Cited by 350Lung Cancer Treatments and MutationsLung Cancer Research StudiesLung Cancer Diagnosis and Treatment

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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)

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Blumenschein, G.R., Smit, E.F., Planchard, D., Kim, D.-W., Cadranel, J., De Pas, T., Dunphy, F., Udud, K., Ahn, M.-J., Hanna, N.H., Kim, J.-H., Mazieres, J., Kim, S.-W., Baas, P., Rappold, E., Redhu, S., Puski, A., Wu, F.S., Jänne, P.A.·2015·Annals of Oncology

DOI 10.1093/annonc/mdv072PMC PMC4855243

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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.

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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.
Gandara, D. R., Hiret, S., Blumenschein, G. R., Barlési, F., Delord, J., Madelaine, J., Infante, J. R., Reckamp, K. L., Lara, P. N., Audebert, C., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.8028 · Cited by 27
Self-citation
MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC).
Blumenschein, G. R., Smit, E. F., Planchard, D., Kim, D., Cadranel, J. L., Pas, T. M. D., Dunphy, F., Udud, K., Ahn, M., Hanna, N. H., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2013.31.15_suppl.8029 · Cited by 21
Self-citation
S1507: Phase II study of docetaxel and trametinib in patients with G12C or non-G12C KRAS mutation positive (+) recurrent non-small cell lung cancer (NSCLC).
Gadgeel, S. M., Miao, J., Riess, J. W., Mack, P. C., Gerstner, G. J., Burns, T. F., Taj, A., Akerley, W. L., Dragnev, K. H., Moon, J., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2019.37.15_suppl.9021 · Cited by 15
A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer
Gandara, D. R., Leighl, N. B., Delord, J., Barlési, F., Bennouna, J., Zalcman, G., Infante, J. R., Reckamp, K. L., Kelly, K. L., Shepherd, F. A., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.11.2218 · Cited by 49
Self-citation
Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study
Jänne, P. A., Shaw, A. T., Pereira, J. R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F. A., Grinsted, L., Zazulina, V., Smith, P., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70489-8 · Cited by 655

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Authors: Blumenschein, G. R., Smit, E. F., Planchard, D., Kim, D.-W., Cadranel, J., De Pas, T., Dunphy, F., Udud, K., Ahn, M.-J., Hanna, N. H., Kim, J.-H., Mazieres, J., Kim, S.-W., Baas, P., Rappold, E., Redhu, S., Puski, A., Wu, F. S., & Jänne, P. A.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Vrije Universiteit Amsterdam (NL)
Institut Gustave Roussy (FR)
Seoul National University (KR)
Assistance Publique – Hôpitaux de Paris (FR)
Duke Medical Center (US)
Országos Korányi Tbc és Pulmonológiai Intézet (HU)
Samsung Medical Center (KR)
Indiana University Health (US)
Yonsei University (KR)
Asan Medical Center (KR)
The Netherlands Cancer Institute (NL)
GlaxoSmithKline (United States) (US)
Corresponding author: Blumenschein, G.R.
ORCID: Blumenschein, G.R.
Smit, E.F.
Planchard, D.
Cadranel, J.
Ahn, M.-J.
Hanna, N.H.
Kim, J.-H.
Kim, S.-W.
Wu, F.S.
Venue: Annals of Oncology
Publisher: Elsevier BV
Published: 2015-05
Volume: 26
Issue: 5
Pages: 894-901
ISSN: 0923-7534 (ISSN-L)
DOI: 10.1093/annonc/mdv072
PMC: PMC4855243
OpenAlex: W2160586729
Cited by: 349
References: 30
Citations by year: 2026: 10 · 2025: 21 · 2024: 39 · 2023: 28 · 2022: 40 · 2021: 53 · 2020: 35 · 2019: 33 · 2018: 29 · 2017: 28 · 2016: 16 · 2015: 15
FWCI: 23.47
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1651 d)
Locations: Annals of Oncology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Pure Amsterdam UMC (submittedVersion)
Seoul National University Open Repository (Seoul National University) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: GlaxoSmithKline (NCT01362296)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
Keywords: trametinib, docetaxel, KRAS-mutant non-small cell lung cancer, targeted therapy, progression-free survival, overall survival, futility boundaries, EGFR wild-type, EGFR tyrosine kinase inhibitors
MeSH terms: Docetaxel, Adult, Aged, Antineoplastic Agents, Phytogenic, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Pyridones, Pyrimidinones, Time Factors, Biomarkers, Tumor, Signal Transduction, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Disease Progression, Disease-Free Survival, Taxoids, Protein Kinase Inhibitors, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Kaplan-Meier Estimate

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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)

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