ABSTRACT
BACKGROUND: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. PATIENTS AND METHODS: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. RESULTS: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. CONCLUSION: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01362296.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 2/antagonists & inhibitors , Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins p21(ras)/genetics , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Taxoids/therapeutic use , Adult , Aged , Antineoplastic Agents, Phytogenic/adverse effects , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Disease Progression , Disease-Free Survival , Docetaxel , Female , Humans , Kaplan-Meier Estimate , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/metabolism , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Pyridones/adverse effects , Pyrimidinones/adverse effects , Signal Transduction/drug effects , Taxoids/adverse effects , Time Factors , Treatment OutcomeABSTRACT
Successive bilateral bronchial stenting (Dumon type) and minimally invasive pull-through esophageal intubation for accompanying malignant bronchial and esophageal involvement was undertaken. External radiation and afterloading brachytherapy for localized endobronchial overgrowth was used. A 13-month survival was achieved using mainly out-patient facilities. During such esophageal intubation, bronchoscopic control is mandatory. Extended complex palliation was obtained using this combined treatment, even in the high-risk stage of advanced tracheobronchial carcinoma with associated esophageal stricture.
