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MEK inhibitor nears approval

The first MEK inhibitor trametinib (GSK 1120212) could be close to reaching the market. On December 4, a US Food and Drug Administration advisory committee discussed materials on the mitogen-activated, extracellular signal–regulated kinase 1 (MEK1) and MEK2 inhibitors submitted by its maker, London-based GlaxoSmithKline. The committee discussed the drug's effectiveness for treating unresectable or metastatic BRAF-V600-mutation-positive melanoma, including safety monitoring in light of ophthalmologic and cardiac toxicities observed in adults receiving the drug. “There's hope that MEK inhibitors will become the standard of care in patients with BRAF mutant tumors,” says David Solit, an associate professor of Medicine, Cell and Developmental Biology at Memorial Sloan-Kettering Cancer Center in New York. Kevin Koch, president and CEO of Array BioPharma in Boulder, Colorado, sees further possibilities. “The pathway MEK resides in is upregulated in a large number of tumor types,” he says, adding that the drugs are similar to VEGF inhibitors and “much more potent in combination.” Array has partnerships around the MEK inhibitor MEK162 with Novartis of Basel and with AstraZenceca of London over selumetinib (AZD 6244). MEK162 is expected to be in phase 3 melanoma studies by 2013, selumetinib could also go into phase 3, but in KRAS-mutated non–small cell lung cancer. Roche of Basel is also starting a phase 3 trial in melanoma combining the company's BRAF inhibitor (Zelboraf/vemurafenib) with Genentech's GADC-0973, a MEK inhibitor. For now, “trametinib is the only MEK inhibitor with major clinical data behind it,” says Solit. Those data include results from a phase 3 trial of combined BRAF and MEK inhibition in almost 250 patients with BRAF-V600-mutation-positive melanoma. The study reported a marked increase (9.4 months versus 5.8 months) in progression-free survival among patients on the combination therapy (NEJM 367, 1694–1703, 2012). Hervé Hoppenot, president of Novartis Oncology, says success will be determined by “what we see in clinical trials and the ability to pursue MEK162 in the right combinations to target multiple pathways.” So far, MEK inhibitors have shown a surprising range of effectiveness, given that they are allosteric inhibitors. “You'd expect them to be extremely specific, but results may start to iron out as more companies go into bigger trials,” says Keiran Smalley, an assistant professor at the Moffitt Cancer Center in Tampa, Florida.

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Allison, M. MEK inhibitor nears approval. Nat Biotechnol 31, 4 (2013). https://doi.org/10.1038/nbt0113-4

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