Mechanism Of Action :
Encorafenib is a kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF in cell-free assays. It also binds to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and reduces ligand binding at clinically achievable concentrations. Encorafenib inhibits the growth of tumor cell lines expressing BRAF V600E, D, and K mutations and produced tumor regression associated with the RAF/MEK/ERK pathway suppression in mice with tumor cells expressing BRAF V600E. Panitumumab is an EGFR antagonist. The interaction of EGFR with its normal ligands results in phosphorylation and activation of intracellular proteins that regulate transcription of genes involved in cell growth and survival, motility, and proliferation. Signal transduction through EGFR results in activation of wild-type KRAS protein, whereas KRAS-mutant protein is continuously active and appears independent of EGFR regulation in cells with activating KRAS somatic mutations.
Efficacy & Safety : The randomized portion of the BEACON trial, including a positive OS result. Within this portion of the study, 665 patients were randomized to receive either the triplet combination, an encorafenib and cetuximab doublet, or a control regimen of cetuximab plus either irinotecan or FOLFIRI. The final results of BEACON reported a median OS of 5.9 months, 9.3 months, and 9.3 months for the control, doublet, and triplet arms, respectively, after a median follow-up of 12.8 months.851 The ORRs were 2%, 20%, and 27%, respectively, and grade 3 or higher AE rates were highest in the triplet arm, although the addition of binimetinib did not improve OS or ORR over the doublet. Quality-of-life assessments showed that the doublet and triplet regimens led to a similarly longer maintenance of quality of life compared with control. Based on this report, the NCCN Panel concluded that only the doublet regimen of encorafenib with either cetuximab or panitumumab should be recommended for patients with BRAF V600Emutated mCRC.
Reference Source : Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Guideline Name V.2.2021.◎ National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed [Jan. 21, 2021]. To view the most recent and complete version of the guideline, go online to NCCN.org.
