In a recent article entitled “Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib” published in The New England Journal of Medicine, a team of researchers lead by Caroline Robert, M.D., Ph.D, tested the efficacy of combining dabafenib and trametinib in patients with metastatic melanoma.
Treatment of metastic melanoma is progressing, with previous findings showing that the BRAF inhibitors vemurafenib and dabrafenib are effective monotherapies in patients with untreated metastatic melanoma that are positive for BRAF V600E or V600K mutations.
This effectiveness has been shown in improved response rates in progression-free and overall survival. Studies have found that treatment with BRAF inhibitors alone may result in reactivation of a protein pathway named mitogen-activated (MAPK), that results in progression-free survival of 6 to 8 months. Furthermore, BRAF inhibitors alone are associated with the development of secondary skin tumours. However, combining a BRAF inhibitor with an inhibitor of MAPK may address these issues.
In this regard, the team of researchers wanted to test the combination of dabrafenib and trametinib versus dabrafenib alone, as potential enhancers of antitumor activity in this clinical population, specifically looking at overall survival.
A total of 704 patients were randomly assigned (352 in each group) as participants in this open-label, phase 3 trial, with inclusion criteria including history of metastatic melanoma (stage IIIC or IV) with a BRAF V600 mutation. Participants were randomized to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.
Using the Kaplan-Meier method of estimation, the overall survival rate at 12 months was 72% in the combination-therapy group and 65% in the vemurafenib group, while the median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group.
Results showed that the combination of dabrafenib plus trametinib was superior to vemurafenib monotherapy in all efficacy hypothesised outcomes, including overall survival, with no additional overall toxicity noted.
Furthermore, researchers concluded that combination therapy significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations.