A study from the German Institute for Quality and Efficiency in Health Care (IQWiG) shows that combination therapy with dabrafenib and trametinib in advanced melanoma is superior to treatment with trametinib alone.
Since 2013, dabrafenib (Tafinlar, GSK) has been approved for the treatment of adults with advanced melanoma with a BRAF V600 mutation. Trametinib (Mekinist, GSK) was approved for the same indication in 2014, and the FDA gave the green light to the combination of the two drugs in September 2015.
The gene for the BRAF enzyme, a key player of the MAP kinase signal pathway, is mutated in about half of all melanomas. Mutations in this gene contribute to increased cell proliferation. Drugs such as dabrafenib or vemurafenib inhibit the activity of the mutated BRAF enzyme, but many melanomas develop resistance to the treatment by bypassing the blocked MAP kinase pathway. Trametinib is another inhibitor targeting a different site, and can be used to lower this risk of resistance.
The two treatment regimens were compared to vemurafenib in a dossier assessment, an action performed when a manufacturer wants its medicinal product to be included in the WHO prequalified products list. In an earlier dossier assessment, monotherapy with dabrafenib was shown to add no benefit compared to vemurafenib.
Since the German Federal Joint Committee recently approved the combination of dabrafenib and trametinib, new early benefit dossier assessments of the combination treatment became necessary. The study evaluated data, submitted by the manufacturer from the COMBI-v study, directly comparing the combination of dabrafenib and trametinib to vemurafenib. This clinical study included adults with unresectable or metastatic melanoma and confirmed BRAF V600 mutation who had not received other systemic anti-cancer treatment before the trial.
In women, the combination treatment led to prolonged survival. The same thing could not be proven for men, but analysis of a range of other outcomes led the authors to conclude that the combination therapy provided a non-quantifiable added benefit for men. This means that the added benefit could not be allocated to one of the categories “minor,” “considerable,” or “major.”
The Federal Joint Committee also wanted to find out whether trametinib alone offers an added benefit in comparison with vemurafenib.
The manufacturer submitted material citing an indirect comparison, but due to methodological concerns, it was not possible to conclude whether trametinib monotherapy provided any added benefit. The IQWiG also concluded that it was not possible to evaluate the submitted data for conclusions about trametinib monotherapy.