Overview
11 DESCRIPTION Encorafenib is a kinase inhibitor. The chemical name is methyl N -{(2 S )-1-[(4-{3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(propan-2-yl)-1 H -pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}carbamate. The molecular formula is C 22 H 27 ClFN 7 O 4 S and the molecular weight is 540 daltons.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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.
Indications
- 1 INDICATIONS AND USAGE 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.
Common Doses
- 450 mg
- 300 mg
- 75 mg
- 225 mg
Dosage
2 DOSAGE AND ADMINISTRATION Melanoma • Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. ( 2.1 ) • The recommended dose is 450 mg orally once daily in combination with binimetinib. ( 2.2 ) CRC • Confirm the presence of BRAF V600E mutation in plasma or tumor specimens prior to the initiation of BRAFTOVI. ( 2.1 ) • 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) ( 2.
Contraindications
- 4 CONTRAINDICATIONS None. None. ( 4 )
Side Effects
- 6 ADVERSE REACTIONS 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.
Interactions
- 7 DRUG INTERACTIONS • 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.