What are BRAF (B-Raf) inhibitors?

From the Guidelines

BRAF inhibitors are targeted cancer medications that block the activity of mutated BRAF proteins, particularly the V600E mutation, which drives uncontrolled cell growth in certain cancers, and are primarily used to treat melanoma, with the most recent and highest quality study 1 supporting their use in combination with MEK inhibitors to improve efficacy and reduce resistance.

Overview of BRAF Inhibitors

BRAF inhibitors, including vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi), are oral medications that target the BRAF V600 mutation in the MAPK pathway, interrupting signals that promote cancer cell proliferation. These drugs are used to treat melanoma, as well as other cancers such as colorectal, non-small cell lung, and certain thyroid cancers.

Administration and Combination Therapy

BRAF inhibitors are typically administered at specific doses (vemurafenib 960mg twice daily, dabrafenib 150mg twice daily, or encorafenib 450mg once daily) and are often combined with MEK inhibitors like trametinib or binimetinib to improve efficacy and reduce resistance, as supported by the study 1. This combination therapy has been shown to have superior response rates, progression-free survival (PFS), and overall survival (OS) compared to BRAF inhibitor monotherapy.

Side Effects and Genetic Testing

Common side effects of BRAF inhibitors include skin reactions, joint pain, fatigue, and potential development of secondary skin cancers. Before starting treatment, patients must undergo genetic testing to confirm the presence of BRAF mutations, as these drugs are ineffective and potentially harmful in BRAF wild-type cancers, as noted in the study 1.

Key Points

• BRAF inhibitors are targeted cancer medications that block the activity of mutated BRAF proteins.
• These drugs are primarily used to treat melanoma, but also have applications in other cancers.
• BRAF inhibitors are often combined with MEK inhibitors to improve efficacy and reduce resistance.
• Genetic testing is necessary to confirm the presence of BRAF mutations before starting treatment.
• Common side effects include skin reactions, joint pain, fatigue, and potential development of secondary skin cancers.

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 BRAF inhibitors are a class of drugs that inhibit the activity of the BRAF protein, which is involved in cell signaling pathways that control cell growth and division.

• Key points about BRAF inhibitors include:
  • They are used to treat certain types of cancer, such as melanoma, that have specific mutations in the BRAF gene.
  • They work by blocking the activity of the mutated BRAF protein, which can help to slow or stop the growth of cancer cells.
  • Examples of BRAF inhibitors include vemurafenib 2, 2, and 2.

From the Research

Definition and Mechanism of BRAF Inhibitors

• BRAF inhibitors are a class of drugs that target the BRAF protein, a serine/threonine protein kinase that activates the MAP kinase/ERK-signaling pathway 3.
• These inhibitors are designed to selectively target mutant BRAF, which is commonly found in melanomas and other cancers 4.
• By inhibiting the BRAF protein, these drugs can block the signaling pathway that promotes cancer cell growth and survival 5.

Types and Examples of BRAF Inhibitors

• Examples of BRAF inhibitors include vemurafenib, dabrafenib, and encorafenib 3, 6, 5.
• These inhibitors have been approved for the treatment of metastatic melanoma with BRAF V600E or V600K mutations 3, 6.
• Combination therapies, such as encorafenib plus binimetinib, have also been approved for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations 6.

Clinical Use and Efficacy of BRAF Inhibitors

• BRAF inhibitors have shown significant efficacy in clinical trials, with improved overall survival and progression-free survival compared to traditional chemotherapy 3, 6.
• However, resistance to BRAF inhibitors can develop, and combination therapies are being explored to overcome this resistance 4, 7.
• BRAF inhibitors have also been shown to have immunomodulatory effects, promoting anti-tumor immune responses and enhancing the efficacy of immune checkpoint inhibitors 5.

Adverse Events and Toxicities Associated with BRAF Inhibitors

• Common adverse events associated with BRAF inhibitors include arthralgia, rash, fatigue, alopecia, and keratoacanthoma or cutaneous squamous-cell carcinoma 3.
• Combination therapies with MEK inhibitors can also increase the risk of serious retinopathy, skin disorders, and cardiovascular toxicities 6.
• Proactive management of adverse events is crucial to minimize toxicity and optimize treatment outcomes 6.