ASCO 2012: New MEK inhibitor, trametinib, improves survival in advanced melanoma

4 Jun 2012
ASCO 2012: New MEK inhibitor, trametinib, improves survival in advanced melanoma

Data from a Phase III study show that the oral investigational drug trametinib delayed tumour growth and extended survival for patients with advanced melanoma who have BRAF mutations, compared with standard chemotherapy.


This is the first Phase III trial evaluating a melanoma treatment that inhibits a protein known as MEK ─ part of the MAP kinase signaling pathway, of which BRAF is also a component.


"This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations. The findings show that targeting the MEK molecular pathway is a viable strategy for treating many people with the disease," said Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussy in Paris, France.


"Trametinib is likely to become another first-line treatment option for patients with advanced melanoma."


Only one targeted therapy, vemurafenib, is currently approved for advanced melanoma. Vemurafenib targets a protein produced by a mutation in the BRAF gene that fuels melanoma growth, and is present in roughly half of patients with melanoma.


MEK lies downstream from BRAF in the same signaling pathway. Since most patients taking vemurafenib eventually develop resistance to the drug and many experience serious side effects, MEK inhibitors could help address a continuing need for new therapies in these patients.


In this study, known as METRIC, patients with advanced BRAF-mutated melanoma who had received up to one prior chemotherapy regimen were randomly assigned to receive trametinib (214 patients) or standard chemotherapy (108 patients; either dacarbazine or paclitaxel). Overall, 22 percent of patients who received trametinib responded to treatment, compared with 8 percent of those who received chemotherapy.


Median progression-free survival was significantly greater in the trametinib group (4.8 months) than the chemotherapy group (1.5 months) – a 55 percent reduction in the risk of progression. Interim overall survival was also longer among the patients treated with trametinib, with a 46 percent reduced risk of death; 81 percent of patients in the trametinib group were alive after six months of follow-up, versus 67 percent in the chemotherapy group.


Approximately half (47 percent) of patients whose disease progressed while on chemotherapy were permitted to take trametinib, so the overall survival advantage may ultimately prove to be greater if this "crossover effect" is taken into account, according to the researchers.


Side effects of trametinib were generally manageable. Severe adverse events included skin rash (7 percent of patients), eye problems (less than 1 percent), high blood pressure (12 percent) and reduced heart function (7 percent). 


Source: ASCO