Improved survival with MEK inhibition in BRAF-mutated melanoma.
BACKGROUND
Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.


METHODS
In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.


RESULTS
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.


CONCLUSIONS
Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
Massachusetts General Hospital Cancer Center, Boston, USA. kflaherty@partners.org
Keith T
KT
Flaherty
Caroline
C
Robert
Peter
P
Hersey
Paul
P
Nathan
Claus
C
Garbe
Mohammed
M
Milhem
Lev V
LV
Demidov
Jessica C
JC
Hassel
Piotr
P
Rutkowski
Peter
P
Mohr
Reinhard
R
Dummer
Uwe
U
Trefzer
James M G
JM
Larkin
Jochen
J
Utikal
Brigitte
B
Dreno
Marta
M
Nyakas
Mark R
MR
Middleton
Jürgen C
JC
Becker
Michelle
M
Casey
Laurie J
LJ
Sherman
Frank S
FS
Wu
Daniele
D
Ouellet
Anne-Marie
AM
Martin
Kiran
K
Patel
Dirk
D
Schadendorf
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
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