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Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

Georgina V. Long, M.D., Ph.D., Daniil Stroyakovskiy, M.D., Helen Gogas, M.D., Evgeny Levchenko, M.D., Filippo de Braud, M.D., James Larkin, M.D., Claus Garbe, M.D., Ph.D., Thomas Jouary, M.D., Axel Hauschild, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., V

Editorial comment by Prof. R. Dummer:
This month we have decided to present two papers. Both papers were published in the New England Journal of Medicine and report on two prospective randomized trials investigating the clinical outcome of a monotherapy with a BRAF inhibitor versus a combination therapy using a BRAF inhibitor and a MEK inhibitor in patients with BRAF mutated advanced melanoma. In both studies there is a clear advantage for the combination therapy with an increase in progression free survival resulting in an improvement of approximately 40% with an improved response rate. The phase III clinical trial presented by Long reached its primary endpoint progression free survival and the secondary endpoint overall survival. Taking together these studies clearly support combination therapy with a BRAF and MEK inhibitor as the standard of care for BRAF mutated melanoma.

Summary

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 Trials.gov number, NCT01584648.)

N Engl J Med 2014; 371:1877-1888November 13, 2014DOI: 10.1056/NEJMoa1406037