BackEncorafenib
Overview + Rationale
- B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion
- Activating mutations in BRAF lead to constitutive activation of BRAF and hence RAF-MEK-ERK signaling cascade, promoting cell proliferation and survival while inhibiting apoptosis, and thus driving cancer growth
- Mutations in this gene, most commonly the V600E mutation, are the most frequently identified driver mutations in melanoma
- BRAF mutations have also been identified in various other cancers including colorectal cancer, thyroid carcinoma, non-small cell lung cancer, and hairy cell leukemia
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 IC50 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.
Stage of Development
Encorafenib is being investigated in combination with other agent(s) in the tumor types shown here. Safety and efficacy of encorafenib for the uses listed below has not been established.
BRAF V600E-mutant + Metastatic Colorectal Cancer (mCRC)
Phase 3 Combination (First Line)
BRAF V600E-mutant and MSI-H Metastatic Colorectal Cancer (mCRC)
Phase 2 Combination (First Line)
BRAF V600E/K-mutant+ Metastatic or Unresectable Locally Advanced Melanoma
Phase 3 Combination (First Line)
BRAF V600 mutant+ Melanoma with Brain Metastases
Phase 2 Combination