2011 Until Now

Since the U.S. approval of Bristol-Myers Squibb's Yervoy (ipilimumab) for unresectable or metastatic malignant melanoma (melanoma) in March 20111, the treatment paradigm for unresectable and metastatic melanoma has undergone a sea change. Yervoy's U.S. approval was closely followed by U.S. approval (August 2011) for Roche/Genentech/Daiichi Sankyo/Chugai's BRAF-inhibitor Zelboraf (vemurafenib) with a companion diagnostic (Roche's cobas 4800 BRAF V600 Mutation Test), also for unresectable or metastatic melanoma2. Zelboraf's launch has driven segmentation of the unresectable and metastatic melanoma population by BRAF mutational status: approximately 40-50 percent of unresectable and metastatic melanomas harbor BRAF mutations (BRAF+), and the remainder are BRAF-wild type tumors3. These mutations are believed to induce aberrant intracellular signaling, resulting in unregulated cell growth, and the loss of regulatory mechanisms governing cellular differentiation and proliferation (see Figure 1, below).

According to research from Decision Resources Group (DRG), surveyed U.S. medical oncologists report that almost all patients are routinely tested for their BRAF mutational status4, and Zelboraf has rapidly become the standard of care for the treatment of BRAF+ unresectable and metastatic melanoma. GlaxoSmithKline has now entered this setting with their BRAF-inhibitor Tafinlar (dabrafenib) and MEK-inhibitor, Mekinist (trametinib). MEK is a downstream component of the BRAF/MEK/ERK signaling pathway, which is believed to be upregulated in response to BRAF-inhibition5. Upregulation of MEK is thought to constitute one mechanism through which tumors develop resistance to BRAF-inhibitors6. Tafinlar and Mekinist both received FDA approval for the treatment of BRAF-mutation positive unresectable or metastatic melanoma on May 29, 20137. The companion diagnostic test, BioMérieux's ThxID-BRAF, was approved simultaneously. Tafinlar, like Zelboraf, is specifically indicated for use in melanoma with BRAF V600E mutations, whereas Mekinist is approved for use in melanoma with BRAF V600E, and the less common, BRAF V600K mutations.


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