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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)
Open accessAbstract
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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“However, due to resistance acquisition, MEK inhibitors have shown limited benefit as monotherapy in KRAS mutant CRC [73,74].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [74]
In the citing paper
“Kinase inhibitors targeting molecules downstream of KRAS-like MEK inhibitors have shown modest efficacy, with response rates of 11% for selumetinib 16 and 12% for trametinib.17”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [17]
In the citing paper
“In a phase II trial, trametinib as a monotherapy showed RR and PFS similar to docetaxel in previously treated KRAS-mutant NSCLC (49).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [49]
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Metadata
- 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
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 26
- Issue
- 5
- Pages
- 894-901
- ISSN
- 0923-7534 (ISSN-L)
- 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
- 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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