DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma

A Gupta, S Love, A Schuh, L Collins, Adelyn Thomason, R Asher, R Lisle, M Churchman, M Shanyinde, R Plummer, PD Nathan, S Danson, CHH Ottensmeier, P Lorigan, JMG Larkin, MR Middleton

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40-50% of patients whose tumours harbour V600 mutations. However, ERK1/2 is constitutively active in melanoma cells regardless of mutation status. Phosphorylated ERK (pERK) is important for melanoma as, in pre-clinical models, it plays key roles in cell cycle entry, invasion and angiogenesis, as well as in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma in a manner independent of BRAF and NRAS mutation status. In melanoma cells, docetaxel induces mitochondrial dependent apoptosis by activation of Bax. Activation of ERK1/2 results in degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis. Selumetinib and docetaxel have demonstrated synergy in a variety of xenograft models, including melanoma. DOC-MEK is a randomised, double-blind, placebo-controlled multi-centre study in patients with wild-type BRAF advanced melanoma. Eighty patients were randomised (1:1) to docetaxel with placebo or selumetinib, with stratification for M stage and performance status. Docetaxel was administered intravenously every 3 weeks at a dose of 75 mg/m2 for a maximum six cycles. Placebo or selumetinib 75 mg was given orally twice per day until disease progression or unacceptable toxicity. Between October 2010 and April 2012 81 patients were randomised at 18 sites from 257 patients screened. Principal reasons for exclusion were presence of a BRAF mutation (n = 43), cerebral metastases (26) and poor performance status (17). In June 2012 the pre-specified number of progression events (58) for analysis was reached. Efficacy and safety results will be available in mid-October and will be presented. DOC-MEK is the first randomised trial specifically for wt BRAF melanoma patients, and will help define the role of MEK inhibitors as chemosensitisers in this patient population.
    Original languageEnglish
    Pages (from-to)9068-9068
    Number of pages1
    JournalJournal of Clinical Oncology
    Volume31
    Issue number15
    Publication statusPublished - 2013

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