Vemurafenib — Drug Monograph

Brand names: Zelboraf

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

ATP-competitive BRAF V600E-selective inhibitor that blocks the MAPK/ERK signaling pathway in BRAF V600E-mutant cells. In BRAF wild-type cells harboring RAS mutations, vemurafenib paradoxically activates the MAPK pathway by promoting CRAF dimerization, which can drive tumor growth and cutaneous squamous cell carcinoma formation.

FDA Indications

• Unresectable or metastatic melanoma with BRAF V600E mutation (FDA approved August 2011; BRIM-3 trial: OS HR 0.37 vs dacarbazine)
• Erdheim-Chester disease with BRAF V600 mutation

Common Side Effects

• Photosensitivity (approximately 60%)
• Arthralgias and myalgias
• Skin rash
• Fatigue
• Alopecia
• Nausea
• Pruritus
• Peripheral edema

Clinical Pearl

Vemurafenib was the first BRAF V600E inhibitor approved and demonstrated a dramatic OS benefit in BRIM-3 (HR 0.37). However, median PFS is only ~6 months due to acquired resistance. Combining with cobimetinib (MEK inhibitor) delays resistance and reduces the incidence of cutaneous squamous cell carcinoma caused by paradoxical MAPK activation. Always confirm BRAF V600E mutation by an FDA-approved test before use — do NOT use in wild-type BRAF or RAS-mutant tumors.

Related Therapies & Mechanisms

• Binimetinib (Mektovi) — Tyrosine Kinase Inhibitor · Melanoma
• Cobimetinib (Cotellic) — Tyrosine Kinase Inhibitor · Melanoma
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · Melanoma
• Encorafenib (Braftovi) — Tyrosine Kinase Inhibitor · Melanoma