MEKINIST

What it is

MEKINIST (trametinib) is available as film-coated tablets in strengths of 0.5 mg and 2 mg, and as a powder for oral solution at 0.05 mg/mL. Trametinib works by inhibiting MEK1 and MEK2 in the MAP kinase pathway.

Approved indications —

Unresectable or metastatic melanoma with BRAF V600 mutation, in combination with dabrafenib. — Unresectable or metastatic melanoma with BRAF V600 mutation, as monotherapy, in patients with intolerance to BRAF inhibitors or in whom BRAF inhibitors cannot be used. — Adjuvant treatment of melanoma with BRAF V600 mutation and lymph node involvement following complete resection, in combination with dabrafenib. — Locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600 mutation and no satisfactory locoregional treatment options, in combination with dabrafenib. — Advanced non-small cell lung cancer (NSCLC) with BRAF V600 mutation, in combination with dabrafenib. — Low-grade glioma (LGG) with BRAF V600E mutation in paediatric patients 1 year of age and older who require systemic therapy, in combination with dabrafenib. — High-grade glioma (HGG) with BRAF V600E mutation in paediatric patients 1 year of age and older who have progressed following prior treatment and have no satisfactory alternative treatment options, in combination with dabrafenib.

Dosing overview

For adults, the recommended dose of MEKINIST used as monotherapy or in combination with dabrafenib is 2 mg given orally once daily independent of body weight. MEKINIST should be taken without food, at least 1 hour before or 2 hours after a meal. Doses below 1 mg once daily are not recommended. Dose reductions may be made to 1.5 mg or 1 mg once daily based on tolerability of adverse events. For paediatric patients weighing at least 26 kg using film-coated tablets, dosing is weight-based: 1 mg daily for 26–37 kg, 1.5 mg daily for 38–50 kg, and 2 mg daily for 51 kg or greater. Treatment duration for unresectable or metastatic melanoma, metastatic NSCLC, or locally advanced or metastatic anaplastic thyroid cancer is until disease progression or unacceptable toxicity, whilst adjuvant melanoma treatment is limited to a maximum of 1 year.

Key safety warnings

Confirmation of the BRAF V600 mutation using an approved or validated test is required for the selection of patients appropriate for MEKINIST monotherapy and in combination with dabrafenib. The efficacy and safety of MEKINIST have not been established in patients with wild-type BRAF tumours and should not be used in such patients. Haemorrhagic events including major haemorrhagic events have occurred in patients taking MEKINIST as monotherapy and in combination with dabrafenib, with six out of 559 patients (1.1%) receiving the combination in phase III trials for unresectable or metastatic melanoma experiencing fatal intracranial haemorrhagic events. If patients develop symptoms of haemorrhage they should immediately seek medical care. MEKINIST has been reported to decrease left ventricular ejection fraction (LVEF), with the median time to onset between two to five months in clinical trials. Across clinical trials at the recommended dose, 11% of patients developed evidence of cardiomyopathy and 5% demonstrated a decrease in LVEF of at least 20% below baseline. LVEF should be evaluated in all patients prior to initiation of treatment, one month after initiation of therapy, and then at approximately three monthly intervals whilst on treatment. Disorders associated with visual disturbance, including retinal pigment epithelial detachment (RPED) and retinal vein occlusion (RVO), have been observed with MEKINIST, and if patients report new visual disturbances such as diminished central vision, blurry vision, or loss of vision, a prompt ophthalmological assessment is recommended. Interstitial lung disease (ILD) or pneumonitis warrants immediate discontinuation of MEKINIST; in a phase 3 trial, 2% of patients treated with MEKINIST monotherapy developed ILD or pneumonitis, with a median time to first presentation of 160 days. Pyrexia was reported in clinical trials with MEKINIST, with increased incidence and severity when used in combination with dabrafenib, and pyrexia may be accompanied by severe rigors, dehydration, and hypotension which in some cases can lead to acute renal insufficiency. Therapy should be interrupted if the patient's temperature is ≥38.0°C or at the first symptom of pyrexia or pyrexia syndrome. Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with MEKINIST in combination with dabrafenib. Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking MEKINIST, and it should be used with caution in patients with risk factors for gastrointestinal perforation. Hepatic adverse events including increased transaminases and hepatic failure have been reported with MEKINIST, and it is recommended that patients have liver function monitored every four weeks for 6 months after treatment initiation.

Contraindications

MEKINIST is contraindicated in patients with known hypersensitivity to the active substance trametinib dimethyl sulfoxide or any of the excipients.

PBS listing

Information regarding PBS listing and pricing is not provided in the source documents.

Regulatory history

MEKINIST trametinib 2 mg and 0.5 mg tablets were first listed on the ARTG on 14 February 2014 under licence category RE. The powder for oral solution formulation (0.05 mg/mL) was first listed on 6 December 2023. The TGA approved MEKINIST as monotherapy and in combination with dabrafenib for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic Stage IV melanoma on 11 February 2014. The TGA evaluated trametinib as a new chemical entity, recognising the limited therapeutic options for BRAF V600 mutation-positive unresectable or metastatic melanoma. In November 2014, the PBAC recommended an amendment to the PBS listing to allow treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation who have progressed on or after prior treatment with ipilimumab. In July 2016, the PBAC recommended a price change, concluding that the clinical benefit had been over-estimated when approved in November 2014. In November 2017, the PBAC recommended new indications for adjuvant treatment of melanoma with BRAF V600 mutation. MEKINIST is subject to additional monitoring in Australia due to approval of an extension of indications, to allow quick identification of new safety information.