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. 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. • 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. 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.

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.

Melanoma • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. • The recommended dose is 450 mg orally once daily in combination with binimetinib. CRC • Confirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. • The recommended dose is 300 mg orally once daily in combination with o biweekly cetuximab and mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) or cetuximab and FOLFIRI (fluorouracil, leucovorin and irinotecan) o weekly cetuximab. NSCLC • Confirm the presence of BRAF V600E mutation in tumor or plasma specimens prior to initiating BRAFTOVI. • The recommended dose is 450 mg orally once daily in combination with binimetinib. Take BRAFTOVI with or without food.

None. None.

• 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. • Tumor Promotion in BRAF Wild-Type Tumors: Increased cell proliferation can occur with BRAF inhibitors. • 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%. • Hepatotoxicity: Monitor liver function tests before and during treatment with BRAFTOVI and binimetinib and as clinically indicated. • Hemorrhage: Major hemorrhagic events can occur in patients receiving BRAFTOVI and binimetinib.

The following adverse reactions are described elsewhere in the labeling: • New Primary Malignancies • Tumor Promotion in BRAF Wild-Type Tumors • Cardiomyopathy • Hepatotoxicity • Hemorrhage • Uveitis • QT Prolongation • Embryo-Fetal Toxicity • Risks Associated with BRAFTOVI as a Single Agent • Risks Associated with Combination Treatment • Melanoma: Most common adverse reactions (≥25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia. • 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.

• Strong or moderate CYP3A4 inhibitors: Avoid coadministration. If unavoidable, reduce BRAFTOVI dosage. • Strong CYP3A4 inducers: Avoid coadministration. • 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. • Transporters: Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.