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IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (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 BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC) 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. 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. 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.

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 in 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). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Hepatotoxicity: Hepatotoxicity can occur. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), 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. 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.

Hemorrhage: In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination 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%). In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological 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.

QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. 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.

Embryo-Fetal Toxicity: BRAFTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose.

Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for additional risk information.

Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose.

Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.

ADVERSE REACTIONS

BREAKWATER Trial (previously untreated BRAF V600E mutation-positive mCRC)

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 the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (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 the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (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%).

BEACON CRC Trial (previously treated BRAF V600E mutation-positive mCRC)

Most common adverse reactions (≥25%, all grades) in the BRAFTOVI with cetuximab arm 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 in combination with cetuximab was pancreatitis.
Most common laboratory abnormalities (all grades) (≥20%) 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%).

DRUG INTERACTIONS

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.

Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for recommended dosing and additional safety information.

Please see full Prescribing Information including Medication Guide for BRAFTOVI.

INDICATIONS AND USAGE

BRAFTOVI® (encorafenib) 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.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC.