From the Journals

Dabrafenib plus trametinib yields long-term benefit in melanoma patients



Dabrafenib plus trametinib treatment was associated with a 5-year overall survival rate of 34% in patients with melanoma harboring a BRAF V600E or V600K mutation, according to a combined analysis of two trials.

The 5-year progression-free survival rate was 19% in the long-term, pooled analysis of the COMBI-d and COMBI-v trials, which included at total of 563 patients with previously untreated, unresectable or metastatic melanoma who received combined treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.

Previously reported 5-year progression-free survival rates for patients treated with anti–programmed death-1 checkpoint inhibitors, either nivolumab or pembrolizumab, “appear to be similar” to these results for dabrafenib plus trametinib, investigators said in a report on the analysis appearing in the New England Journal of Medicine.

To date, however, 5-year survival data have not been reported for other BRAF-targeted therapies, according to the investigators, who were led by Caroline Robert, MD, PhD, of Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France.

“These data will be critical to assess the potential of therapy to exert long-term disease control through analysis of survival plateaus and to understand factors predictive of long-term survival,” Dr. Robert and coauthors wrote in their report.

A total of 211 patients in the COMBI-d trial were randomly allocated to receive the combination of dabrafenib plus trametinib, while in COMBI-v, 352 received this combination therapy, according to investigators.

Notably, the survival curves for dabrafenib plus trametinib appear to plateau starting at 3 years, investigators reported. In a previously published report on pooled COMBI-d and COMBI-v data, the 3-year progression-free survival rate was 23%, and the 3-year overall survival rate was 44%.

In this more recent analysis, progression-free survival rates were 21% at 4 years and 19% at 5 years, while overall survival rates were 37% at 4 years and 34% at 5 years.

“This finding suggests stabilization of rates of progression-free survival and overall survival over time in this population,” Dr. Robert and colleagues wrote.

Survival rates were higher in patients with normal lactate dehydrogenase (LDH) levels at baseline, and they were especially high in those with normal LDH and three or fewer disease sites at baseline, according to the report. Specifically, the reported 5-year rates of progression-free and overall survival were 31% and 55%, respectively.

Other factors associated with prolonged progression-free survival included female sex, older age, better performance status, and BRAF V600E genotype, according to results of a multivariate analysis that investigators said confirmed findings from the previously reported 3-year data.

The study was supported by GlaxoSmithKline and Novartis. Dr. Robert provided disclosures related to BMS, Pierre Fabre, Novartis, Amgen, Merck, Roche, MSD, and Sanofi.

SOURCE: Robert C et al. N Engl J Med. 2019 Aug 15. doi: 10.1056/NEJMoa1904059

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