PMID- 25722381 OWN - NLM STAT- MEDLINE DCOM- 20160519 LR - 20220416 IS - 1569-8041 (Electronic) IS - 0923-7534 (Print) IS - 0923-7534 (Linking) VI - 26 IP - 5 DP - 2015 May TI - A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)dagger. PG - 894-901 LID - S0923-7534(19)31514-5 [pii] LID - 10.1093/annonc/mdv072 [doi] AB - 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. CI - (c) The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Blumenschein, G R Jr AU - Blumenschein GR Jr AD - MD Anderson Cancer Center, The University of Texas, Houston, USA. Electronic address: gblumens@mdanderson.org. FAU - Smit, E F AU - Smit EF AD - Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, The Netherlands. FAU - Planchard, D AU - Planchard D AD - Medical Oncology Department, Gustave Roussy (GR), Villejuif, France. FAU - Kim, D-W AU - Kim DW AD - Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. FAU - Cadranel, J AU - Cadranel J AD - Department of Respiratory Medicine, Hopital Tenon, Assistance Publique - Hopitaux de Paris, Paris, France. FAU - De Pas, T AU - De Pas T AD - European Institute of Oncology, Milan, Italy. FAU - Dunphy, F AU - Dunphy F AD - Duke University Medical Center, Durham, USA. FAU - Udud, K AU - Udud K AD - Koranyi National Institute of Tuberculosis and Pulmonology, Budapest, Hungary. FAU - Ahn, M-J AU - Ahn MJ AD - Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. FAU - Hanna, N H AU - Hanna NH AD - IU Melvin and Bren Simon Cancer Center, Indianapolis, USA. FAU - Kim, J-H AU - Kim JH AD - Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea. FAU - Mazieres, J AU - Mazieres J AD - Hopital Larrey CHU Toulouse, Toulouse, France. FAU - Kim, S-W AU - Kim SW AD - Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. FAU - Baas, P AU - Baas P AD - Netherlands Cancer Institute, Amsterdam, The Netherlands. FAU - Rappold, E AU - Rappold E AD - GlaxoSmithKline, Collegeville, USA. FAU - Redhu, S AU - Redhu S AD - GlaxoSmithKline, Collegeville, USA. FAU - Puski, A AU - Puski A AD - GlaxoSmithKline Kft., Budapest, Hungary. FAU - Wu, F S AU - Wu FS AD - GlaxoSmithKline, Collegeville, USA. FAU - Janne, P A AU - Janne PA AD - Lowe Center for Thoracic Oncology, Belfer Institute for Applied Cancer Science Dana-Farber Cancer Institute, Boston, USA. LA - eng SI - ClinicalTrials.gov/NCT01362296 PT - Clinical Trial, Phase II PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20150226 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Biomarkers, Tumor) RN - 0 (KRAS protein, human) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyridones) RN - 0 (Pyrimidinones) RN - 0 (Taxoids) RN - 15H5577CQD (Docetaxel) RN - 33E86K87QN (trametinib) RN - EC 2.7.1.- (MAP2K2 protein, human) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 2.7.12.2 (MAP Kinase Kinase 2) RN - EC 2.7.12.2 (MAP2K1 protein, human) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Adult MH - Aged MH - Antineoplastic Agents, Phytogenic/adverse effects/*therapeutic use MH - Biomarkers, Tumor/*genetics MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/genetics/mortality/pathology MH - Disease Progression MH - Disease-Free Survival MH - Docetaxel MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Lung Neoplasms/*drug therapy/enzymology/genetics/mortality/pathology MH - MAP Kinase Kinase 1/*antagonists & inhibitors/metabolism MH - MAP Kinase Kinase 2/*antagonists & inhibitors/metabolism MH - Male MH - Middle Aged MH - *Mutation MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use MH - Proto-Oncogene Proteins p21(ras)/*genetics MH - Pyridones/adverse effects/*therapeutic use MH - Pyrimidinones/adverse effects/*therapeutic use MH - Signal Transduction/drug effects MH - Taxoids/adverse effects/*therapeutic use MH - Time Factors MH - Treatment Outcome PMC - PMC4855243 OTO - NOTNLM OT - KRAS OT - MEK inhibitor OT - NSCLC OT - docetaxel OT - progression-free survival OT - trametinib EDAT- 2015/02/28 06:00 MHDA- 2016/05/20 06:00 PMCR- 2016/05/01 CRDT- 2015/02/28 06:00 PHST- 2014/11/07 00:00 [received] PHST- 2015/02/11 00:00 [accepted] PHST- 2015/02/28 06:00 [entrez] PHST- 2015/02/28 06:00 [pubmed] PHST- 2016/05/20 06:00 [medline] PHST- 2016/05/01 00:00 [pmc-release] AID - S0923-7534(19)31514-5 [pii] AID - mdv072 [pii] AID - 10.1093/annonc/mdv072 [doi] PST - ppublish SO - Ann Oncol. 2015 May;26(5):894-901. doi: 10.1093/annonc/mdv072. Epub 2015 Feb 26.