What are B-Raf (B-Rapidly Accelerated Fibrosarcoma) inhibitors, their indications, and mechanism of action?

From the Guidelines

BRAF inhibitors are targeted cancer therapies used primarily for treating melanoma with BRAF V600E or V600K mutations, and they work by specifically blocking the activity of mutated BRAF proteins in the MAPK/ERK pathway. BRAF inhibitors, such as vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi), are used to treat melanoma with BRAF V600E or V600K mutations, as well as other BRAF-mutated cancers. The indications for BRAF inhibitors include:

• Unresectable or distant metastatic melanoma with BRAF V600E or V600K mutations
• Other BRAF-mutated cancers The mechanism of action of BRAF inhibitors involves:
• Blocking the activity of mutated BRAF proteins in the MAPK/ERK pathway
• Interrupting the signaling cascade that regulates cell growth and division
• Causing cancer cell death and tumor shrinkage BRAF inhibitors are typically administered orally at specific doses, such as:
• Vemurafenib 960mg twice daily
• Dabrafenib 150mg twice daily
• Encorafenib 450mg once daily They are often used in combination with MEK inhibitors, such as trametinib or cobimetinib, to improve efficacy and reduce resistance 1. Common side effects of BRAF inhibitors include:
• Skin reactions
• Photosensitivity
• Joint pain
• Fatigue
• Potential development of secondary skin cancers Genetic testing for BRAF mutations is required before initiating therapy to identify patients who will benefit from these targeted treatments 1. It is essential to select patients for BRAF-targeted therapy based on the presence of BRAF V600 mutations, and to consider the tempo of disease, presence or absence of cancer-related symptoms, and patient's personal history of autoimmune disease or estimated risk of triggering autoimmunity by immunotherapy 1. In cases where the disease is symptomatic or rapidly progressing, BRAF-targeted therapy may be preferred, while patients with asymptomatic metastatic melanoma may be good candidates for immune checkpoint inhibitor therapy 1. The safety profiles and AE management approaches differ significantly for BRAF-targeted therapy versus immune checkpoint inhibitor therapy, and treatment selection should be informed by consideration of the patient's overall health, medical history, concomitant therapies, comorbidities, and compliance 1.

From the FDA Drug Label

Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E.

BRAF inhibitors are a class of drugs that target the BRAF protein, which is involved in cell signaling pathways.

• Indications: BRAF inhibitors, such as vemurafenib, are used to treat patients with unresectable or metastatic melanoma with a BRAF V600E mutation.
• Mechanism of action: BRAF inhibitors work by blocking the activity of the BRAF protein, which can help to slow down or stop the growth of cancer cells.
• Key points:
  • BRAF inhibitors are specifically designed to target cancer cells with a BRAF V600E mutation.
  • They have been shown to be effective in treating unresectable or metastatic melanoma with this mutation.
  • However, they may also promote malignancies associated with activation of RAS through mutation or other mechanisms.
  • Patients should be closely monitored for signs or symptoms of new malignancies while receiving BRAF inhibitors. 2

From the Research

BRAF Inhibitors

• BRAF inhibitors are a class of targeted therapy drugs that inhibit the activity of the BRAF protein, which is involved in sending signals inside cells and directing cell growth [(3,4,5,6,7)].
• These inhibitors are specifically designed to target and inhibit the activity of the BRAF V600 mutation, which is present in approximately 50% of melanoma cases 6.

Indications

• BRAF inhibitors, such as dabrafenib and vemurafenib, are indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation [(3,4,6,7)].
• They are also being investigated for use in other solid tumors with BRAF mutations, such as papillary thyroid cancer 6.

Mechanism of Action

• The mechanism of action of BRAF inhibitors involves selective inhibition of the mutated BRAF V600E kinase, which leads to reduced signaling through the aberrant mitogen-activated protein kinase (MAPK) pathway 6.
• By inhibiting the BRAF protein, these drugs can help to slow down or stop the growth of cancer cells [(3,4,5,6,7)].
• Combination therapy with BRAF and MEK inhibitors has been shown to be effective in delaying the onset of resistance and producing additional clinical benefit across cancers 5.