TY - JOUR
T1 - Improved overall survival in melanoma with combined dabrafenib and trametinib
AU - Robert, Caroline
AU - Karaszewska, Boguslawa
AU - Schachter, Jacob
AU - Rutkowski, Piotr
AU - Mackiewicz, Andrzej
AU - Stroiakovski, Daniil
AU - Lichinitser, Michael
AU - Dummer, Reinhard
AU - Grange, Florent
AU - Mortier, Laurent
AU - Chiarion-Sileni, Vanna
AU - Drucis, Kamil
AU - Krajsova, Ivana
AU - Hauschild, Axel
AU - Lorigan, Paul
AU - Wolter, Pascal
AU - Long, Georgina V.
AU - Flaherty, Keith
AU - Nathan, Paul
AU - Ribas, Antoni
AU - Martin, Anne Marie
AU - Sun, Peng
AU - Crist, Wendy
AU - Legos, Jeff
AU - Rubin, Stephen D.
AU - Little, Shonda M.
AU - Schadendorf, Dirk
N1 - Publisher Copyright:
© 2015 Massachusetts Medical Society.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Background The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. Methods In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. Results At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P = 0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combinationtherapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. Conclusions Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
AB - Background The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. Methods In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. Results At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P = 0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combinationtherapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combinationtherapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. Conclusions Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity.
UR - http://www.scopus.com/inward/record.url?scp=84920394727&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1412690
DO - 10.1056/NEJMoa1412690
M3 - Article
C2 - 25399551
AN - SCOPUS:84920394727
SN - 0028-4793
VL - 372
SP - 30
EP - 39
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 1
ER -