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)†.

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.

[1]  John V Heymach,et al.  Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. , 2012, Journal of the National Cancer Institute.

[2]  M. Albitar,et al.  Somatic mutations of signaling genes in non-small-cell lung cancer. , 2010, Cancer genetics and cytogenetics.

[3]  Travis J Cohoon,et al.  Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. , 2013, Cancer cell.

[4]  W. Pao,et al.  KRAS mutations in non-small cell lung cancer. , 2009, Proceedings of the American Thoracic Society.

[5]  M. Ladanyi,et al.  ALK Rearrangements Are Mutually Exclusive with Mutations in EGFR or KRAS: An Analysis of 1,683 Patients with Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[6]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[7]  M. Ostland,et al.  Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Roy S Herbst,et al.  KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer , 2007, Clinical Cancer Research.

[9]  K. Flaherty,et al.  Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. , 2012, The Lancet. Oncology.

[10]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[11]  M Paesmans,et al.  The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis , 2004, British Journal of Cancer.

[12]  R W Wilkinson,et al.  The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models , 2012, British Journal of Cancer.

[13]  Lucio Crinò,et al.  Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. , 2013, The Lancet. Oncology.

[14]  Gregory J Riely,et al.  Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcomes in Previously Untreated Non–Small Cell Lung Cancer Patients: Results of an Online Tumor Registry of Clinical Trials , 2009, Clinical Cancer Research.

[15]  K. Okudela,et al.  KRAS gene mutations in lung cancer: Particulars established and issues unresolved , 2010, Pathology international.

[16]  M Broggini,et al.  Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[17]  O. Fiala,et al.  The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. , 2013, Cancer genetics.

[18]  M. Socinski,et al.  Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  J. Wisell,et al.  Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma , 2013 .

[20]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

[21]  M. Ladanyi,et al.  Association of KRAS and EGFR mutations with survival in patients with advanced lung adenocarcinomas , 2013, Cancer.

[22]  Renato Martins,et al.  Non-small cell lung cancer. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[23]  J. Holbrook,et al.  Comprehensive Predictive Biomarker Analysis for MEK Inhibitor GSK1120212 , 2011, Molecular Cancer Therapeutics.

[24]  G. Giaccone,et al.  Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations. , 2013 .

[25]  Keunchil Park,et al.  Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. , 2013 .

[26]  M. Ladanyi,et al.  Driver mutations determine survival in smokers and never‐smokers with stage IIIB/IV lung adenocarcinomas , 2012, Cancer.

[27]  M. Okada,et al.  [New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)]. , 2009, Gan to kagaku ryoho. Cancer & chemotherapy.