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.


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.


CONCLUSIONS
Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.


BACKGROUND
NCT01362296.
MD Anderson Cancer Center, The University of Texas, Houston, USA. Electronic address: gblumens@mdanderson.org.
G R
GR
Blumenschein
Department of Pulmonary Diseases, Vrije Universiteit VU Medical Centre, Amsterdam, The Netherlands.
E F
EF
Smit
Medical Oncology Department, Gustave Roussy (GR), Villejuif, France.
D
D
Planchard
Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
D-W
DW
Kim
Department of Respiratory Medicine, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
J
J
Cadranel
European Institute of Oncology, Milan, Italy.
T
T
De Pas
Duke University Medical Center, Durham, USA.
F
F
Dunphy
Korányi National Institute of Tuberculosis and Pulmonology, Budapest, Hungary.
K
K
Udud
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
M-J
MJ
Ahn
IU Melvin and Bren Simon Cancer Center, Indianapolis, USA.
N H
NH
Hanna
Yonsei Cancer Center, Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.
J-H
JH
Kim
Hopital Larrey CHU Toulouse, Toulouse, France.
J
J
Mazieres
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
S-W
SW
Kim
Netherlands Cancer Institute, Amsterdam, The Netherlands.
P
P
Baas
GlaxoSmithKline, Collegeville, USA.
E
E
Rappold
GlaxoSmithKline, Collegeville, USA.
S
S
Redhu
GlaxoSmithKline Kft., Budapest, Hungary.
A
A
Puski
GlaxoSmithKline, Collegeville, USA.
F S
FS
Wu
Lowe Center for Thoracic Oncology, Belfer Institute for Applied Cancer Science Dana-Farber Cancer Institute, Boston, USA.
P A
PA
Jänne
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D043823:Taxoids; D000077143:Docetaxel; C560077:trametinib; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
KRAS; MEK inhibitor; NSCLC; docetaxel; progression-free survival; trametinib