DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma
| Autor: | Ruth Asher, Mark R. Middleton, L Collins, Richard Lisle, Ottensmeier Chh., Paul Nathan, Larkin Jmg., A Thomason, Ruth Plummer, Avinash Gupta, M Churchman, Sarah Danson, Milensu Shanyinde, Sharon Love, Anna Schuh, Paul Lorigan |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 31:9068-9068 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2013.31.15_suppl.9068 |
| Popis: | 9068 Background: Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40% of patients whose tumors harbor V600 mutations. ERK1/2 is constitutively active in melanoma cells regardless of mutation status, and plays key roles in cell cycle entry, invasion, angiogenesis and in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma 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. Methods: DOC-MEK (NCT01256359) is a randomised, double-blind, placebo-controlled multi-centre study in patients with wild-type BRAF advanced melanoma. 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 75mg/m2 for a maximum 6 cycles. Placebo or selumetinib 75mg was given orally twice per day until disease progression or unacceptable toxicity. Results: Between October 2010 and April 2012 eighty three patients were randomised at 18 sites from 257 patients screened. Progression free survival (PFS) favored combination therapy (HR 0.753, p=0.13), as did response rate (32 vs 14%, p=0.059) and 6 month PFS (40 vs 26%, p=0.19). Patients on docetaxel with selumetinib experienced more rash, diarrhea, febrile neutropenia and edema, but less neuropathy. Overall survival data and outcomes according to tumor NRAS mutation status will be presented. Conclusions: Although PFS and response rates favored docetaxel with selumetinib further interest in the regimen will be dependent on overall survival outcomes and/or the identification of a sub-population that benefit most from this approach. Clinical trial information: NCT01256359. |
| Databáze: | OpenAIRE |
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