Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

摘要: Summary Background MEK is a member of the MAPK signalling cascade that commonly activated in melanoma. Direct inhibition blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, genotyping data for oral, small-molecule inhibitor trametinib patients with Methods undertook multicentre, phase 1 three-part study (dose escalation, cohort expansion, pharmacodynamic assessment). The main results this are reported elsewhere; here we present relating obtained tumour samples assess BRAF mutational status, available tissues underwent exploratory analysis. Disease response was measured by Response Evaluation Criteria Solid Tumors, adverse events were defined common toxicity criteria. This registered ClinicalTrials.gov, number NCT00687622. Findings 97 melanoma enrolled, including 81 cutaneous or unknown primary (36 mutant, 39 wild-type, six status unknown), 16 uveal most treatment-related rash dermatitis acneiform (n=80; 82%) diarrhoea (44; 45%), which grade 2 lower. No squamous-cell carcinomas recorded. Of 36 mutations, 30 had not received before; two complete responses (both confirmed) ten partial (eight noted subgroup (confirmed rate, 33%). Median progression-free survival 5·7 months (95% CI 4·0–7·4). who previous inhibition, one unconfirmed wild-type melanoma, four confirmed 10%). Interpretation Our show substantial clinical activity suggest valid therapeutic target. Differences rates according mutations indicate importance analyses future. Funding GlaxoSmithKline.