Trametinib

Introduction

On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved trametinib (MEKINIST™ tablets, GlaxoSmithKline, LLC), as a single agent treatment for patients with non-operable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test, called the THxID™ – BRAF assay from bioMérieux S.A. In November 2015, the FDA approved the combination of dabrafenib and trametinib for the treatment of metastatic melanoma. Trametinib is approved by MedSafe, alone and in combination with dabrafenib, but it is not subsidised by PHARMAC in New Zealand.

BRAF mutations occur in 50% of melanomas. Trametinib targets mutant BRAF protein by inhibiting the MAPK signalling pathway, which mediates cell growth and survival.

How does trametinib work?

• Trametinib has a related but slightly different mechanism of action to dabrafenib.
• It acts as a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor in the mitogen-activated protein kinase (MAPK) signalling pathway, which mediates cell growth and survival.
• The RAS/RAF/MEK/ERK (MAPK pathway) is a critical signal transduction cascade implicated in the uncontrolled proliferation of many human cancers.
• In cancer, mutated RAF (e.g. mutant B-RAF) and RAS proteins may lead to hyperactivation of the MAPK pathway, resulting in increased cell proliferation, dissemination and survival.
• Mutations that lock the B-RAF protein in an active state can cause excessive signalling in MAPK pathway, leading to uncontrolled growth of melanocytes (pigment cells).
• MEK is thought to be an important drug target for treating cancer that may involve enhanced RAS/RAF signalling, because of its central role in this pathway.
• When the activity of mutant B-RAF is blocked via MEK inhibitors, cancer cells stop growing and die.

Which patients benefit most from trametinib?

• Trametinib is specifically indicated for patients with melanoma whose tumours express gene mutations called BRAF V600E and V600K, as detected by an FDA-approved test.
• The BRAF protein produced as a result of this gene mutation has the amino acid (building block of protein) glutamate, instead of the amino acid valine, at position 600.
• Trametinib is not indicated for use for melanoma without V600 mutation.
• Trametinib is also not indicated for the treatment of patients who have received prior BRAF inhibitor therapy for melanoma.

Link to key clinical-trial evidence about trametinib.

Dosage and administration

The recommended dose of trametinib is 2 mg orally once daily, taken at least 1 hour before or at least 2 hours after a meal. A missed dose must not be taken within 12hours of the next dose.

Dose modification or partial/complete withdrawal of the drug is recommended in the case of severe skin toxicity, cardiomyopathy, ocular and pulmonary abnormalities.

What are the side effects of trametinib?

In clinical trials with trametinib, the most common side effects affecting ≥10% patients, and of any grade, were:

• rash (57%),
• diarrhoea (43%),
• lymphoedema (32%)
• acneiform dermatitis (19%)
• stomatitis (15%)
• hypertension (15%)
• abdominal pain (13%)
• haemorrhage (13%)
• dry skin (11%)
• pruritus/itch (10%)
• paronychia (10%).

Serious adverse reactions (affecting ≥2%), i.e. grades 3 and 4 were:

• hypertension (12%)
• rash (8%)
• pruritus (2%)
• stomatitis (2%).

Warnings and precautions

In clinical trials, the following adverse reactions have also been observed with trametinib.

• Cardiomyopathy
  11% of patients developed evidence of cardiomyopathy (decrease in left ventricular ejection fraction below lower limits of normal).
• Retinal pigment epithelial detachments
  The incidence of rapid pigment epithelial detachment was 0.8%. Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina.
• Retinal vein occlusion
  The incidence of retinal vein occlusion (RVO) was 0.2%. RVO may lead to macular oedema, decreased visual function, neovascularization (new blood vessel formation), and glaucoma.
• Interstitial lung disease
  At the recommended dose, interstitial lung disease or pneumonitis occurred in 1.8% of patients requiring hospitalisation.

Pregnancy

Trametinib can cause fetal harm when administered to a pregnant woman (pregnancy category D). The patient should be warned of the potential hazard to the fetus, if this drug is used during pregnancy or if the patient becomes pregnant while taking this drug. Female patients should be advised to use highly effective contraceptives during treatment with trametinib and for 4 months after treatment has stopped.

Paediatric use

To date studies evaluating trametinib in children have not been conducted.

Geriatric use

Clinical studies of trametinib did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Hepatic and renal impairment

No formal clinical study has been conducted to evaluate the effect of renal and hepatic impairment on the pharmacokinetics of trametinib. No dose adjustments are recommended in patients with mild renal or hepatic impairment based on population pharmacokinetic studies.

Drug interactions

No formal drug interaction studies have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib.

Future directions for trametinib

• Compared to most other MEK inhibitors in development, trametinib has a unique pharmacokinetic (PK) profile which provides prolonged exposure after once-daily dosing, with a low peak to trough concentration ratio and sustained levels of molecular target inhibition.
• Dabrafenib and trametinib were approved for use as monotherapy in 2013. The combination of dabrafenib and trametinib, Mekinist™, was provisionally approved by the FDA for unresectable and metastatic melanoma with BRAF V600E or V600K mutations, in 2014, and regular approval was gained in November 2015. The combination therapy targets multiple components of cell signalling and provides higher response rates and more durable clinical benefit than dabrafenib monotherapy.
• As both drugs target the MAPK pathway, combined blockade may circumvent or delay acquired resistance because of the reactivation of the MAPK pathway.