Trametinib, a new protein kinase inhibitor for BRAF V600 positive melanoma

Mekinist (trametinib) can be used as monotherapy or in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Prior to treatment with trametinib, patients must be tested to confirm their tumour has a BRAF V600 mutation. | SCIENCE PHOTO LIBRARY

Mekinist is available as 500 microgram and 2mg tablets; the recommended daily dose is 2mg once daily, which may be adjusted if adverse events occur. Treatment should continue until benefit is no longer derived or toxicity becomes unacceptable.

Further information
View Mekinist drug record 
Summary of Product Characteristics
Manufacturer: Novartis

Trametinib is a reversible, selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinases MEK1 and MEK2, components of the Ras/Raf/MEK/ERK signalling cascade. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF. 

Trametinib/dabrafenib versus dabrafenib alone

Combined use of trametinib and dabrafenib, a Raf kinase inhibitor, provides dual inhibition of the Ras/Raf/MEK/ERK pathway. 

In the phase III, randomised, double-blind COMBI-d study, 423 patients were given dabrafenib plus trametinib, or dabrafenib plus placebo. Participants had either a V600E or V600K BRAF mutation.

There were significant differences between the two treatment groups in both the primary endpoint of progression-free survival and the key secondary endpoint of overall survival.

Median progression-free survival was 9.3 months in patients taking dabrafenib plus trametinib and 8.8 months in those receiving dabrafenib plus placebo (hazard ratio for progression or death in the dabrafenib/trametinib group 0.75; 95% CI 0.57–0.99; p=0.03).

Median overall survival was 25.1 months in the combination group compared with 18.7 months in the dabrafenib-only group (hazard ratio HR 0.71, 95% CI 0.55–0.92; p=0.0107). There was also a significantly higher overall response rate in patients given the combination (67% vs 51%, p=0.002).

Trametinib/dabrafenib versus vemurafenib

The phase III, randomised, open-label COMBI-v study compared the trametinib/dabrafenib combination to monotherapy with the Raf inhibitor vemurafenib (n=704).

Overall survival, the primary endpoint, was significantly greater with the combination than with vemurafenib alone, at 72% and 65% in the two groups, respectively (hazard ratio for death in the combination group 0.69; 95% CI 0.53–0.89; p=0.005). 

Median progression-free survival was 11.4 months with the combination and 7.3 months with vemurafenib (hazard ratio 0.56; 95% CI 0.46–0.69; p<0.001). The objective response rate was 64% in the combination group and 51% in the vemurafenib group (p<0.001).

Cardiac monitoring required

The most common adverse events seen with trametinib in both monotherapy and combination therapy are fatigue, diarrhoea and nausea. Ocular and skin disorders are also common.

Left ventricular ejection fraction should be monitored in all patients before and during treatment as it can be decreased by trametinib. 

Haemorrhage often occurs but is generally mild. The risk may be increased with concomitant use of antiplatelet or anticoagulant therapy.

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