drug · small molecule

BRAFTOVI

updated 2mo ago

by $AVBP ArriVent BioPharma, Inc.🔗 ChEMBL

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Small molecule drug with a maximum clinical stage of Approval (across all indications), with 4 approved and 5 investigational indications.

targets

Serine/threonine-protein kinase B-raf

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brand

BRAFTOVI

trade names

Braftovi

generic

ENCORAFENIB

MOA

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. 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. Compared with either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone. In a BRAF V600E mutant NSCLC patient-derived xenograft model in mice, coadministration of encorafenib and binimetinib resulted in greater anti-tumor activity compared to binimetinib alone, with respect to tumor growth inhibition. Increased tumor growth delay after dosing cessation was also observed with the coadministration compared to either drug alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors. Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistanc

indication

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 , 2.1 ) • 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. ( 1.2 , 2.1 ) 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. ( 1.3 , 2.1 ) Limitations of Use BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma, wild-type BRAF CRC, or wild-type BRAF NSCLC. ( 1.4 , 5.2 ) 1.1 BRAF V600E or V600K Mutation–Positive Unresectable or Metastatic Melanoma BRAFTOVI is indicated, 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 [see Dosage and Administration (2.1) ] . 1.2 BRAF V600E Mutation-Positive Metastatic Colorectal Cancer (mCRC) • BRAFTOVI is indicated, 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 [see Dosage and Administration (2.1) ]. • 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- authorized test, after prior therapy [see Dosage and Administration (2.1) ]. 1.

BRAFTOVI

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