WARNINGS AND PRECAUTIONS

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. Perform dermatopathologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.

• BRAF-mutant type (BRAF-mt) metastatic melanoma (COLUMBUS trial): Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. Median time to first occurrence of cuSCC/KA was 5.8 months.
• BRAF-mt metastatic CRC (BEACON CRC trial): cuSCC, including KA, occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI with cetuximab.
• BRAF-mt metastatic NSCLC (PHAROS trial): cuSCC and skin papilloma (SP), each occurred in 2% of patients.

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 exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.

Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported. Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

• Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment.
• The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN).
• BRAF-mt metastatic melanoma (COLUMBUS trial): Evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients.
• BRAF-mt metastatic NSCLC (PHAROS trial): Evidence of cardiomyopathy occurred in 11% and Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients.

• BRAF-mt metastatic melanoma (COLUMBUS trial): The incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI with BRAFTOVI was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase.
• BRAF-mt metastatic NSCLC (PHAROS trial): The incidence of Grade 3 or 4 increases in liver function laboratory tests was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with MEKTOVI and Grade 3 or higher 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.
• BRAF-mt metastatic CRC (BEACON CRC trial): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with cetuximab; Grade 3 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%).
• BRAF-mt metastatic NSCLC (PHAROS trial): Hemorrhage occurred in 12% of patients, including fatal intracranial hemorrhage (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).

• BRAF-mt metastatic melanoma (COLUMBUS trial): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 4%.
• BRAF-mt metastatic NSCLC (PHAROS trial): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 1%.

• BRAF-mt metastatic melanoma (COLUMBUS trial): An increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI with MEKTOVI.
• BRAF-mt metastatic NSCLC (PHAROS trial): An increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI with MEKTOVI.

• BRAF-mt metastatic melanoma (COLUMBUS trial) and BRAF-mt metastatic NSCLC (PHAROS trial): Effective, non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI with MEKTOVI.
• BRAF-mt metastatic CRC (BEACON CRC trial): Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Grades 3 or 4 dermatologic reactions occurred in 21% of patients receiving BRAFTOVI as a single agent compared to 2% in patients receiving the combination of BRAFTOVI with MEKTOVI.
• If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

• In BRAF-mt metastatic melanoma (COLUMBUS trial), BRAFTOVI is used in combination with MEKTOVI so refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.
• In BRAF-mt metastatic CRC (BEACON CRC trial), BRAFTOVI is used in combination with cetuximab so refer to the prescribing information for cetuximab for additional risk information.
• In BRAF-mt metastatic NSCLC (PHAROS trial), BRAFTOVI is indicated for use as part of a regimen in combination with MEKTOVI, so refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.

• Serous retinopathy
  • Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, 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.
  • BRAF-mt metastatic melanoma (COLUMBUS trial): serous retinopathy occurred in 20% of patients receiving MEKTOVI with BRAFTOVI; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months.
  • BRAF-mt metastatic NSCLC (PHAROS trial): serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness.
• Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients receiving MEKTOVI with BRAFTOVI. In BRAF-mt metastatic melanoma (COLUMBUS trial), 1 patient experienced RVO (0.1%) in the MEKTOVI with BRAFTOVI group (n=690).
  • The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO, including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.
  • Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Elevation of laboratory values of serum CPK occurred in 58% of patients receiving MEKTOVI with BRAFTOVI. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI.
• BRAF-mt metastatic NSCLC (PHAROS trial): Elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients. No patient experienced rhabdomyolysis.

• Most common adverse reactions (≥20%, all grades) for patients receiving BRAFTOVI with MEKTOVI compared to vemurafenib were fatigue (43% vs 46%), nausea (41% vs 34%), diarrhea (36% vs 34%), vomiting (30% vs 16%), abdominal pain (28% vs 16%), arthralgia (26% vs 46%), myopathy (23% vs 22%), hyperkeratosis (23% vs 49%), rash (22% vs 53%), headache (22% vs 20%), constipation (22% vs 6%), visual impairment (20% vs 4%), serous retinopathy/RPED (20% vs 2%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were facial paresis, pancreatitis, panniculitis, drug hypersensitivity, and colitis.
• Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI with MEKTOVI compared to vemurafenib included increased creatinine (93% vs 92%), increased CPK (58% vs 3.8%), increased gamma glutamyl transferase (GGT) (45% vs 34%), anemia (36% vs 34%), increased ALT (29% vs 27%), hyperglycemia (28% vs 20%), increased AST (27% vs 24%), and increased alkaline phosphatase (21% vs 35%).

• Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with cetuximab compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with cetuximab was pancreatitis.
• Most common laboratory abnormalities (≥20%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%).

• Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with MEKTOVI were fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), visual impairment (29%), constipation (27%), dyspnea (27%), rash (27%), and cough (26%).
• Serious adverse reactions occurred in 38% of patients receiving BRAFTOVI with MEKTOVI. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%).
• Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were peripheral neuropathy, dysgeusia, facial paresis, pancreatitis, hyperkeratosis, erythema, and drug hypersensitivity.
• Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI and MEKTOVI included increased creatinine (91%), hyperglycemia (48%), anemia (47%), increased creatine kinase (41%), lipase increased (40%), increased ALT (34%), hypoalbuminemia (32%), increased alkaline phosphatase (31%), increased AST (31%), hyperkalemia (31%), hyponatremia (26%), lymphopenia (24%), serum amylase increased (22%), and thrombocytopenia (20%).

• Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose.
• Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.
• Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a 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.
• Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.
• Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.

BRAFTOVI® (encorafenib) is indicated, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

BRAFTOVI and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

BRAFTOVI and MEKTOVI are kinase inhibitors indicated for use in combination for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

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.

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. Perform dermatopathologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment.

• BRAF-mutant type (BRAF-mt) metastatic melanoma (COLUMBUS trial): Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. Median time to first occurrence of cuSCC/KA was 5.8 months.

• BRAF-mt metastatic CRC previously untreated (BREAKWATER trial): skin papilloma was reported in 2.6%, 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% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.

• BRAF-mt metastatic CRC previously treated (BEACON CRC trial): cuSCC, including KA, occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI with cetuximab.

• BRAF-mt metastatic NSCLC (PHAROS trial): cuSCC and skin papilloma (SP), each occurred in 2% of patients.

• Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment.
• The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN).
• BRAF-mt metastatic melanoma (COLUMBUS trial): Evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients.
• BRAF-mt metastatic NSCLC (PHAROS trial): Evidence of cardiomyopathy occurred in 11% and Grade 3 left ventricular dysfunction occurred in 1% of patients. Cardiomyopathy resolved in 82% of patients.

• BRAF-mt metastatic melanoma (COLUMBUS trial): The incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI with BRAFTOVI was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase.
   
• BRAF-mt metastatic CRC previously untreated (BREAKWATER trial): The incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for AST. 

• BRAF-mt metastatic NSCLC (PHAROS trial): The incidence of Grade 3 or 4 increases in liver function laboratory tests was 10% for AST, 9% for ALT, and 3.2% for alkaline phosphatase.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with MEKTOVI and Grade 3 or higher 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.
• BRAF-mt metastatic CRC previously untreated (BREAKWATER trial): Hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients.

• BRAF-mt metastatic CRC previously treated (BEACON CRC trial): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with cetuximab; Grade 3 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%).
• BRAF-mt metastatic NSCLC (PHAROS trial): Hemorrhage occurred in 12% of patients, including fatal intracranial hemorrhage (1%); Grade 3 or 4 hemorrhage occurred in 4.1% of patients. The most frequent hemorrhagic events were anal hemorrhage and hemothorax (2% each).

• BRAF-mt metastatic melanoma (COLUMBUS trial): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 4%.
• BRAF-mt metastatic NSCLC (PHAROS trial): The incidence of uveitis among patients treated with BRAFTOVI with MEKTOVI was 1%.

• BRAF-mt metastatic melanoma (COLUMBUS trial): An increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI with MEKTOVI.
• BRAF-mt metastatic CRC previously untreated (BREAKWATER trial): An increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6.

• BRAF-mt metastatic NSCLC (PHAROS trial): An increase in QTcF to >500 ms was measured in 2.1% (2/95) of patients who received BRAFTOVI with MEKTOVI.

• BRAF-mt metastatic melanoma (COLUMBUS trial) and BRAF-mt metastatic NSCLC (PHAROS trial): Effective, non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI with MEKTOVI.
• BRAF-mt metastatic CRC previously treated (BEACON CRC trial): Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Grades 3 or 4 dermatologic reactions occurred in 21% of patients receiving BRAFTOVI as a single agent compared to 2% in patients receiving the combination of BRAFTOVI with MEKTOVI.
• If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

• In BRAF-mt metastatic melanoma (COLUMBUS trial), BRAFTOVI is used in combination with MEKTOVI so refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.

• In BRAF-mt metastatic CRC previously untreated (BREAKWATER trial), BRAFTOVI is used in combination with cetuximab and mFOLFOX6 so refer to the prescribing information for BRAFTOVI, cetuximab, and individual product components of mFOLFOX6 for additional risk information.
• In BRAF-mt metastatic CRC previously treated (BEACON CRC trial), BRAFTOVI is used in combination with cetuximab so refer to the prescribing information for BRAFTOVI and cetuximab for additional risk information.
• In BRAF-mt metastatic NSCLC (PHAROS trial), BRAFTOVI is indicated for use as part of a regimen in combination with MEKTOVI, so refer to the prescribing information for BRAFTOVI and MEKTOVI for additional risk information.

• Serious retinopathy
  • Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, 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.
  • BRAF-mt metastatic melanoma (COLUMBUS trial): serous retinopathy occurred in 20% of patients receiving MEKTOVI with BRAFTOVI; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months.
  • BRAF-mt metastatic NSCLC (PHAROS trial): serous retinopathy (retinal detachment) occurred in 2% of patients with no cases of blindness. 

• Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients receiving MEKTOVI with BRAFTOVI. In BRAF-mt metastatic melanoma (COLUMBUS trial), 1 patient experienced RVO (0.1%) in the MEKTOVI with BRAFTOVI group (n=690).
  • The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO, including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes.
  • Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO.

• BRAF-mt metastatic melanoma (COLUMBUS trial): Elevation of laboratory values of serum CPK occurred in 58% of patients receiving MEKTOVI with BRAFTOVI. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI.
• BRAF-mt metastatic NSCLC (PHAROS trial): Elevation of laboratory values of serum creatine kinase (CK) occurred in 41% of patients. No patient experienced rhabdomyolysis.

• Most common adverse reactions (≥20%, all grades) for patients receiving BRAFTOVI with MEKTOVI compared to vemurafenib were fatigue (43% vs 46%), nausea (41% vs 34%), diarrhea (36% vs 34%), vomiting (30% vs 16%), abdominal pain (28% vs 16%), arthralgia (26% vs 46%), myopathy (23% vs 22%), hyperkeratosis (23% vs 49%), rash (22% vs 53%), headache (22% vs 20%), constipation (22% vs 6%), visual impairment (20% vs 4%), serous retinopathy/RPED (20% vs 2%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were facial paresis, pancreatitis, panniculitis, photosensitivity, drug hypersensitivity, and colitis.
• Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI with MEKTOVI compared to vemurafenib included increased creatinine (93% vs 92%), increased CPK (58% vs 3.8%), increased gamma glutamyl transferase (GGT) (45% vs 34%), anemia (36% vs 34%), increased ALT (29% vs 27%), hyperglycemia (28% vs 20%), increased AST (27% vs 24%), and increased alkaline phosphatase (21% vs 35%).

• Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (3.5%) and pyrexia (3.5%).
• Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6.

• Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with cetuximab and mFOLFOX6 compared to the control (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51% vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs 47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%), hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia (26% vs 14%).
• Most common laboratory abnormalities (≥10%, grade 3 or 4) in patients receiving BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%), decreased white blood cell count (12% vs 7%), and increased glucose (11% vs 2%).

• Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with cetuximab compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with cetuximab was pancreatitis.
• Most common laboratory abnormalities (≥20%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%).

• Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with MEKTOVI were fatigue (61%), nausea (58%), diarrhea (52%), musculoskeletal pain (48%), vomiting (37%), abdominal pain (32%), visual impairment (29%), constipation (27%), dyspnea (27%), rash (27%), and cough (26%).
• Serious adverse reactions occurred in 38% of patients receiving BRAFTOVI with MEKTOVI. Serious adverse reactions occurring in ≥2% of patients were hemorrhage (6%), diarrhea (4.1%), anemia (3.1%), dyspnea (3.1%), pneumonia (3.1%), arrhythmia (2%), device related infection (2%), edema (2%), myocardial infarction (2%), and pleural effusion (2%).
• Fatal adverse reactions occurred in 2% of patients, including intracranial hemorrhage (1%) and myocardial infarction (1%).
• Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were peripheral neuropathy, dysgeusia, facial paresis, pancreatitis, hyperkeratosis, erythema, photosensitivity, and drug hypersensitivity.
• Most common laboratory abnormalities (≥20%, all grades) for BRAFTOVI and MEKTOVI included increased creatinine (91%), hyperglycemia (48%), anemia (47%), increased creatine kinase (41%), lipase increased (40%), increased ALT (34%), hypoalbuminemia (32%), increased alkaline phosphatase (31%), increased AST (31%), hyperkalemia (31%), hyponatremia (26%), lymphopenia (24%), serum amylase increased (22%), and thrombocytopenia (20%). 

• Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose. 
• Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers.
• Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a 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.
• Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. 
• Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.

BRAFTOVI^® (encorafenib) and MEKTOVI^® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

BRAFTOVI is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

BRAFTOVI and MEKTOVI are  indicated for use in combination for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

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.