Encorafenib

BRAFTOVI is a kinase inhibitor indicated: Melanoma

• in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test. ( 1.1 , 2.1 ) Colorectal Cancer (CRC)
• in combination with cetuximab and fluorouracil-based chemotherapy, for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA‑authorized test. ( 1.2 , 2.1 )
• in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-authorized test, after prior therapy. ( 1.2 , 2.1 ) Non-Small Cell Lung Cancer (NSCLC)
• in combination with binimetinib, for the treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test. ( 1.3 , 2.1 ) Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC. ( 1.4 , 5.2 ) 1.1 BRAF V600E or V600K Mutation–Positive Unresectable or Metastatic Melanoma BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1) ] . 1.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC)
• BRAFTOVI is indicated, in combination with cetuximab and fluorouracil-based chemotherapy , for the treatment of adult patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA- authorized test [see Dosage and Administration (2.1) ].
• BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA- authorized test, after prior therapy [see Dosage and Administration (2.1) ]. 1.3 BRAF V600E Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC) BRAFTOVI is indicated, in combination with binimetinib, for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-authorized test [see Dosage and Administration (2.1) ] .

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

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

None. None. ( 4 )

• New 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 )
• Tumor Promotion in BRAF Wild-Type Tumors : Increased cell proliferation can occur with BRAF inhibitors. ( 5.2 )
• Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before initiating treatment with BRAFTOVI and binimetinib, and after one month of treatment, then every 2 to 3 months thereafter. The safety of BRAFTOVI in combination with binimetinib has not been established in patients with LVEF below 50%. ( 5.3 )
• Hepatotoxicity : Monitor liver function tests before and during treatment with BRAFTOVI and binimetinib and as clinically indicated. ( 5.4 )
• Hemorrhage : Major hemorrhagic events can occur in patients receiving BRAFTOVI and binimetinib. ( 5.5 )
• Uveitis : Perform ophthalmologic evaluation at regular intervals and for any visual disturbances. ( 5.6 )
• QT 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 )
• Embryo-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 )
• Risks Associated with BRAFTOVI as a Single Agent : If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. ( 5.9 )
• Risks Associated with Combination Treatment : BRAFTOVI is indicated for use as part of a 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 Malignancies In 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 1 to 9 months) [see Adverse Reactions (6.1) ] . For patients who received BRAFTOVI as a single agent, cuSCC/KA was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients. In BEACON CRC, cuSCC/KA occurred in 1.4% of patients with CRC, and a 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 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. Noncutaneous Malignancies Based 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 3 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 0 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 3 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 2 to 3 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 3 or 4 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 3 or 4 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 3 or 4 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 3 or 4 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 3 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. […]

The following adverse reactions are described elsewhere in the labeling:

• New Primary Malignancies [see Warnings and Precautions (5.1) ]
• Tumor Promotion in BRAF Wild-Type Tumors [see Warnings and Precautions (5.2) ]
• Cardiomyopathy [see Warnings and Precautions (5.3) ]
• Hepatotoxicity [see Warnings and Precautions (5.4) ]
• Hemorrhage [see Warnings and Precautions (5.5) ]
• Uveitis [see Warnings and Precautions (5.6) ]
• QT Prolongation [see Warnings and Precautions (5.7) ]
• Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ]
• Risks Associated with BRAFTOVI as a Single Agent [see Warnings and Precautions (5.9) ]
• Risks Associated with Combination Treatment [see Warnings and Precautions (5.10) ]
• Melanoma : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia. ( 6.1 )
• CRC : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab and mFOLFOX6, are peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, and constipation. ( 6.1 )
• Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab and FOLFIRI are nausea, diarrhea, fatigue, vomiting, alopecia, constipation, abdominal pain, decreased appetite, and rash. ( 6.1 )
• Most common adverse reactions (≥25%) for BRAFTOVI, in combination with cetuximab, are fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash. ( 6.1 )
• NSCLC : Most common adverse reactions (≥25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, and cough. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS). The COLUMBUS trial [see Clinical Studies (14.1) ] excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib. The most common (≥25%) adverse reactions in patients receiving BRAFTOVI in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia. Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%), and pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%), and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common were hemorrhage in 2% and headache in 1% of patients. Table 5 and Table 6 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 5. Table 5: Adverse Reactions Occurring in ≥10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS Grades per National Cancer Institute CTCAE v4.03. Adverse Reaction BRAFTOVI with binimetinib N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1), and rash (n=1) in the BRAFTOVI with binimetinib arm. (%) All Grades (%) Grades 3 and 4 (%) General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms. 43 3 46 6 Pyrexia 18 4 30 0 Gastrointestinal Disorders Nausea 41 2 34 2 Vomiting 30 2 16 1 Abdominal pain 28 4 16 1 Constipation 22 0 6 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 26 1 46 6 Myopathy 23 0 22 1 Pain in extremity 11 1 13 1 Skin and Subcutaneous Tissue Disorders Hyperkeratosis 23 1 49 1 Rash 22 1 53 13 Dry skin 16 0 26 0 Alopecia 14 0 38 0 Pruritus 13 1 21 1 Nervous System Disorders Headache 22 2 20 1 Dizziness 15 3 4 0 Peripheral neuropathy 12 1 13 2 Vascular Disorders Hemorrhage 19 3 9 2 BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate (≥5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with binimetinib were: Nervous system disorders: Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Panniculitis, Photosensitivity Immune system disorders: Drug hypersensitivity Table 6: Laboratory Abnormalities Occurring in ≥10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS Laboratory Abnormality BRAFTOVI with binimetinib Grades per National Cancer Institute CTCAE v4.03. N=192 Vemurafenib N=186 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Hematology Anemia 36 3.6 34

2.2 Leukopenia 13 0 10

0.5 Lymphopenia 13 2.1 30 7 Neutropenia 13 3.1 4.8

0.5 Chemistry Increased Creatinine 93 3.6 92

1.1 Increased Gamma Glutamyl Transferase 45 11 34

4.8 Increased ALT 29 6 27

2.2 Increased AST 27 2.6 24

1.6 Hyperglycemia 28 5 20

2.7 Increased Alkaline Phosphatase 21 0.5 35

2.2 Hyponatremia 18 3.6 15

0.5 Hypermagnesemia 10 1.0 26 0.5 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) in Combination with Cetuximab and fluorouracil-based chemotherapy The safety of BRAFTOVI 300 mg once daily in combination with cetuximab (500 mg/m 2 every 2 weeks) and mFOLFOX6 was evaluated in 232 patients with BRAF V600E mutation-positive metastatic CRC in a randomized, open-label, active-controlled trial (BREAKWATER) [see Clinical Studies (14.2) ] . In a separate cohort of BREAKWATER (Cohort 3), 139 patients with BRAF V600E mutation-positive mCRC were evaluated; of which 71 patients received BRAFTOVI in combination with cetuximab (500 mg/m 2 every 2 weeks) and FOLFIRI. […]

• Strong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. ( 2.6 , 7.1 )
• Strong CYP3A4 inducers: Avoid coadministration. ( 7.1 )
• Sensitive CYP3A4 substrates: Avoid coadministration with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. ( 7.2 )
• Transporters: 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 Inhibitors Coadministration of BRAFTOVI with a 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 Inducers Coadministration of BRAFTOVI with a 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 Substrates BRAFTOVI is a 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 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. OATP1B1, OATP1B3, or BCRP Substrates Coadministration 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.

• Lactation : Advise not to breastfeed. ( 8.2 )
• Males of Reproductive Potential : BRAFTOVI may impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a 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 a 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 Data In 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 a 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 a 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 Summary There 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 a breastfed child from BRAFTOVI, advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for 2 weeks after the last dose. Counsel patients to use a nonhormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2) ] . Infertility Males Based 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 9 (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) ] . A 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) ] . A recommended dosage has not been established in patients with severe renal impairment (CLcr <30 mL/min).

Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC 50 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 µM). Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K 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 a 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 a mechanism of resistance to BRAF inhibitors. Combinations of a 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 a mouse model of colorectal cancer with mutated BRAF V600E.