Περίληψη:
Results The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P = 0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P = 0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P = 0.02). However, a specified efficacy-stopping boundary (two-sided P = 0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib- trametinib group. Conclusions A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.
Background Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.
Methods In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. © 2014 Massachusetts Medical Society. All rights reserved.
Συγγραφείς:
Long, G.V.
Stroyakovskiy, D.
Gogas, H.
Levchenko, E.
De Braud, F.
Larkin, J.
Garbe, C.
Jouary, T.
Hauschild, A.
Grob, J.J.
Chiarion Sileni, V.
Lebbe, C.
Mandalà, M.
Millward, M.
Arance, A.
Bondarenko, I.
Haanen, J.B.A.G.
Hansson, J.
Utikal, J.
Ferraresi, V.
Kovalenko, N.
Mohr, P.
Probachai, V.
Schadendorf, D.
Nathan, P.
Robert, C.
Ribas, A.
DeMarini, D.J.
Irani, J.G.
Casey, M.
Ouellet, D.
Martin, A.-M.
Le, N.
Patel, K.
Flaherty, K.
Λέξεις-κλειδιά:
B Raf kinase; dabrafenib; ipilimumab; mitogen activated protein kinase kinase; trametinib; antineoplastic agent; B Raf kinase; dabrafenib; imidazole derivative; mitogen activated protein kinase kinase; oxime; pyridone derivative; pyrimidinone derivative; trametinib, abdominal pain; alopecia; arthralgia; Article; asthenia; backache; cancer combination chemotherapy; cancer growth; cancer staging; cancer survival; chill; constipation; controlled study; coughing; decreased appetite; diarrhea; dizziness; double blind procedure; drug dose reduction; drug efficacy; drug fatality; drug response; drug withdrawal; dry skin; fatigue; fever; hand foot syndrome; headache; human; hyperkeratosis; hypertension; limb pain; major clinical study; melanoma; myalgia; nausea; overall survival; peripheral edema; phase 3 clinical trial; progression free survival; pruritus; rash; rhinopharyngitis; skin carcinoma; skin papilloma; survival rate; treatment duration; vomiting; adult; aged; antagonists and inhibitors; chemically induced; clinical trial; comparative study; disease free survival; female; fever; genetics; Kaplan Meier method; male; melanoma; middle aged; mortality; multicenter study; mutation; randomized controlled trial, Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Fever; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones
