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Ann Oncol. 2015 May;26(5):894-901. doi: 10.1093/annonc/mdv072. Epub 2015 Feb 26.

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)†.

Author information

1
MD Anderson Cancer Center, The University of Texas, Houston, USA gblumens@mdanderson.org.
2
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, The Netherlands.
3
Medical Oncology Department, Gustave Roussy (GR), Villejuif, France.
4
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
5
Department of Respiratory Medicine, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
6
European Institute of Oncology, Milan, Italy.
7
Duke University Medical Center, Durham, USA.
8
Korányi National Institute of Tuberculosis and Pulmonology, Budapest, Hungary.
9
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
10
IU Melvin and Bren Simon Cancer Center, Indianapolis, USA.
11
Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.
12
Hopital Larrey CHU Toulouse, Toulouse, France.
13
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
14
Netherlands Cancer Institute, Amsterdam, The Netherlands.
15
GlaxoSmithKline, Collegeville, USA.
16
GlaxoSmithKline Kft., Budapest, Hungary.
17
Lowe Center for Thoracic Oncology, Belfer Institute for Applied Cancer Science Dana-Farber Cancer Institute, Boston, USA.

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.

KEYWORDS:

KRAS; MEK inhibitor; NSCLC; docetaxel; progression-free survival; trametinib

PMID:
25722381
PMCID:
PMC4855243
DOI:
10.1093/annonc/mdv072
[Indexed for MEDLINE]
Free PMC Article

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