Dabrafenib and trametinib in the management of advanced melanoma

The aim of this study was to assess the benefits of dabrafenib (Tafinlar) and trametinib (Mekinist)  as single as well as  as combination therapy in advanced melanoma patients with a specific genetic status.

In the advanced stage of melanoma (stage III/IV), cancer spreads from the skin to other parts of the body (metastasis). In the majority of metastatic melanoma patients, BRAF genes are mutated (permanently changed). These genes are involved in cellular signaling and functioning of important proteins named MAPK and MEK. In melanoma with BRAF mutations, these proteins remain permanently active. This results in uncontrolled growth of cancer cells. Dabrafenib and trametinib are approved drugs for BRAF-mutated melanoma. Dabrafenib inhibits the action of MAPK and trametinib inhibits the activity of MEK protein in melanoma cells.

In this study the authors evaluated the effect of dabrafenib and trametinib in the management of advanced melanoma (stage III/ IV) patients with BRAF mutations.

In the study of dabrafenib alone, 250 patients were randomly assigned to receive either dabrafenib or dacarbazine (Dtic-dome). The overall survival was 18.2 months for dabrafenib compared to 15.6 months fordacarbazine.  The average progression free survival (time following treatment before the disease progressed) was 6.9 months for dabrafenib compared to 2.7 months with dacarbazine.  Overall, 59% of patients had a reduction in tumor volume.

A total of 321 patients who never received BRAF inhibitors before were enrolled in a study of trametinib alone. They were randomly assigned to receive either trametinib or chemotherapy. The overall survival was 15.6 months for trametinib compared to 11.3 months with chemotherapy.  The average progression free survival was 4.8 months for trametinib compared to 1.4 months for chemotherapy.  Overall, 22% of patients had reduction in tumor volume.

In a study of dabrafenib and trametinib as combination therapy, 76% had reduction in tumor volume compared to 54% with dabrafenib only. The average progression free survival was 9.4 months for combination therapy compared to 5.8 months with dabrafenib only.

The authors concluded that the combination therapy of dabrafenib and trametinib significantly improved survival in advanced melanoma with BRAF mutations and therefore holds promise as the treatment of choice.

The combination therapy best suited those patients who never had dabrafenib as single therapy. The percentage of patients with reduced tumor was only 9% if they previously had dabrafenib followed by combination therapy compared to 76% with combination therapy only.

If you have BRAF mutations and have not had MAPK inhibitors before, ask your doctor about the dabrafenib- trametinib combination therapy.