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Five-Year Outcomes with Combination Targeted Therapy in Metastatic Melanoma

Long terms outcomes in BRAF V600-mutated unresectable or metastatic melanoma
18 Jun 2019
Anticancer Agents;  Melanoma

To determine 5-year survival rates and characteristics of the patients with durable treatment benefit, a group of renowned melanoma researchers analyzed pooled extended-survival data from two clinical trials, COMBI-d and COMBI-v, that involved previously untreated patients who received BRAF inhibitor dabrafenib plus MEK inhibitor trametinib. They found that first-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

The results were presented at 2019 ASCO Annual Meeting by Paul Nathan of the Mount Vernon Cancer Centre, Northwood, United Kingdom and simultaneously published in The New England Journal of Medicine byCaroline Robert of the Institut Gustave Roussy and Paris-Sud-Paris-Saclay University, Villejuif, France as a corresponding author and colleagues.

The authors explained in the study background that patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation have prolonged progression-free survival (PFS) and overall survival (OS) when receiving treatment with BRAF inhibitors plus MEK inhibitors. However, long-term clinical outcomes in these patients were not defined.

Therefore, in order to determine long-term survival and confirm baseline predictive factors, the researchers performed analysis of pooled extended-survival data from COMBI-d and COMBI-v studies that involved previously untreated patients who had received dabrafenib at a dose of 150 mg twice daily plus trametinib 2 mg once daily.

The median duration of follow-up was 22 months (range, 0 to 76). The primary endpoints in the COMBI-d and COMBI-v trials were PFS and OS. A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib; 211 in the COMBI-d trial and 352 in the COMBI-v trial.

The PFS rates were 21% at four years and 19% at five years. The OS rates were 37% at four years and 34% at five years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both PFS and OS. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an OS rate of 71% at five years.

This is the largest data set and longest follow-up in previously untreated patients with BRAF V600-mutated unresectable or metastatic melanoma treated with BRAF plus MEK inhibitors.

The authors concluded that dabrafenib plus trametinib led to five-year disease control in approximately one-fifth and five-year survival in approximately one-third. Complete response appears to strongly predict long-term benefit. Lower baseline tumour burden and less aggressive tumour biology were associated with prolonged PFS and OS.

These results suggest that first-line treatment with dabrafenib plus trametinib provides long-term survival benefit in a sizeable cohort of patients.

This work was funded by GlaxoSmithKline and Novartis.


Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. NEJM; Published online on 4 June, 2019. DOI: 10.1056/NEJMoa1904059. 



Last update: 18 Jun 2019

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