Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.
BACKGROUND
MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.


METHODS
We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622.


RESULTS
97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%).


CONCLUSIONS
Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future.


BACKGROUND
GlaxoSmithKline.
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA. gfalchoo@mdanderson.org
Gerald S
GS
Falchook
Karl D
KD
Lewis
Jeffrey R
JR
Infante
Michael S
MS
Gordon
Nicholas J
NJ
Vogelzang
Douglas J
DJ
DeMarini
Peng
P
Sun
Christopher
C
Moy
Stephen A
SA
Szabo
Lori T
LT
Roadcap
Vijay G R
VG
Peddareddigari
Peter F
PF
Lebowitz
Ngocdiep T
NT
Le
Howard A
HA
Burris
Wells A
WA
Messersmith
Peter J
PJ
O'Dwyer
Kevin B
KB
Kim
Keith
K
Flaherty
Johanna C
JC
Bendell
Rene
R
Gonzalez
Razelle
R
Kurzrock
Leslie A
LA
Fecher
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D055815:Young Adult; D000098943:Uveal Melanoma
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human