Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

Long, G.V. and Stroyakovskiy, D. and Gogas, H. and Levchenko, E. and de Braud, F. and Larkin, J. and Garbe, C. and Jouary, T. and Hauschild, A. and Grob, J.J. and Chiarion Sileni, V. and Lebbe, C. and Mandalà, M. and Millward, M. and Arance, A. and Bondarenko, I. and Haanen, J.B.A.G. and Hansson, J. and Utikal, J. and Ferraresi, V. and Kovalenko, N. and Mohr, P. and Probachai, V. and Schadendorf, D. and Nathan, P. and Robert, C. and Ribas, A. and DeMarini, D.J. and Irani, J.G. and Casey, M. and Ouellet, D. and Martin, A.-M. and Le, N. and Patel, K. and Flaherty, K. (2014) Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. The New England Journal of Medicine = N Engl J Med, 371. pp. 1877-1888. ISSN 0028-4793 (print); 1533-4406 (online)

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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. 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. (Funded by GlaxoSmithKline; Clinical number, NCT01584648.)

Item Type: Article
Subjects: Oncology
Divisions: Departments > Department of Oncology and Medical Radiology
Depositing User: Елена Шрамко
Date Deposited: 28 Dec 2021 16:26
Last Modified: 28 Dec 2021 16:26

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