The two drugs are reversible inhibitors of mitogen-activated extracellular signal regulated kinases MEK1 and MEK2, components of the Ras/Raf/MEK/ERK signalling cascade. This pathway can be activated by mutated forms of BRAF.
Trametinib/dabrafenib versus dabrafenib alone
In the phase III, randomised, double-blind COMBI-d study (n = 423), median progression-free survival (primary endpoint) was significantly greater in patients taking dabrafenib plus trametinib than in those receiving dabrafenib plus placebo (9.3 months versus 8.8 months, p = 0.03), as was overall survival (25.1 months versus 18.7 months, p = 0.0107).
Trametinib/dabrafenib versus vemurafenib
The open-label COMBI-v study compared trametinib/dabrafenib to monotherapy with vemurafenib (n = 704). Overall survival was significantly greater with the combination than with vemurafenib alone, at 72% and 65% in the two groups, respectively (p = 0.005).
Cobimetinib/vemurafenib versus vemurafenib alone
In the phase III coBRIM study in 495 previously untreated patients, median progression-free survival was 9.9 months among those who received vemurafenib and cobimetinib, compared with 6.2 months in those who received vemurafenib and placebo (p <0.001).
The most common adverse events seen with trametinib in 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, because it can be decreased by trametinib.
In trials of cobimetinib, serous retinopathy occurred in more than 10% of patients treated with the drug. Patients reporting new or worsening visual disturbances should be referred for ophthalmological examination. Treatment discontinuation, interruption or dose reduction should be considered if a diagnosis of serous retinopathy is confirmed.