Vemurafenib: First-in-Class BRAF-Mutated Inhibitor for the Treatment of Unresectable or Metastatic Melanoma

Authors' disclosures of potential conflicts of interest are found at the end of this article. S kin cancer is the most common cancer in the United States, with more than 3.5 million people diagnosed every year (American Cancer Society, 2013). Melanoma is a life-threatening form of skin cancer that occurs due to genetic and environmental factors. The risk factors most associated with malignant melanoma include a family history of melanoma, atypical moles, and previous melano-ma. Exposure to ultraviolet radiation and sun sensitivity are additional risk factors for the disease. Although melanoma makes up a small percentage (less than 2%) of all skin cancers, it leads to the majority of all skin cancer–related deaths (American Cancer Society, 2013). Melanoma develops in stages starting with structurally normal melanocytes or epidermal skin cells. Melanocytes that rapidly multiply form raised or flat lesions, which can develop into abnormal growths that can invade the dermis, ultimately allowing spread to other areas of skin and organs. The initial growth in melanocytes results from atypical activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which may be due to mutations of the BRAF protein in about 50% of melanoma cases (Miller & Mihm, 2006). Ideally, melanoma is discovered at an early stage, when excision of the cancerous skin cells is recommended with curative intent. In stage II and re-sectable stage III melanoma, patients may undergo regional lymphadenec-tomy or removal of local lymph nodes to ensure removal of possible micro-metastases. Conflicting evidence exists for the adjuvant use of high-dose interferon alfa-2b (Intron A) therapy in stage II patients with a high risk of relapse (National Cancer Institute [NCI], 2014). Patients with unresect-able stage III or stage IV disease can be treated with immunotherapy, signal transduction inhibitors (BRAF and MEK inhibitors), chemotherapy, or palliative local therapy (NCI, 2014). Survival of stage IV disease is low at 15% to 20% at 5 years and 10% to 15% at 10 years (American Cancer Society, 2013). Therapies are needed to further increase overall survival for patients with later stages of unre-sectable disease. BRAF protein was