies [see Warnings and Precautions (5.1)]. oTumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2)]. oCardiomyopathy [see Warnings and Precautions (5.3)]. oHepatotoxicity [see Warnings and Precautions (5.4)]. oHemorrhage [see Warnings and Precautions (5.5)]. oUveitis [see Warnings and Precautions (5.6)]. oQT Prolongation [see Warnings and Precautions (5.7)]. oEmbryo-Fetal Toxicity [see Warnings and Precautions (5.8)]. oRisks Associated with BRAFTOVI as Single Agent [see Warnings and Precautions (5.9)]. oRisks Associated with Combination Treatment [see Warnings and Precautions (5.10)]. oMelanoma: Most common adverse reactions (>=25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia. (6.1)oCRC: 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)oMost 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) oMost 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)oNSCLC: 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 .. oMelanoma: Most common adverse reactions (>=25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia. (6.1). oCRC: 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). oMost 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) oMost 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). oNSCLC: 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). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 MelanomaThe 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 randomized open-label, active-controlled trial (COLUMBUS).The COLUMBUS trial [see Clinical Studies (14.1)] excluded patients with history of Gilberts 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 and Table present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate 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 COLUMBUSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with binimetinibN=192VemurafenibN=186All Grades(%)Grades and 4Grade adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm.(%)All Grades(%)Grades and 4(%)General Disorders and Administration Site Conditions FatigueRepresents composite of multiple, related preferred terms. 433466 Pyrexia 184300Gastrointestinal Disorders Nausea412342 Vomiting 302161 Abdominal pain 284161 Constipation22061Musculoskeletal and Connective Tissue Disorders Arthralgia 261466 Myopathy 230221 Pain in extremity111131Skin and Subcutaneous Tissue Disorders Hyperkeratosis 231491 Rash 2215313 Dry skin 160260 Alopecia 140380 Pruritus 131211Nervous System Disorders Headache 222201 Dizziness 15340 Peripheral neuropathy 121132Vascular Disorders Hemorrhage 19392BRAFTOVI when used as 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 single agent, the following adverse reactions were observed at 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 AbnormalityBRAFTOVIwith binimetinibGrades per National Cancer Institute CTCAE v4.03.N=192VemurafenibN=186All Grades(%)Grades and 4(%)All Grades(%)Grades and 4(%)Hematology Anemia363.6342.2 Leukopenia130100.5 Lymphopenia132.1307 Neutropenia133.14.80.5Chemistry Increased Creatinine933.6921.1 Increased Gamma Glutamyl Transferase4511344.8 Increased ALT296272.2 Increased AST272.6241.6 Hyperglycemia285202.7 Increased Alkaline Phosphatase210.5352.2 Hyponatremia183.6150.5 Hypermagnesemia101.0260.5. BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in Combination with Cetuximab and fluorouracil-based chemotherapyThe safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every weeks) and mFOLFOX6 was evaluated in 232 patients with BRAF V600E mutation-positive metastatic CRC in randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)]. In 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 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 mFOLFOX6Among patients who received BRAFTOVI, 73% were exposed for 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 or 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 and Table 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with cetuximab and mFOLFOX6N=232mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumabN=229mFOLFOX6 with or without bevacizumabN=115Represents 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 or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Nervous System DisordersPeripheral neuropathyRepresents multiple related terms. 64195395710Headache 150.490120Dysgeusia 150140190Neurotoxicity11680120Gastrointestinal DisordersNausea543503.9442.6Diarrhea421.3504.8442.6Vomiting363.9222.2171.7Abdominal pain 325311.7301.7Constipation270.4230.4250.9Stomatitis 172.2161.3191.7General Disorders and Administration Site ConditionsFatigue 537414.8457Pyrexia 292.2160.4170.9Metabolism and Nutrition DisordersDecreased appetite 382.2271.3302.6Skin and Subcutaneous Tissue DisordersRash 361.36050Alopecia230110120Dry skin 220.46050Dermatitis acneiform 200.91.300.90Skin hyperpigmentation1903.101.70Pruritus 1403.90.450.9Vascular DisordersHemorrhage 342.6211.3151.7Edema 1104.4060Musculoskeletal and Connective Tissue DisordersArthralgia 322.660.470.9Myopathy 1904.80.460.9Musculoskeletal pain 140.9101.3131.7Infections and InfestationsCOVID-19 160.9170.4160.9Respiratory tract infection 110.9110.490.9Psychiatric DisordersInsomnia 1309050Other 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityThe denominator used to calculate the rate varied from 220 to 227 based on the number of patients with baseline and at least one post-treatment value.BRAFTOVIwith cetuximab and mFOLFOX6mFOLFOX6 with or without bevacizumaborFOLFOXIRI with or without bevacizumaborCAPOX with or without bevacizumabmFOLFOX6 with or without bevacizumabRepresents 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 or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Hematology Hemoglobin decreased6819506457 Activated partial thromboplastin time prolonged675431502 Neutrophil count decreased663763356233 White blood cell decreased6612598566 Platelet count decreased651573614 INR increased471231242Chemistry Lipase increased855357285323 Creatinine increased701721750 Glucose increased5611402391 Alanine aminotransferase increased431443464 Albumin decreased421271251 Aspartate aminotransferase increased401412373 Alkaline phosphatase increased403351323 Potassium decreased385235173 Calcium decreased334222192 Magnesium decreased27112190 Sodium decreased233174165BRAFTOVI in combination with cetuximab and FOLFIRIAmong patients who received BRAFTOVI, 81% were exposed for 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 or 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 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI in Cohort of BREAKWATER.Table 9: Adverse Reactions Occurring in >=10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and FOLFIRI (Cohort 3) in BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with cetuximaband FOLFIRIN=71FOLFIRI with or without bevacizumabN=68All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal Disorders Nausea612.8571.5 DiarrheaRepresents multiple related terms. 5510499 Vomiting472.8310 Constipation311.4291.5 Abdominal pain 300221.5General Disorders and Administration Site Conditions Fatigue 474.2506 Pyrexia 1704.41.5Skin and Subcutaneous Tissue Disorders Alopecia351.4220 Rash 2701.50 Dry skin 24060 Skin hyperpigmentation2402.90 Palmar-plantar erythrodysaesthesia syndrome17070 Dermatitis acneiform 11000 Pruritus 1104.40Metabolism and Nutrition Disorders Decreased appetite304.2322.9Musculoskeletal and Connective Tissue Disorders Arthralgia 2404.40 Myopathy 13090Vascular Disorders Hemorrhage 210220Nervous System Disorders Dysgeusia1404.40 Headache 130130Psychiatric Disorders Insomnia 130130Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) Melanocytic nevus11000Cardiac Disorders Arrhythmia 1101.50Other 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityThe denominator used to calculate the rate varied from 65 to 68 based on the number of patients with baseline and at least one post-treatment value.BRAFTOVIwith cetuximab and FOLFIRIFOLFIRI with or without bevacizumabAll Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Hematology White blood cell decreased7220676 Neutrophil count decreased69306232 Hemoglobin decreased6110583 INR increased430210 Activated partial thromboplastin time prolonged332430 Platelet count decreased210260Chemistry Creatinine increased592823 Lipase increased46223212 Glucose increased438353 Alanine aminotransferase increased342333 Albumin decreased342260 Potassium decreased346186 Calcium decreased272245 Alkaline phosphatase increased220365BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with CetuximabThe 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 randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.3)] excluded patients with history of Gilberts 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 CRCGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVIwith cetuximabN=216Irinotecan with cetuximab or FOLFIRI with cetuximabN=193All Grades(%)>=Grade 3Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade hemorrhage (n=1).(%)All Grades(%)>=Grade 3(%)General Disorders and Administration Site Conditions FatigueRepresents composite of multiple, related preferred terms. 517508 Pyrexia 171151Gastrointestinal Disorders Nausea341411 Diarrhea 3324810 Abdominal pain 304325 Vomiting211293 Constipation150181Metabolism and Nutrition Disorders Decreased appetite271273Musculoskeletal and Connective Tissue Disorders Arthralgia 27130 Myopathy 15140 Pain in extremity10010Skin and Subcutaneous Tissue Disorders Dermatitis acneiform 321433 Rash 260262 Pruritus 14060 Melanocytic nevus14000 Dry skin 130121Nervous System Disorders Headache 20030 Peripheral neuropathy 12160Vascular Disorders Hemorrhage 19290Psychiatric Disorders Insomnia 13060Other 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 CRCGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test.BRAFTOVIwith cetuximabIrinotecan with cetuximab or FOLFIRI with cetuximabAll Grades (%)Grades and (%)All Grades (%)Grades and (%)Hematology Anemia344485 Lymphopenia247355 Increased activated partial thromboplastin time13171Chemistry Hypomagnesemia190221 Increased alkaline phosphatase184307 Increased ALT170293 Increased AST151222 Hypokalemia123325 Hyponatremia112132BRAF 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). 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 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 PHAROSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVIwith binimetinib N=98All Grades(%)Grades and 4One Grade adverse reaction of hemorrhage occurred.(%)General Disorders and Administration Site Conditions FatigueFatigue includes fatigue, asthenia. 618 EdemaEdema includes edema peripheral, generalized edema, swelling, localized edema, face edema. 231 Pyrexia220Gastrointestinal Disorders Nausea583.1 DiarrheaDiarrhea includes diarrhea, colitis. 527 Vomiting371 Abdominal painAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. 321 Constipation270Eye Disorders Visual impairmentVisual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. 292Musculoskeletal and Connective Tissue Disorders Musculoskeletal painMusculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck pain. 484.1Skin and Subcutaneous Tissue Disorders RashRash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. 273.1 PruritisPruritis includes pruritus, pruritus genital. 160 Dry skin130 Alopecia120Respiratory, Thoracic and Mediastinal Disorders DyspneaDyspnea includes dyspnea, dyspnea exertional. 278 CoughCough includes cough, productive cough. 260Nervous System Disorders DizzinessDizziness includes dizziness, balance disorder. 171 Headache110Metabolism and Nutrition Disorders Decreased appetite141Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. 124.1 Hypertension105Cardiac Disorders Left ventricular dysfunction/cardiomyopathyLeft ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. 111Investigations Weight increased111Psychiatric Disorders Insomnia100Other 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 BinimetinibGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test.BRAFTOVI with binimetinibAll Grades(%)Grades and 4(%)Hematology Anemia4711 Lymphopenia246 Thrombocytopenia201.1 Leukopenia120 Neutropenia121.1Chemistry Increased creatinine913.2 Hyperglycemia486 Increased creatine kinase413.3 Lipase increased4014 Increased ALT349 Hypoalbuminemia320 Increased AST3110 Increased alkaline phosphatase313.2 Hyperkalemia312.1 Hyponatremia2611 Serum amylase increased221.1 Hypocalcemia122.1.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both and 13-week studies.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.No dedicated fertility studies were performed with encorafenib in animals. In general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the nonhuman primate toxicity studies.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Encorafenib is kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduce ligand binding to these kinases at clinically achievable concentrations (<=0.9 uM).Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as mechanism of resistance to BRAF inhibitors. Combinations of BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in mouse model of colorectal cancer with mutated BRAF V600E.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyA dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation. Based on central tendency analysis of QTc in study of adult patients with melanoma who received the recommended dose of BRAFTOVI in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline (QTcF) was 18 (14 to 22) ms [see Warnings and Precautions (5.7) ].. 12.3 Pharmacokinetics. The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%.. AbsorptionThe median Tmax of encorafenib is hours. At least 86% of the dose is absorbed.. Effect of FoodFollowing administration of single dose of BRAFTOVI 100 mg (0.2 times the maximum recommended dose of 450 mg) with high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (Cmax) decreased by 36% and there was no effect on AUC.. DistributionThe geometric mean (CV%) of apparent volume of distribution is 164 (70%). The protein binding of encorafenib is 86% in vitro. The blood-to-plasma concentration ratio is 0.58. EliminationThe mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state at the maximum recommended dose of 450 mg.. MetabolismEncorafenib is primarily metabolized by CYP3A4 (83%) and to lesser extent by CYP2C19 (16%) and CYP2D6 (1%).. ExcretionFollowing single radiolabeled dose of 100 mg encorafenib, 47% (5% unchanged) of the administered dose was recovered in feces and 47% (2% unchanged) in urine.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of encorafenib were observed based on age (19 to 94 years), sex, body weight (34 to 168 kg), mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to <90 mL/min). The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class or C), and severe renal impairment (CLcr <30 mL/min) on encorafenib pharmacokinetics have not been studied.. Drug Interaction Studies. Clinical Studies. CYP3A4 Inhibitors: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased AUC of encorafenib by 183% and 83%, respectively, and increased Cmax by 68% and 45%, respectively, after single dose of 50 mg BRAFTOVI (0.1 times the maximum recommended dose of 450 mg).. Strong CYP3A4 Inducers: The effect of strong CYP3A4 inducer on encorafenib exposure has not been studied [see Drug Interactions (7.1)].Moderate CYP3A4 Inducers: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with modafinil, moderate CYP3A4 inducer, decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to BRAFTOVI alone.Effect of encorafenib on CYP3A4 Substrates: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with single dose of midazolam mg, sensitive CYP3A4 substrate, decreased midazolam AUC by 82% and Cmax by 74% relative to midazolam mg alone.Effect of encorafenib on Other CYP Substrates: There was no clinically significant effect of repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily on the exposure of substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6.. Proton Pump Inhibitors: No clinically significant differences in encorafenib pharmacokinetics were observed when coadministered with rabeprazole.. Binimetinib: No clinically significant differences in the pharmacokinetics of binimetinib (UGT1A1 substrate) were observed when coadministered with BRAFTOVI (UGT1A1 inhibitor). Oxaliplatin: No clinically significant differences in the pharmacokinetics of oxaliplatin were observed when BRAFTOVI 300 mg once daily was coadministered with mFOLFOX6.. Irinotecan: No clinically significant differences in the pharmacokinetics of irinotecan or SN-38 were observed when repeat dose BRAFTOVI 300 mg once daily was coadministered with FOLFIRI.Transporters: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with single dose of rosuvastatin (a sensitive substrate for OATP1B1, OATP1B3, and BCRP) increased rosuvastatin Cmax by 168% and AUC by 57%.. In Vitro Studies. CYP/UGT Enzymes: Encorafenib is reversible inhibitor of UGT1A1.. Transporters: Encorafenib is substrate of P-glycoprotein (P-gp) but not of breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations.Encorafenib is an inhibitor of P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not of OCT1 or MRP2 at clinically relevant plasma concentrations.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma. BRAFTOVI in combination with binimetinib was evaluated in randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID(TM) BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no).Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib 45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) are described below.The major efficacy outcome measure was progression-free survival (PFS), as assessed by blinded independent central review, to compare BRAFTOVI in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review.A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm, 194 to the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the BRAFTOVI in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninety-five percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had >=3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%).BRAFTOVI in combination with binimetinib demonstrated statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 15 and Figure 1.Table 15: Efficacy Results for COLUMBUSCI Confidence interval; CR Complete response; DoR Duration of response; HR Hazard ratio; NE Not estimable; ORR Overall response rate; OS Overall survival; PFS Progression-free survival; PR Partial response.BRAFTOVIwith binimetinibN=192VemurafenibN=191Progression-Free Survival Number of events (%)98 (51)106 (55) Progressive disease88 (46)104 (54) Death10 (5)2 (1) Median PFS, months (95% CI)14.9 (11.0, 18.5)7.3 (5.6, 8.2) HR (95% CI)Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1). 0.54 (0.41, 0.71) P-valueLog-rank test adjusted by the same stratification factors. <0.0001Overall SurvivalBased on cutoff date of 82.4 months after the date of the PFS analysis. Number of events (%)139 (72)147 (77) Median OS, months (95% CI)33.6 (24.4, 39.2)16.9 (14.0, 24.5) HR (95% CI) 0.67 (0.53, 0.84)Overall Response Rate ORR (95% CI)63% (56%, 70%)40% (33%, 48%) CR8%6% PR55%35%Duration of Response Median DoR, months (95% CI)16.6 (12.2, 20.4)12.3 (6.9, 16.9)Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS. Figure 1. 14.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) BREAKWATER BRAFTOVI with Cetuximab and mFOLFOX6BRAFTOVI in combination with cetuximab and mFOLFOX6 was evaluated in randomized, active-controlled, open-label, multicenter trial (BREAKWATER CRC; NCT04607421). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit. Other key eligibility criteria included no prior systemic treatment in the metastatic setting, absence of prior treatment with any selective BRAF inhibitor or EGFR inhibitor, tumor that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unless the patient is ineligible to receive immune checkpoint inhibitors, tumor that is not RAS-mutated or for which RAS mutation status is unknown, and Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Randomization was stratified by ECOG performance status (0 versus 1) and region (US/Canada versus Europe versus Rest of World). Patients were initially randomized 1:1:1 to one of the following treatment arms, and then 1:1 after discontinuation of enrollment of the BRAFTOVI+cetuximab arm (158 patients):oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks (BRAFTOVI+cetuximab arm)oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks and mFOLFOX6 every weeks (BRAFTOVI+cetuximab+mFOLFOX6 arm)omFOLFOX6 (every weeks), or FOLFOXIRI (every weeks), or CAPOX (every weeks), each with or without bevacizumab (administered per prescribing instructions)mFOLFOX6 consisted of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours; CAPOX consisted of oxaliplatin 130 mg/m2 IV infusion and capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14; FOLFOXIRI consisted of irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 or 3200 mg/m2 (per local standard of care) continuous IV infusion over 46-48 hours. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, or death. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab and mFOLFOX6) are described below. The major efficacy outcome measures were confirmed objective response rate (ORR) and progression-free survival as assessed by BICR. Additional efficacy outcome measures included overall survival (OS) and duration of response (DoR) as assessed by BICR. PFS and OS were evaluated in all randomized patients. ORR and DoR were evaluated in the first 110 participants randomized in each arm.A total of 236 patients were randomized to the BRAFTOVI+cetuximab+mFOLFOX6 arm and 243 to the control arm. Of these patients, the median age was 61 years, 49% were female, 59% were White, 37% were Asian, 0.4% were Multiracial, 0.2% were Black or African American, and 2.5% were not reported. Twelve percent (12%) were Hispanic or Latino, 81% were not Hispanic or Latino, and 7% were not reported. Fifty-four percent (54%) had baseline ECOG performance status of 0.BRAFTOVI in combination with cetuximab and mFOLFOX6 demonstrated statistically significant improvements in ORR, PFS, and OS compared to the active comparator. Efficacy results are summarized in Table 16.Table 16: Efficacy Results for BRAFTOVI with Cetuximab and mFOLFOX6CI Confidence interval; CR Complete response; DoR Duration of response; = Number of patients; NE Not estimable; ORR Objective response rate; PR Partial response; HR Hazard ratio; OS Overall survival; PFS Progression-free survival.Efficacy ParameterBRAFTOVIwith cetuximab and mFOLFOX6N=236mFOLFOX6 +- bevacizumaborFOLFOXIRI +- bevacizumaborCAPOX +- bevacizumabN=243Progression-Free Survival Number of events (%)122 (52)132 (54) Progressive disease105 (45)109 (45) Death17 (7)23 (9) Median PFS, months (95% CI)12.8 (11.2, 15.9)7.1 (6.8, 8.5) HR (95% CI)Hazard ratio based on stratified Cox proportional hazards model. Stratified by ECOG performance status and geographic region at randomization. 0.53 (0.41, 0.68) P-value Stratified log-rank test. Tested at 1-sided alpha level of 0.023. <0.0001Objective Response RateORR Subset included the first 110 participants in each arm. ORR (95% CI)61% (52%, 70%)40% (31%, 49%) CR2.7%1.8% PR58%38% P-value Cochran-Mantel-Haenszel test; tested at 1-sided alpha level of 0.001. 0.0008Duration of Response Median DoR, months (95% CI)13.9 (8.5, NE)11.1 (6.7, 12.7)Overall SurvivalInterim OS analysis conducted at 81.5% of total events required for final analysis. Number of events (%)94 (40%)148 (61%) Median OS, months (95% CI)30.3 (21.7, NE)15.1 (13.7, 17.7) HR (95% CI) 0.49 (0.38, 0.63) P-value Stratified log-rank test. Tested at 1-sided alpha level of 0.012. <0.0001 Figure 2:Kaplan-Meier Curves for Progression-Free Survival in BREAKWATER (BRAFTOVI plus cetuximab and mFOLFOX6) Figure 3:Kaplan-Meier Curves for Overall Survival in BREAKWATER (BRAFTOVI plus cetuximab and mFOLFOX6)BREAKWATER BRAFTOVI with Cetuximab and FOLFIRIBRAFTOVI in combination with cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) was evaluated in separate cohort (Cohort 3) of BREAKWATER CRC (NCT04607421). Patients were randomized 1:1 to one of the following treatment arms:oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks and FOLFIRI every weeks (BRAFTOVI+cetuximab+FOLFIRI arm)oFOLFIRI (every weeks) with or without bevacizumab (administered per prescribing instructions)FOLFIRI consisted of irinotecan 180 mg/m2 (90 minute IV infusion); leucovorin 400 mg/m2 (120 minute IV infusion); and 5-FU (400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46 48 hours).Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up, or death. The major efficacy outcome measure was confirmed objective response rate (ORR) as assessed by BICR. An additional efficacy outcome measure included duration of response (DoR) as assessed by BICR. total of 73 patients were randomized to the BRAFTOVI+cetuximab+FOLFIRI arm and 74 to the control arm. Of these patients, the median age was 62 years, 54% were female, 61% were White, 33% were Asian, 1.4% were Native Hawaiian or Other Pacific Islander, 0.7% were Multiracial, and 3.4% were not reported; 10% were Hispanic or Latino, 83% were not Hispanic or Latino, and 7% were not reported. There were no Black or African American patients enrolled in Cohort of BREAKWATER. Sixty percent (60%) had baseline ECOG performance status of 0.BRAFTOVI in combination with cetuximab and FOLFIRI demonstrated statistically significant improvement in ORR compared to the active comparator. Efficacy results are summarized in Table 17.Table 17: Efficacy Results for BRAFTOVI with Cetuximab and FOLFIRICI Confidence interval; CR Complete response; DoR Duration of response; = Number of patients; ORR Objective response rate; PR Partial response.Efficacy ParameterBRAFTOVIwith cetuximab and FOLFIRIN=73FOLFIRI with or without bevacizumabN=74Objective Response Rate ORR (95% CI)64% (53%, 74%)39% (29%, 51%) CR4.1%1.4% PR60%38% P-valueStratified by ECOG performance status at randomization. Cochran-Mantel-Haenszel test; tested at 1-sided alpha level of 0.025. 0.0011Duration of Response with DoR >=6 months57%35%BEACON CRC-BRAFTOVI with Cetuximab following prior therapyBRAFTOVI in combination with cetuximab was evaluated in randomized, active-controlled, open-label, multicenter trial (BEACON CRC; NCT02928224). Eligible patients were required to have BRAF V600E mutation-positive metastatic colorectal cancer (CRC), as detected using the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction (PCR) Kit, with disease progression after or prior regimens. Other key eligibility criteria included absence of prior treatment with RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labeling with respect to tumor RAS status, and ECOG performance status (PS) 0-1. Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-authorized). Patients were randomized 1:1:1 to one of the following treatment arms:oBRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)oBRAFTOVI 300 mg orally once daily in combination with binimetinib and cetuximab oIrinotecan with cetuximab or FOLFIRI with cetuximab (control arm)The dosage of cetuximab in all patients was 400 mg/m2 intravenously for the first dose followed by 250 mg/m2 weekly. Patients in the control arm received cetuximab with either irinotecan 180 mg/m2 intravenously on Days and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m2 on Days and 15; folinic acid 400 mg/m2 on Days and 15; then 5-FU 400 mg/m2 bolus on Days and 15 followed by 5-FU 2400 mg/m2/day by continuous infusion over days). Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved regimen (BRAFTOVI in combination with cetuximab) are described below. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures included progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomized patients. ORR and DoR were assessed in the subset of the first 220 patients included in the randomized portion of the BRAFTOVI/cetuximab and control arm of the study.A total of 220 patients were randomized to the BRAFTOVI/cetuximab arm and 221 to the control arm. Of these 441 patients, the median age was 61 years; 53% were female; 80% were White, 15% were Asian, and 5% were other or not reported. Four percent (4%) were Hispanic or Latino, 90% were not Hispanic or Latino, and 6% were not reported or unknown. Fifty percent (50%) had baseline ECOG performance status of 0; 66% received prior therapy and 34% received 2; 93% received prior oxaliplatin and 52% received prior irinotecan.BRAFTOVI in combination with cetuximab demonstrated statistically significant improvement in OS, ORR, and PFS compared to the active comparator. Efficacy results are summarized in Table 18 and Figure 4Table 18: Efficacy Results from BEACON CRCCI Confidence interval; CR Complete response; DoR Duration of response; HR Hazard ratio; NR Not reached; ORR Overall response rate; OS Overall survival; PFS Progression-free survival; PR Partial response.BRAFTOVI with cetuximabN=220Irinotecan with cetuximab or FOLFIRI with cetuximabN=221Overall Survival Number of Events (%)93 (42)114 (52) Median OS, months (95% CI)8.4 (7.5, 11.0)5.4 (4.8, 6.6) HR (95% CI)Stratified by ECOG PS, source of cetuximab (US-licensed versus EU-authorized) and prior irinotecan use at randomization. Stratified Cox proportional hazard model. 0.60 (0.45, 0.79) P-value Stratified log-rank test, tested at alpha level of 0.0084. 0.0003Overall Response Rate (per BICR) ORR (95% CI)BRAFTOVI/cetuximab arm (n=113) and control arm (n=107). 20% (13%, 29%)2% (0%, 7%) CR5%0% PR15%2% P-value Cochran-Mantel-Haenszel test; tested at alpha level of 0.05. <0.0001Median DoR, months (95% CI)6.1 (4.1, 8.3)NR (2.6, NR)Progression-Free Survival (per BICR) Number of events (%)133 (60)128 (58) Progressive disease110 (50)101 (46) Death23 (10)27 (12) Median PFS, months (95% CI)4.2 (3.7, 5.4)1.5 (1.4, 1.7) HR (95% CI) 0.40 (0.31, 0.52) P-value Stratified log-rank test, tested at alpha level of 0.0234. <0.0001Figure 4:Kaplan-Meier Curves for Overall Survival in BEACON CRC. oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks (BRAFTOVI+cetuximab arm). oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks and mFOLFOX6 every weeks (BRAFTOVI+cetuximab+mFOLFOX6 arm). omFOLFOX6 (every weeks), or FOLFOXIRI (every weeks), or CAPOX (every weeks), each with or without bevacizumab (administered per prescribing instructions). Figure 2:Kaplan-Meier Curves for Progression-Free Survival in BREAKWATER (BRAFTOVI plus cetuximab and mFOLFOX6). Figure 3:Kaplan-Meier Curves for Overall Survival in BREAKWATER (BRAFTOVI plus cetuximab and mFOLFOX6). oBRAFTOVI 300 mg orally once daily in combination with cetuximab 500 mg/m2 IV infusion every weeks and FOLFIRI every weeks (BRAFTOVI+cetuximab+FOLFIRI arm). oFOLFIRI (every weeks) with or without bevacizumab (administered per prescribing instructions). oBRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm). oBRAFTOVI 300 mg orally once daily in combination with binimetinib and cetuximab oIrinotecan with cetuximab or FOLFIRI with cetuximab (control arm). Figure 2. Figure 3. Figure 4. 14.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer BRAFTOVI in combination with binimetinib was evaluated in an open-label, multicenter, single-arm study in patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer (NSCLC) (PHAROS; NCT03915951). Eligible patients had diagnosis of histologically-confirmed metastatic NSCLC with BRAF V600E mutation that was treatment-naive or had been previously treated with prior line of systemic therapy in the metastatic setting (platinum-based chemotherapy and/or anti-PD-1/PD-L1 therapies), age 18 years or older, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of or 1, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Prior use of BRAF inhibitors or MEK inhibitors was not allowed. Patients received BRAFTOVI 450 mg once daily and binimetinib 45 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) per RECIST v1.1 and duration of response (DoR) as assessed by independent review committee (IRC).In the efficacy population, BRAF V600E mutation status was determined by prospective local testing using tumor tissue (78%) or blood (22%) specimens. Of the 98 patients with BRAF V600E mutation, patients were enrolled into the trial based on testing of their tumor tissue specimens with the FoundationOne CDx tissue test. Of the remaining 92 patients enrolled based on local testing, 68 patients had their tumor tissue specimens retrospectively confirmed as having BRAF V600E positive status by the FoundationOne CDx tissue test. The remaining patients had either BRAF V600E negative status (n=5) or had unevaluable results (n=19) by the FoundationOne CDx tissue test. In addition, plasma samples from 81 out of 98 patients were retrospectively tested using the FoundationOne Liquid CDx assay. Of the 81 patients, 48 were confirmed positive for BRAF V600E, while 33 patients were BRAF V600E mutation negative by FoundationOne Liquid CDx assay. The remaining 17 samples had unevaluable results with FoundationOne Liquid CDx assay.The efficacy population included 59 treatment-naive patients and 39 previously-treated patients. Among these 98 patients, the median age was 70 years (range: 47 to 86); 53% female; 88% White, 7% Asian, 3% Black or African American, and 1% American Indian or Alaska Native; 99% were not Hispanic or Latino; 13% were current smokers and 57% were former smokers; 73% had ECOG PS of 1; and 97% had adenocarcinoma. All patients had metastatic disease, and 8% had brain metastases at baseline. Efficacy results for patients with BRAF V600E mutation-positive metastatic NSCLC are summarized in Table 19.Table 19: Efficacy Results for PHAROSCI Confidence interval; CR Complete response; DoR Duration of response; = Number of patients; NE Not estimable; ORR Objective response rate; PR Partial response.BRAFTOVI with binimetinibEfficacy ParameterTreatment-naive(N=59)Previously-treated(N=39)Objective Response RateAssessed by Independent Central Review (ICR). ORR (95% CI)75% (62, 85)46% (30, 63) CR15%10% PR59%36%Duration of ResponseBased on observed duration of response.N=44N=18 Range in months1.4, 51.6+3.8, 45.8+ with DoR >=12 months64%44% with DoR >=24 months43%22%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 MelanomaThe 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 randomized open-label, active-controlled trial (COLUMBUS).The COLUMBUS trial [see Clinical Studies (14.1)] excluded patients with history of Gilberts 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 and Table present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate 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 COLUMBUSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with binimetinibN=192VemurafenibN=186All Grades(%)Grades and 4Grade adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm.(%)All Grades(%)Grades and 4(%)General Disorders and Administration Site Conditions FatigueRepresents composite of multiple, related preferred terms. 433466 Pyrexia 184300Gastrointestinal Disorders Nausea412342 Vomiting 302161 Abdominal pain 284161 Constipation22061Musculoskeletal and Connective Tissue Disorders Arthralgia 261466 Myopathy 230221 Pain in extremity111131Skin and Subcutaneous Tissue Disorders Hyperkeratosis 231491 Rash 2215313 Dry skin 160260 Alopecia 140380 Pruritus 131211Nervous System Disorders Headache 222201 Dizziness 15340 Peripheral neuropathy 121132Vascular Disorders Hemorrhage 19392BRAFTOVI when used as 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 single agent, the following adverse reactions were observed at 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 AbnormalityBRAFTOVIwith binimetinibGrades per National Cancer Institute CTCAE v4.03.N=192VemurafenibN=186All Grades(%)Grades and 4(%)All Grades(%)Grades and 4(%)Hematology Anemia363.6342.2 Leukopenia130100.5 Lymphopenia132.1307 Neutropenia133.14.80.5Chemistry Increased Creatinine933.6921.1 Increased Gamma Glutamyl Transferase4511344.8 Increased ALT296272.2 Increased AST272.6241.6 Hyperglycemia285202.7 Increased Alkaline Phosphatase210.5352.2 Hyponatremia183.6150.5 Hypermagnesemia101.0260.5. BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in Combination with Cetuximab and fluorouracil-based chemotherapyThe safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m2 every weeks) and mFOLFOX6 was evaluated in 232 patients with BRAF V600E mutation-positive metastatic CRC in randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2)]. In 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 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 mFOLFOX6Among patients who received BRAFTOVI, 73% were exposed for 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 or 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 and Table 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with cetuximab and mFOLFOX6N=232mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumabN=229mFOLFOX6 with or without bevacizumabN=115Represents 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 or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Nervous System DisordersPeripheral neuropathyRepresents multiple related terms. 64195395710Headache 150.490120Dysgeusia 150140190Neurotoxicity11680120Gastrointestinal DisordersNausea543503.9442.6Diarrhea421.3504.8442.6Vomiting363.9222.2171.7Abdominal pain 325311.7301.7Constipation270.4230.4250.9Stomatitis 172.2161.3191.7General Disorders and Administration Site ConditionsFatigue 537414.8457Pyrexia 292.2160.4170.9Metabolism and Nutrition DisordersDecreased appetite 382.2271.3302.6Skin and Subcutaneous Tissue DisordersRash 361.36050Alopecia230110120Dry skin 220.46050Dermatitis acneiform 200.91.300.90Skin hyperpigmentation1903.101.70Pruritus 1403.90.450.9Vascular DisordersHemorrhage 342.6211.3151.7Edema 1104.4060Musculoskeletal and Connective Tissue DisordersArthralgia 322.660.470.9Myopathy 1904.80.460.9Musculoskeletal pain 140.9101.3131.7Infections and InfestationsCOVID-19 160.9170.4160.9Respiratory tract infection 110.9110.490.9Psychiatric DisordersInsomnia 1309050Other 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityThe denominator used to calculate the rate varied from 220 to 227 based on the number of patients with baseline and at least one post-treatment value.BRAFTOVIwith cetuximab and mFOLFOX6mFOLFOX6 with or without bevacizumaborFOLFOXIRI with or without bevacizumaborCAPOX with or without bevacizumabmFOLFOX6 with or without bevacizumabRepresents 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 or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Hematology Hemoglobin decreased6819506457 Activated partial thromboplastin time prolonged675431502 Neutrophil count decreased663763356233 White blood cell decreased6612598566 Platelet count decreased651573614 INR increased471231242Chemistry Lipase increased855357285323 Creatinine increased701721750 Glucose increased5611402391 Alanine aminotransferase increased431443464 Albumin decreased421271251 Aspartate aminotransferase increased401412373 Alkaline phosphatase increased403351323 Potassium decreased385235173 Calcium decreased334222192 Magnesium decreased27112190 Sodium decreased233174165BRAFTOVI in combination with cetuximab and FOLFIRIAmong patients who received BRAFTOVI, 81% were exposed for 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 or 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 and Table 10 present adverse drug reactions and laboratory abnormalities, respectively, identified in patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI in Cohort of BREAKWATER.Table 9: Adverse Reactions Occurring in >=10% of Patients Receiving BRAFTOVI in Combination with Cetuximab and FOLFIRI (Cohort 3) in BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVI with cetuximaband FOLFIRIN=71FOLFIRI with or without bevacizumabN=68All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Gastrointestinal Disorders Nausea612.8571.5 DiarrheaRepresents multiple related terms. 5510499 Vomiting472.8310 Constipation311.4291.5 Abdominal pain 300221.5General Disorders and Administration Site Conditions Fatigue 474.2506 Pyrexia 1704.41.5Skin and Subcutaneous Tissue Disorders Alopecia351.4220 Rash 2701.50 Dry skin 24060 Skin hyperpigmentation2402.90 Palmar-plantar erythrodysaesthesia syndrome17070 Dermatitis acneiform 11000 Pruritus 1104.40Metabolism and Nutrition Disorders Decreased appetite304.2322.9Musculoskeletal and Connective Tissue Disorders Arthralgia 2404.40 Myopathy 13090Vascular Disorders Hemorrhage 210220Nervous System Disorders Dysgeusia1404.40 Headache 130130Psychiatric Disorders Insomnia 130130Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) Melanocytic nevus11000Cardiac Disorders Arrhythmia 1101.50Other 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 BREAKWATERGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityThe denominator used to calculate the rate varied from 65 to 68 based on the number of patients with baseline and at least one post-treatment value.BRAFTOVIwith cetuximab and FOLFIRIFOLFIRI with or without bevacizumabAll Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Hematology White blood cell decreased7220676 Neutrophil count decreased69306232 Hemoglobin decreased6110583 INR increased430210 Activated partial thromboplastin time prolonged332430 Platelet count decreased210260Chemistry Creatinine increased592823 Lipase increased46223212 Glucose increased438353 Alanine aminotransferase increased342333 Albumin decreased342260 Potassium decreased346186 Calcium decreased272245 Alkaline phosphatase increased220365BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC) in Combination with CetuximabThe 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 randomized, open-label, active-controlled trial (BEACON CRC). The BEACON CRC trial [see Clinical Studies (14.3)] excluded patients with history of Gilberts 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 CRCGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVIwith cetuximabN=216Irinotecan with cetuximab or FOLFIRI with cetuximabN=193All Grades(%)>=Grade 3Grade 4-5 adverse reactions in the BRAFTOVI with cetuximab arm were limited to Grade hemorrhage (n=1).(%)All Grades(%)>=Grade 3(%)General Disorders and Administration Site Conditions FatigueRepresents composite of multiple, related preferred terms. 517508 Pyrexia 171151Gastrointestinal Disorders Nausea341411 Diarrhea 3324810 Abdominal pain 304325 Vomiting211293 Constipation150181Metabolism and Nutrition Disorders Decreased appetite271273Musculoskeletal and Connective Tissue Disorders Arthralgia 27130 Myopathy 15140 Pain in extremity10010Skin and Subcutaneous Tissue Disorders Dermatitis acneiform 321433 Rash 260262 Pruritus 14060 Melanocytic nevus14000 Dry skin 130121Nervous System Disorders Headache 20030 Peripheral neuropathy 12160Vascular Disorders Hemorrhage 19290Psychiatric Disorders Insomnia 13060Other 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 CRCGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test.BRAFTOVIwith cetuximabIrinotecan with cetuximab or FOLFIRI with cetuximabAll Grades (%)Grades and (%)All Grades (%)Grades and (%)Hematology Anemia344485 Lymphopenia247355 Increased activated partial thromboplastin time13171Chemistry Hypomagnesemia190221 Increased alkaline phosphatase184307 Increased ALT170293 Increased AST151222 Hypokalemia123325 Hyponatremia112132BRAF 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). 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 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 PHAROSGrades per National Cancer Institute CTCAE v4.03. Adverse ReactionBRAFTOVIwith binimetinib N=98All Grades(%)Grades and 4One Grade adverse reaction of hemorrhage occurred.(%)General Disorders and Administration Site Conditions FatigueFatigue includes fatigue, asthenia. 618 EdemaEdema includes edema peripheral, generalized edema, swelling, localized edema, face edema. 231 Pyrexia220Gastrointestinal Disorders Nausea583.1 DiarrheaDiarrhea includes diarrhea, colitis. 527 Vomiting371 Abdominal painAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, epigastric discomfort. 321 Constipation270Eye Disorders Visual impairmentVisual impairment includes vision blurred, visual impairment, vitreous floaters, photophobia, visual acuity reduced, photopsia. 292Musculoskeletal and Connective Tissue Disorders Musculoskeletal painMusculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal chest pain, noncardiac chest pain, neck pain. 484.1Skin and Subcutaneous Tissue Disorders RashRash includes rash, rash macular, rash maculo-papular, rash papular, rash pustular, dermatitis acneiform, palmar-plantar erythrodysesthesia syndrome, eczema, skin exfoliation. 273.1 PruritisPruritis includes pruritus, pruritus genital. 160 Dry skin130 Alopecia120Respiratory, Thoracic and Mediastinal Disorders DyspneaDyspnea includes dyspnea, dyspnea exertional. 278 CoughCough includes cough, productive cough. 260Nervous System Disorders DizzinessDizziness includes dizziness, balance disorder. 171 Headache110Metabolism and Nutrition Disorders Decreased appetite141Vascular Disorders Hemorrhage Hemorrhage includes anal hemorrhage, hemothorax, gastrointestinal hemorrhage, hematochezia, hematuria, hemoptysis, hemorrhage intracranial, hyphema, small intestinal hemorrhage, upper gastrointestinal hemorrhage, vaginal hemorrhage. 124.1 Hypertension105Cardiac Disorders Left ventricular dysfunction/cardiomyopathyLeft ventricular dysfunction/cardiomyopathy includes ejection fraction decreased, cardiac failure, cardiac failure congestive. 111Investigations Weight increased111Psychiatric Disorders Insomnia100Other 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 BinimetinibGrades per National Cancer Institute CTCAE v4.03. Laboratory AbnormalityBased on the number of patients with available baseline and at least one on-treatment laboratory test.BRAFTOVI with binimetinibAll Grades(%)Grades and 4(%)Hematology Anemia4711 Lymphopenia246 Thrombocytopenia201.1 Leukopenia120 Neutropenia121.1Chemistry Increased creatinine913.2 Hyperglycemia486 Increased creatine kinase413.3 Lipase increased4014 Increased ALT349 Hypoalbuminemia320 Increased AST3110 Increased alkaline phosphatase313.2 Hyperkalemia312.1 Hyponatremia2611 Serum amylase increased221.1 Hypocalcemia122.1.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Encorafenib is kinase inhibitor. The chemical name is methyl N-(2S)-1-[(4-3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-ylpyrimidin-2-yl)amino]propan-2-ylcarbamate. The molecular formula is C22H27ClFN7O4S and the molecular weight is 540 daltons. The chemical structure of encorafenib is shown below:Encorafenib is white to almost white powder. In aqueous media, encorafenib is slightly soluble at pH 1, very slightly soluble at pH 2, and insoluble at pH and higher.BRAFTOVI (encorafenib) capsules for oral use contain 75 mg of encorafenib with the following inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. MelanomaoConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. (2.1)oThe recommended dose is 450 mg orally once daily in combination with binimetinib. (2.2)CRCoConfirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. (2.1)oThe recommended dose is 300 mg orally once daily in combination withobiweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) (2.3)oweekly cetuximab (2.3) NSCLCoConfirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI. (2.1)oThe recommended dose is 450 mg orally once daily in combination with binimetinib. (2.2)Take BRAFTOVI with or without food. (2.4). oConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. (2.1). oThe recommended dose is 450 mg orally once daily in combination with binimetinib. (2.2). oConfirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. (2.1). oThe recommended dose is 300 mg orally once daily in combination withobiweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) (2.3)oweekly cetuximab (2.3) obiweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) (2.3). oweekly cetuximab (2.3) oConfirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI. (2.1). oThe recommended dose is 450 mg orally once daily in combination with binimetinib. (2.2). 2.1 Patient Selection. BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic MelanomaConfirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.1)]. Information on FDA-authorized tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: http://www.fda.gov/CompanionDiagnostics.. BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)Confirm the presence of BRAF V600E mutation in plasma or tumor tissue prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.2 14.3)]. If no mutation is detected in plasma specimen, test tumor tissue. Information on FDA-authorized tests for the detection of BRAF V600E mutations in CRC is available at: http://www.fda.gov/CompanionDiagnostics.BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14.3) ]. If no mutation is detected in plasma specimen, test tumor tissue. Information on FDA-authorized tests for the detection of BRAF V600E mutations in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage for BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma and for BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC). The recommended dosage of BRAFTOVI is 450 mg (six 75 mg capsules) orally once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information.. 2.3 Recommended Dosage for BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC). The recommended dosage of BRAFTOVI is 300 mg (four 75 mg capsules) orally once daily until disease progression or unacceptable toxicity in combination with: obiweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or biweekly cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan)[see Clinical Studies (14.2)]oweekly cetuximab [see Clinical Studies (14.2)].. obiweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or biweekly cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan)[see Clinical Studies (14.2)]. oweekly cetuximab [see Clinical Studies (14.2)].. 2.4 Administration. BRAFTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take missed dose of BRAFTOVI within 12 hours of the next dose of BRAFTOVI.Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next scheduled dose.. 2.5 Dosage Modifications for Adverse Reactions. BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma or BRAF V600E Mutation-Positive Metastatic NSCLCIf binimetinib is withheld, reduce BRAFTOVI to maximum dose of 300 mg (four 75 mg capsules) once daily until binimetinib is resumed [see Warnings and Precautions (5.9) ].Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1.Table 1: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions Melanoma or NSCLCActionRecommended DoseFirst dose reduction300 mg (four 75 mg capsules) orally once dailySecond dose reduction225 mg (three 75 mg capsules) orally once dailySubsequent modificationPermanently discontinue if unable to tolerate BRAFTOVI 225 mg (three 75 mg capsules) once daily. BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC)When BRAFTOVI is administered in combination with cetuximab and mFOLFOX6 or FOLFIRIoContinue BRAFTOVI with mFOLFOX6 or FOLFIRI if cetuximab is permanently discontinued. oPermanently discontinue BRAFTOVI if cetuximab and mFOLFOX6 or FOLFIRI are permanently discontinued.When BRAFTOVI is administered in combination with cetuximaboPermanently discontinue BRAFTOVI when cetuximab is permanently discontinued.Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 2.Table 2: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions CRCActionRecommended DoseFirst dose reduction225 mg (three 75 mg capsules) orally once dailySecond dose reduction150 mg (two 75 mg capsules) orally once dailySubsequent modificationPermanently discontinue if unable to tolerate BRAFTOVI 150 mg (two 75 mg capsules) once daily. oContinue BRAFTOVI with mFOLFOX6 or FOLFIRI if cetuximab is permanently discontinued. oPermanently discontinue BRAFTOVI if cetuximab and mFOLFOX6 or FOLFIRI are permanently discontinued.. oPermanently discontinue BRAFTOVI when cetuximab is permanently discontinued.. BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma, BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (CRC), or BRAF V600E Mutation-Positive NSCLCDosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 3.Table 3: Recommended Dosage Modifications for BRAFTOVI for Adverse ReactionsSeverity of Adverse ReactionNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.Dose Modification for BRAFTOVINew Primary Malignancies [see Warnings and Precautions (5.1)]Noncutaneous RAS Mutation-positive MalignanciesPermanently discontinue BRAFTOVI.Cardiomyopathy [see Warnings and Precautions (5.3)]oSymptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLNReduce BRAFTOVI by one dose level [see Dosage and Administration (2.3)].oIf LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose [see Dosage and Administration (2.3)].oIf no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level.Hepatotoxicity [see Warnings and Precautions (5.4)]oGrade AST or ALT increasedMaintain BRAFTOVI dose. oIf no improvement within weeks, withhold BRAFTOVI until improves to Grade 0-1 or to pretreatment/baseline levels and then resume at same dose.oGrade or AST or ALT increasedSee Other Adverse Reactions. Uveitis [see Warnings and Precautions (5.6)]oGrade 1-3If Grade or does not respond to specific ocular therapy, or for Grade uveitis, withhold BRAFTOVI for up to weeks.oIf improved, resume at same or reduced dose.oIf not improved, permanently discontinue BRAFTOVI.o Grade 4Permanently discontinue BRAFTOVI.QTc Prolongation [see Warnings and Precautions (5.7)]oQTcF greater than 500 ms and less than or equal to 60 ms increase from baselineWithhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose.oIf more than one recurrence, permanently discontinue BRAFTOVI.oQTcF greater than 500 ms and greater than 60 ms increase from baselinePermanently discontinue BRAFTOVI.Dermatologic [Other than Hand-foot Skin Reaction (HFSR)] [see Adverse Reactions (6.1)]oGrade 2If no improvement within weeks, withhold BRAFTOVI until Grade 0-1. Resume at same dose.oGrade 3Withhold BRAFTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent.oGrade 4Permanently discontinue BRAFTOVI.Other Adverse Reactions (including Hemorrhage) [see Warnings and Precautions (5)] and HFSR [see Adverse Reactions (6.1)]Dose modification of BRAFTOVI when administered with binimetinib or with cetuximab is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism.oRecurrent Grade oroFirst occurrence of any Grade 3Withhold BRAFTOVI for up to weeks.oIf improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose.oIf no improvement, permanently discontinue BRAFTOVI.oFirst occurrence of any Grade 4Permanently discontinue BRAFTOVI orWithhold BRAFTOVI for up to weeks.oIf improves to Grade 0-1 or to pretreatment/baseline level, then resume at reduced dose.oIf no improvement, permanently discontinue BRAFTOVI.oRecurrent Grade 3Consider permanently discontinuing BRAFTOVI.oRecurrent Grade 4Permanently discontinue BRAFTOVI.Refer to the binimetinib or cetuximab prescribing information for dose modifications for adverse reactions associated with each product, as appropriate. oSymptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN. oIf LVEF improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline, continue BRAFTOVI at the reduced dose [see Dosage and Administration (2.3)].. oIf no improvement, withhold BRAFTOVI until improves to at least institutional LLN and absolute decrease to less than or equal to 10% compared to baseline and then resume at the reduced dose or reduce dose an additional dose level.. oGrade AST or ALT increased. oIf no improvement within weeks, withhold BRAFTOVI until improves to Grade 0-1 or to pretreatment/baseline levels and then resume at same dose.. oGrade or AST or ALT increased. oGrade 1-3. oIf improved, resume at same or reduced dose.. oIf not improved, permanently discontinue BRAFTOVI.. Grade 4. oQTcF greater than 500 ms and less than or equal to 60 ms increase from baseline. oIf more than one recurrence, permanently discontinue BRAFTOVI.. oQTcF greater than 500 ms and greater than 60 ms increase from baseline. oGrade 2. oGrade 3. oGrade 4. oRecurrent Grade or. oFirst occurrence of any Grade 3. oIf improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose.. oIf no improvement, permanently discontinue BRAFTOVI.. oFirst occurrence of any Grade 4. oIf improves to Grade 0-1 or to pretreatment/baseline level, then resume at reduced dose.. oIf no improvement, permanently discontinue BRAFTOVI.. oRecurrent Grade 3. oRecurrent Grade 4. 2.6 Dose Modifications for Coadministration with Strong or Moderate CYP3A4 Inhibitors. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce the BRAFTOVI dose according to the recommendations in Table 4. After the inhibitor has been discontinued for to elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Table 4: Recommended Dose Reductions for BRAFTOVI for Coadministration with Strong or Moderate CYP3A4 InhibitorsCurrent Daily DoseCurrent daily dose refers to recommended dose of BRAFTOVI based on indication or reductions for adverse reactions based on dosing recommendations in Table (Melanoma) and Table (CRC).Dose for Coadministration with Moderate CYP3A4 InhibitorDose for Coadministration with Strong CYP3A4 Inhibitor450 mg225 mg (three 75 mg capsules)150 mg (two 75 mg capsules)300 mg150 mg (two 75 mg capsules)75 mg225 mg75 mg75 mg150 mg75 mg75 mgEncorafenib exposure at the 75 mg QD BRAFTOVI dosage when coadministered with strong CYP3A4 inhibitor is expected to be higher than at the 150 mg QD dosage in the absence of CYP3A4 inhibitor and similar to exposure at the 225 mg QD dosage in the absence of CYP3A4 inhibitor. Monitor patients closely for adverse reactions and use clinical judgment when using BRAFTOVI with strong CYP3A4 inhibitors at the 150 mg dose level.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Capsules: 75 mg, hard gelatin, stylized A on beige cap and LGX 75mg on white body.. Capsules: 75 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oStrong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. (2.6, 7.1)oStrong CYP3A4 inducers: Avoid coadministration. (7.1)oSensitive CYP3A4 substrates: Avoid coadministration with CYP3A4 substrates (including hormonal contraceptives) for which decrease in plasma concentration may lead to reduced efficacy of the substrate. (7.2)oTransporters: Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. (7.2, 12.3). oStrong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. (2.6, 7.1). oStrong CYP3A4 inducers: Avoid coadministration. (7.1). oSensitive CYP3A4 substrates: Avoid coadministration with CYP3A4 substrates (including hormonal contraceptives) for which decrease in plasma concentration may lead to reduced efficacy of the substrate. (7.2). oTransporters: Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. (7.2, 12.3). 7.1 Effect of Other Drugs on BRAFTOVI. Strong or Moderate CYP3A4 InhibitorsCoadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitor increases encorafenib plasma concentrations [see Clinical Pharmacology (12.3)] and may increase encorafenib adverse reactions. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose [see Dosage and Administration (2.6)].. Strong CYP3A4 InducersCoadministration of BRAFTOVI with strong CYP3A4 inducer may decrease encorafenib plasma concentrations [see Clinical Pharmacology (12.3)] and may decrease encorafenib efficacy. Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.. 7.2 Effect of BRAFTOVI on Other Drugs. Sensitive CYP3A4 SubstratesBRAFTOVI is strong CYP3A4 inducer at steady-state. Concomitant use of BRAFTOVI may decrease the plasma concentrations of CYP3A4 substrates (including hormonal contraceptives), [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. Avoid the coadministration of BRAFTOVI with CYP3A4 substrates for which decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations.. OATP1B1, OATP1B3, or BCRP SubstratesCoadministration of BRAFTOVI with OATP1B1, OATP1B3, or BCRP substrates can result in increased concentrations of the substrates, and may increase toxicity of these agents. When used in combination, monitor patients closely for signs and symptoms of increased exposure and consider adjusting the dose of these substrates [see Clinical Pharmacology (12.3)]. 7.3 Drugs That Prolong the QT Interval. BRAFTOVI is associated with dose-dependent QTc interval prolongation [see Warnings and Precautions (5.7) Clinical Pharmacology (12.2)]. Avoid coadministration of BRAFTOVI with drugs known to prolong the QT/QTc interval.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. BRAFTOVI can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in Specific Populations (8.1)]. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for weeks after the last dose. Counsel patients to use nonhormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].. Infertility. MalesBased on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI in combination with binimetinib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Studies (14.1)].Of the 232 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and mFOLFOX6, 84 (36%) were 65 years of age and over and 16 (7%) were 75 years of age and over [see Clinical Studies (14.2)].Of the 71 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and FOLFIRI, 35 (49%) were 65 years of age and over and (13%) were 75 years of age and over [see Clinical Studies (14.2)].Of the 216 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies (14.2) ].Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies (14.3) ].No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib, BRAFTOVI plus cetuximab, or BRAFTOVI plus cetuximab and mFOLFOX6 or FOLFIRI were observed in older patients as compared to younger patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. No BRAFTOVI dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)]. recommended dosage has not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. BRAFTOVI (encorafenib) is supplied as 75 mg hard gelatin capsules.75 mg: stylized A on beige cap and LGX 75mg on white body, available in cartons (NDC 70255-025-01) containing two bottles of 90 capsules each (NDC 70255-025-02) and cartons (NDC 70255-025-03) containing two bottles of 60 capsules each (NDC 70255-025-04).. Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BRAFTOVI is kinase inhibitor indicated:Melanomaoin combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-authorized test. (1.1, 2.1)Colorectal Cancer (CRC)oin combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation, as detected by an FDA-authorized test. (1.2, 2.1)oin combination with cetuximab, for the treatment of adult patients with mCRC with BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy. (1.2, 2.1)Non-Small Cell Lung Cancer (NSCLC)oin combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-authorized test. (1.3, 2.1)Limitations of UseBRAFTOVI 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). oin combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-authorized test. (1.1, 2.1). oin combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation, as detected by an FDA-authorized test. (1.2, 2.1). oin combination with cetuximab, for the treatment of adult patients with mCRC with BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy. (1.2, 2.1). oin combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation, as detected by an FDA-authorized test. (1.3, 2.1). 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 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). oBRAFTOVI is indicated, in combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1)]. oBRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy [see Dosage and Administration (2.1)]. oBRAFTOVI is indicated, in combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1)]. oBRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with 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 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-authorized patient labeling (Medication Guide).Inform patients of the following:. New Primary MalignanciesAdvise patients that BRAFTOVI increases the risk of developing new primary cutaneous and noncutaneous malignancies. Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions [see Warnings and Precautions (5.1)].Tumor Promotion in BRAF Wild-Type TumorsAdvise patients of the need to confirm BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Warnings and Precautions (5.2)].CardiomyopathyAdvise patients to report any symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3)].HepatotoxicityAdvise patients that serial testing of serum liver tests (ALT, AST, bilirubin) is recommended during treatment with BRAFTOVI. Instruct patients to report symptoms of liver dysfunction including jaundice, dark urine, nausea, vomiting, loss of appetite, fatigue, bruising, or bleeding [see Warnings and Precautions (5.4)].. HemorrhageAdvise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding [see Warnings and Precautions (5.5) ].. UveitisAdvise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6) ].. QT ProlongationAdvise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.7) ].. Embryo-Fetal ToxicityoAdvise females with reproductive potential of the potential risk to fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BRAFTOVI [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].oAdvise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for weeks after the last dose [see Use in Specific Populations (8.3)].. oAdvise females with reproductive potential of the potential risk to fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BRAFTOVI [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].. oAdvise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for weeks after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with BRAFTOVI and for weeks after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential that BRAFTOVI may impair fertility [see Use in Specific Populations (8.3)].. Drug InteractionsCoadministration of BRAFTOVI with strong or moderate CYP3A inhibitor may increase encorafenib concentrations; coadministration of BRAFTOVI with strong CYP3A inducer may decrease encorafenib concentrations. Advise patients that they may need to avoid certain medications while taking BRAFTOVI and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit and grapefruit juice while taking BRAFTOVI [see Drug Interactions (7.1)].. StorageBRAFTOVI is moisture sensitive. Advise patients to store BRAFTOVI in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and for weeks after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Encorafenib is kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduce ligand binding to these kinases at clinically achievable concentrations (<=0.9 uM).Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression.Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone.In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as mechanism of resistance to BRAF inhibitors. Combinations of BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of encorafenib and cetuximab had an anti-tumor effect greater than either drug alone, in mouse model of colorectal cancer with mutated BRAF V600E.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats.No dedicated fertility studies were performed with encorafenib in animals. In general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the nonhuman primate toxicity studies.. 13.2 Animal Toxicology and/or Pharmacology. Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both and 13-week studies.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with BRAFTOVI.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 75 mg Capsule Bottle Label 025-02. DISPENSE THE ENCLOSED MEDICATION GUIDE TO EACH PATIENTNDC 70255-025-02BRAFTOVI(R) (encorafenib) capsules75 mgRx only90 Capsules. PRINCIPAL DISPLAY PANEL 75 mg Capsule Bottle Label 025-02.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyA dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation. Based on central tendency analysis of QTc in study of adult patients with melanoma who received the recommended dose of BRAFTOVI in combination with binimetinib, the largest mean (90% CI) QTcF change from baseline (QTcF) was 18 (14 to 22) ms [see Warnings and Precautions (5.7) ].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring BRAF V600E or V600K mutation, BRAF V600E mutation-positive metastatic CRC. After single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg (0.1 to 1.6 times the maximum recommended dose of 450 mg). After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg (0.1 to 1.8 times the maximum recommended dose of 450 mg). Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%.. AbsorptionThe median Tmax of encorafenib is hours. At least 86% of the dose is absorbed.. Effect of FoodFollowing administration of single dose of BRAFTOVI 100 mg (0.2 times the maximum recommended dose of 450 mg) with high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) the mean maximum encorafenib concentration (Cmax) decreased by 36% and there was no effect on AUC.. DistributionThe geometric mean (CV%) of apparent volume of distribution is 164 (70%). The protein binding of encorafenib is 86% in vitro. The blood-to-plasma concentration ratio is 0.58. EliminationThe mean (CV%) terminal half-life (t1/2) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state at the maximum recommended dose of 450 mg.. MetabolismEncorafenib is primarily metabolized by CYP3A4 (83%) and to lesser extent by CYP2C19 (16%) and CYP2D6 (1%).. ExcretionFollowing single radiolabeled dose of 100 mg encorafenib, 47% (5% unchanged) of the administered dose was recovered in feces and 47% (2% unchanged) in urine.. Specific PopulationsNo clinically significant differences in the pharmacokinetics of encorafenib were observed based on age (19 to 94 years), sex, body weight (34 to 168 kg), mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to <90 mL/min). The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class or C), and severe renal impairment (CLcr <30 mL/min) on encorafenib pharmacokinetics have not been studied.. Drug Interaction Studies. Clinical Studies. CYP3A4 Inhibitors: Coadministration of posaconazole (strong CYP3A4 inhibitor) or diltiazem (moderate CYP3A4 inhibitor) increased AUC of encorafenib by 183% and 83%, respectively, and increased Cmax by 68% and 45%, respectively, after single dose of 50 mg BRAFTOVI (0.1 times the maximum recommended dose of 450 mg).. Strong CYP3A4 Inducers: The effect of strong CYP3A4 inducer on encorafenib exposure has not been studied [see Drug Interactions (7.1)].Moderate CYP3A4 Inducers: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with modafinil, moderate CYP3A4 inducer, decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to BRAFTOVI alone.Effect of encorafenib on CYP3A4 Substrates: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with single dose of midazolam mg, sensitive CYP3A4 substrate, decreased midazolam AUC by 82% and Cmax by 74% relative to midazolam mg alone.Effect of encorafenib on Other CYP Substrates: There was no clinically significant effect of repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily on the exposure of substrates of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6.. Proton Pump Inhibitors: No clinically significant differences in encorafenib pharmacokinetics were observed when coadministered with rabeprazole.. Binimetinib: No clinically significant differences in the pharmacokinetics of binimetinib (UGT1A1 substrate) were observed when coadministered with BRAFTOVI (UGT1A1 inhibitor). Oxaliplatin: No clinically significant differences in the pharmacokinetics of oxaliplatin were observed when BRAFTOVI 300 mg once daily was coadministered with mFOLFOX6.. Irinotecan: No clinically significant differences in the pharmacokinetics of irinotecan or SN-38 were observed when repeat dose BRAFTOVI 300 mg once daily was coadministered with FOLFIRI.Transporters: Repeat dose administration of BRAFTOVI 450 mg once daily and binimetinib 45 mg twice daily with single dose of rosuvastatin (a sensitive substrate for OATP1B1, OATP1B3, and BCRP) increased rosuvastatin Cmax by 168% and AUC by 57%.. In Vitro Studies. CYP/UGT Enzymes: Encorafenib is reversible inhibitor of UGT1A1.. Transporters: Encorafenib is substrate of P-glycoprotein (P-gp) but not of breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations.Encorafenib is an inhibitor of P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not of OCT1 or MRP2 at clinically relevant plasma concentrations.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, BRAFTOVI can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of BRAFTOVI during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data). Advise pregnant women and females of reproductive potential of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1.2)2/2026 Dosage and Administration (2.1, 2.3, 2.5)2/2026Warnings and Precautions (5.1, 5.4, 5.5, 5.6, 5.7, 5.10)2/2026.

RENAL IMPAIRMENT SUBSECTION.

8.7 Renal Impairment. No BRAFTOVI dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. recommended dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min).

SPL MEDGUIDE SECTION.

MEDICATION GUIDEBRAFTOVI(R) (braf-TOE-vee)(encorafenib)capsulesImportant 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 should know about BRAFTOVIBRAFTOVI 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:onew wartoskin sore or reddish bump that bleeds or does not healochange in size or color of moleYour healthcare provider should check your skin before treatment with BRAFTOVI, every months during treatment, and for up to 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 BRAFTOVIBRAFTOVI is prescription medicine used:oin combination with medicine called binimetinib to treat people with type of skin cancer called melanoma: othat has spread to other parts of the body or cannot be removed by surgery, andothat has certain type of abnormal BRAF geneoin 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):othat has spread to other parts of the body, andothat has certain type of abnormal BRAF geneoin combination with medicine called cetuximab to treat adults with cancer of the colon or rectum (colorectal cancer) after past treatment:othat has spread to other parts of the body, andothat has certain type of abnormal BRAF geneoin combination with medicine called binimetinib to treat adults with type of lung cancer called non-small-cell lung cancer (NSCLC): othat has spread to other parts of the body, and othat has 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 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:ohave had bleeding problems ohave eye problems ohave heart problems, including condition called long QT syndromeohave been told that you have low blood levels of potassium, calcium, or magnesiumohave liver or kidney problems oare pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby. Females who are able to become pregnant: oUse effective nonhormonal birth control (contraception) during treatment with BRAFTOVI and for 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. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do 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. oare 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 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 list of them to show your healthcare provider and pharmacist when you get new medicine.How should take BRAFTOVI oTake BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking BRAFTOVI unless your healthcare provider tells you to. oTake BRAFTOVI by mouth time each day.oBRAFTOVI may be taken with or without food.oAvoid grapefruit and grapefruit juice during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in your body.oIf you miss 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. oDo not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time. oIf 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: oSee What is the most important information should know about BRAFTOVIoHeart 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 heart problem: ofeeling like your heart is pounding or racing oshortness of breathoswelling in your hands, ankles legs or feet ofeeling faint or lightheadedoLiver 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 liver problem:oyellowing of your skin or your eyesodark or brown (tea-colored) urine onausea or vomitingoloss of appetiteotirednessobruisingobleedingoBleeding 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:oheadaches, dizziness, or feeling weakocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsored or black stools that look like taronose bleeds oEye 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: oblurred vision, loss of vision, or other vision changesosee colored dots osee halos (blurred outline around objects)oeye pain, swelling, or redness oChanges 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: ofatigueonauseaovomitingoabdominal painopain 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:onumbness, tingling or burning in your hands or feet (peripheral neuropathy)onauseaofatigueodiarrheaodecreased appetiteorashovomitingobleeding (hemorrhage)ostomach-area (abdominal) painopain or swelling of your joints (arthralgia)ofeveroconstipationThe most common side effects of BRAFTOVI when taken in combination with cetuximab and FOLFIRI for colorectal cancer include:onauseaodiarrheaofatigueovomitingohair loss (alopecia)oconstipationostomach-area (abdominal) painodecreased appetite orash The most common side effects of BRAFTOVI when taken in combination with cetuximab for colorectal cancer include:ofatigueonauseaodiarrheaoacne-like rash (dermatitis acneiform)ostomach-area (abdominal) painodecreased appetiteopain or swelling of your joints (arthralgia)orashThe most common side effects of BRAFTOVI when taken in combination with binimetinib for NSCLC include: ofatigueonauseaodiarrheaomuscle or joint painovomitingostomach-area (abdominal) painoblurred vision, loss of vision, or other vision changes oconstipationoshortness of breathorashocoughBRAFTOVI may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if this is 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 store BRAFTOVI oStore BRAFTOVI at room temperature between 68F to 77F (20C to 25C).oStore BRAFTOVI in the original bottle.oKeep the BRAFTOVI bottle tightly closed and protect it from moisture. oBRAFTOVI comes with 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 Medication Guide. Do not use BRAFTOVI for 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 BRAFTOVIActive 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., wholly owned subsidiary of Pfizer Inc. Boulder, Colorado 80301.BRAFTOVI(R) is registered trademark of Array BioPharma Inc. in the United States and various other countries.LAB-1429-5.0For more information, go to www.braftovi.com or call 1-844-792-7729.(C) 2024 Array BioPharma Inc. All rights reserved. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 02/2026. onew wart. oskin sore or reddish bump that bleeds or does not heal. ochange in size or color of mole. oin combination with medicine called binimetinib to treat people with type of skin cancer called melanoma: othat has spread to other parts of the body or cannot be removed by surgery, andothat has certain type of abnormal BRAF gene. othat has spread to other parts of the body or cannot be removed by surgery, and. othat has certain type of abnormal BRAF gene. oin 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):othat has spread to other parts of the body, andothat has certain type of abnormal BRAF gene. othat has spread to other parts of the body, and. othat has certain type of abnormal BRAF gene. oin combination with medicine called cetuximab to treat adults with cancer of the colon or rectum (colorectal cancer) after past treatment:othat has spread to other parts of the body, andothat has certain type of abnormal BRAF gene. othat has spread to other parts of the body, and. othat has certain type of abnormal BRAF gene. oin combination with medicine called binimetinib to treat adults with type of lung cancer called non-small-cell lung cancer (NSCLC): othat has spread to other parts of the body, and othat has certain type of abnormal BRAF gene othat has spread to other parts of the body, and othat has certain type of abnormal BRAF gene. ohave had bleeding problems ohave eye problems ohave heart problems, including condition called long QT syndrome. ohave been told that you have low blood levels of potassium, calcium, or magnesium. ohave liver or kidney problems oare pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby. Females who are able to become pregnant:. oUse effective nonhormonal birth control (contraception) during treatment with BRAFTOVI and for 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. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do 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. oUse effective nonhormonal birth control (contraception) during treatment with BRAFTOVI and for 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. oTalk to your healthcare provider about birth control methods that may be right for you during this time. oYour healthcare provider will do 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. oare 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 weeks after the last dose of BRAFTOVI. Talk to your healthcare provider about the best way to feed your baby during this time. oTake BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking BRAFTOVI unless your healthcare provider tells you to. oTake BRAFTOVI by mouth time each day.. oBRAFTOVI may be taken with or without food.. oAvoid grapefruit and grapefruit juice during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in your body.. oIf you miss 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. oDo not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time. oIf 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. oSee What is the most important information should know about BRAFTOVI. oHeart 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 heart problem: ofeeling like your heart is pounding or racing oshortness of breathoswelling in your hands, ankles legs or feet ofeeling faint or lightheaded. ofeeling like your heart is pounding or racing oshortness of breath. oswelling in your hands, ankles legs or feet ofeeling faint or lightheaded. oLiver 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 liver problem:. oyellowing of your skin or your eyes. odark or brown (tea-colored) urine onausea or vomiting. oloss of appetite. otiredness. obruising. obleeding. oBleeding 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:oheadaches, dizziness, or feeling weakocough up blood or blood clotsovomit blood or your vomit looks like coffee groundsored or black stools that look like taronose bleeds oheadaches, dizziness, or feeling weak. ocough up blood or blood clots. ovomit blood or your vomit looks like coffee grounds. ored or black stools that look like tar. onose bleeds. oEye 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: oblurred vision, loss of vision, or other vision changesosee colored dots osee halos (blurred outline around objects)oeye pain, swelling, or redness oblurred vision, loss of vision, or other vision changes. osee colored dots osee halos (blurred outline around objects). oeye pain, swelling, or redness. oChanges 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. ofatigue. onausea. ovomiting. oabdominal pain. opain or swelling of your joints (arthralgia). onumbness, tingling or burning in your hands or feet (peripheral neuropathy). onausea. ofatigue. odiarrhea. odecreased appetite. orash. ovomiting. obleeding (hemorrhage). ostomach-area (abdominal) pain. opain or swelling of your joints (arthralgia). ofever. oconstipation. onausea. odiarrhea. ofatigue. ovomiting. ohair loss (alopecia). oconstipation. ostomach-area (abdominal) pain. odecreased appetite orash ofatigue. onausea. odiarrhea. oacne-like rash (dermatitis acneiform). ostomach-area (abdominal) pain. odecreased appetite. opain or swelling of your joints (arthralgia). orash. ofatigue. onausea. odiarrhea. omuscle or joint pain. ovomiting. ostomach-area (abdominal) pain. oblurred vision, loss of vision, or other vision changes oconstipation. oshortness of breath. orash. ocough. oStore BRAFTOVI at room temperature between 68F to 77F (20C to 25C).. oStore BRAFTOVI in the original bottle.. oKeep the BRAFTOVI bottle tightly closed and protect it from moisture. oBRAFTOVI comes with desiccant packet in the bottle to help protect your medicine from moisture. Do not remove the desiccant packet from the bottle.

SPL UNCLASSIFIED SECTION.

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 BRAF V600E or V600K mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1)].

STORAGE AND HANDLING SECTION.

Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Advise not to breastfeed. (8.2)oMales of Reproductive Potential: BRAFTOVI may impair fertility. (8.3). oLactation: Advise not to breastfeed. (8.2). oMales of Reproductive Potential: BRAFTOVI may impair fertility. (8.3). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, BRAFTOVI can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of BRAFTOVI during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data). Advise pregnant women and females of reproductive potential of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentration-time curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure.. 8.2 Lactation. Risk SummaryThere are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and for weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. BRAFTOVI can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in Specific Populations (8.1)]. ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for weeks after the last dose. Counsel patients to use nonhormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)].. Infertility. MalesBased on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of BRAFTOVI have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI in combination with binimetinib across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older [see Clinical Studies (14.1)].Of the 232 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and mFOLFOX6, 84 (36%) were 65 years of age and over and 16 (7%) were 75 years of age and over [see Clinical Studies (14.2)].Of the 71 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab and FOLFIRI, 35 (49%) were 65 years of age and over and (13%) were 75 years of age and over [see Clinical Studies (14.2)].Of the 216 patients with BRAF V600E mutation-positive metastatic CRC who received BRAFTOVI in combination with cetuximab, 62 (29%) were 65 years of age to up to 75 years of age, while 20 (9%) were 75 years of age and over [see Clinical Studies (14.2) ].Of the 98 patients with BRAF V600E mutation-positive metastatic NSCLC who received BRAFTOVI with binimetinib, 62 (63%) were 65 years of age and over and 20 (20%) were 75 years and over [see Clinical Studies (14.3) ].No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib, BRAFTOVI plus cetuximab, or BRAFTOVI plus cetuximab and mFOLFOX6 or FOLFIRI were observed in older patients as compared to younger patients.. 8.6 Hepatic Impairment. No BRAFTOVI dosage adjustment is recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)]. recommended dosage has not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.. 8.7 Renal Impairment. No BRAFTOVI dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. recommended dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNew Primary Malignancies, cutaneous and noncutaneous: Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. (5.1)oTumor Promotion in BRAF Wild-Type Tumors: Increased cell proliferation can occur with BRAF inhibitors. (5.2)oCardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment with BRAFTOVI and binimetinib, and after one month of treatment, then every to months thereafter. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with LVEF below 50%. (5.3)oHepatotoxicity: Monitor liver function tests before and during treatment with BRAFTOVI and binimetinib and as clinically indicated. (5.4)oHemorrhage: Major hemorrhagic events can occur in patients receiving BRAFTOVI and binimetinib. (5.5)oUveitis: Perform ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.6)oQT Prolongation: Monitor electrolytes before and during treatment. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater. (5.7)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective nonhormonal method of contraception. (5.8, 8.1, 8.3)oRisks Associated with BRAFTOVI as Single Agent: If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. (5.9)oRisks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of regimen in combination with binimetinib or cetuximab. (5.10). oNew Primary Malignancies, cutaneous and noncutaneous: Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. (5.1). oTumor Promotion in BRAF Wild-Type Tumors: Increased cell proliferation can occur with BRAF inhibitors. (5.2). oCardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment with BRAFTOVI and binimetinib, and after one month of treatment, then every to months thereafter. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with LVEF below 50%. (5.3). oHepatotoxicity: Monitor liver function tests before and during treatment with BRAFTOVI and binimetinib and as clinically indicated. (5.4). oHemorrhage: Major hemorrhagic events can occur in patients receiving BRAFTOVI and binimetinib. (5.5). oUveitis: Perform ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.6). oQT Prolongation: Monitor electrolytes before and during treatment. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater. (5.7). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective nonhormonal method of contraception. (5.8, 8.1, 8.3). oRisks Associated with BRAFTOVI as Single Agent: If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. (5.9). oRisks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of regimen in combination with binimetinib or cetuximab. (5.10). 5.1 New Primary Malignancies. New primary malignancies, cutaneous and noncutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI.. Cutaneous MalignanciesIn COLUMBUS, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuSCC/KA was 5.8 months (range to months) [see Adverse Reactions (6.1)].For patients who received BRAFTOVI as single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and new primary melanoma in 5% of patients.In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab. In PHAROS, cuSCC and skin papilloma, each occurred in 2% of patients who received BRAFTOVI in combination with binimetinib. In BREAKWATER, the following cutaneous malignancies occurred in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6: melanocytic nevus in 5.6%, skin papilloma in 3%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4%. In patients who received BRAFTOVI in combination with cetuximab and FOLFIRI, skin papilloma occurred in 2.8% and keratoacanthoma in 1.4% of patients. Perform dermatologic evaluations prior to initiating treatment, every months during treatment, and for up to months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies.. Noncutaneous MalignanciesBased on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving BRAFTOVI for signs and symptoms of noncutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive noncutaneous malignancies [see Dosage and Administration (2.5)].. 5.2 Tumor Promotion in BRAF Wild-Type Tumors. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Indications and Usage (1), Dosage and Administration (2.1)].. 5.3 Cardiomyopathy. Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, evidence of cardiomyopathy (decreased in LVEF below the institutional LLN with an absolute decreased in LVEF >=10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving BRAFTOVI plus binimetinib. Grade left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving BRAFTOVI in combination with binimetinib was 3.6 months (range to 21 months). Cardiomyopathy resolved in 87% of patients receiving BRAFTOVI plus binimetinib.In PHAROS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >=10% below baseline as detected by echocardiography or MUGA) occurred in 11% of patients receiving BRAFTOVI in combination with binimetinib. Grade left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients receiving BRAFTOVI plus binimetinib. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and every to months during treatment. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with BRAFTOVI.Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.4 Hepatotoxicity. Hepatotoxicity can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, the incidence of Grade or increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. In PHAROS, the incidence of Grade or increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with binimetinib was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase. In BREAKWATER, the incidence of Grade or increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.6% for alkaline phosphatase, and 1.3% each for ALT and AST. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, the incidence of Grade or increases in liver function laboratory tests was 1.5% each for ALT and AST.Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)].. 5.5 Hemorrhage. In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; Grade or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients.In BEACON CRC, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%).In PHAROS, hemorrhage occurred in 12% of patients receiving BRAFTOVI in combination with binimetinib including fatal hemorrhage intracranial (1%); Grade or hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each). In BREAKWATER, hemorrhage occurred in 34% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade or hemorrhage occurred in 3% of patients. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, hemorrhage occurred in 21% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].. 5.6 Uveitis. Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%. In PHAROS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 1%. In BREAKWATER, the incidence of uveitis among patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6 was 0.4%. Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.5), Adverse Reactions (6.1)].. 5.7 QT Prolongation. BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology (12.2)]. In COLUMBUS, an increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. In PHAROS, an increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI in combination with binimetinib.In BREAKWATER, an increase of QTcF >500 ms was measured in 4% (9/226) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. In patients receiving BRAFTOVI in combination with cetuximab and FOLFIRI, an increase of QTcF >500 ms was measured in 1.5% (1/65) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms [see Dosage and Administration (2.5), Adverse Reactions (6.1)].. 5.8 Embryo-Fetal Toxicity. Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses.Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use an effective, nonhormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for weeks after the last dose of BRAFTOVI [see Use in Specific Populations (8.1, 8.3)].. 5.9 Risks Associated with BRAFTOVI as Single Agent BRAFTOVI when used as single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. In COLUMBUS, Grades or dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended [see Dosage and Administration (2.5)].. 5.10 Risks Associated with Combination Treatment BRAFTOVI is indicated for use as part of regimen in combination with binimetinib, in combination with cetuximab, in combination with cetuximab and mFOLFOX6 or FOLFIRI. Refer to the prescribing information for binimetinib, cetuximab and individual product components of mFOLFOX6 and FOLFIRI for additional risk information.