ABSTRACT
BACKGROUND: MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma. METHODS: We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622. FINDINGS: 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%). INTERPRETATION: Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future. FUNDING: GlaxoSmithKline.
Subject(s)
Antineoplastic Agents/administration & dosage , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Melanoma/drug therapy , Protein Kinase Inhibitors/administration & dosage , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Skin Neoplasms/drug therapy , Uveal Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Agents/adverse effects , DNA Mutational Analysis , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Melanoma/enzymology , Melanoma/genetics , Melanoma/mortality , Melanoma/pathology , Middle Aged , Molecular Targeted Therapy , Mutation , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins B-raf/genetics , Pyridones/adverse effects , Pyrimidinones/adverse effects , Skin Neoplasms/enzymology , Skin Neoplasms/genetics , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Time Factors , Treatment Outcome , United States , Uveal Neoplasms/enzymology , Uveal Neoplasms/genetics , Uveal Neoplasms/mortality , Uveal Neoplasms/pathology , Young AdultABSTRACT
Bacteriolytic anti-cancer therapies employ attenuated bacterial strains that selectively proliferate within tumors. Clostridium novyi-NT spores represent one of the most promising of these agents, as they generate potent anti-tumor effects in experimental animals. We have determined the 2.55-Mb genomic sequence of C. novyi-NT, identifying a new type of transposition and 139 genes that do not have homologs in other bacteria. The genomic sequence was used to facilitate the detection of transcripts expressed at various stages of the life cycle of this bacterium in vitro as well as in infections of tumors in vivo. Through this analysis, we found that C. novyi-NT spores contained mRNA and that the spore transcripts were distinct from those in vegetative forms of the bacterium.
