Trametinib

Selumetinib is a MEK inhibitor from the class of serine/threonine kinase inhibitors. The drug was developed for the therapy of melanoma.

Trametinib is approved in combination with dabrafenib for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation (V600E/K). Furthermore, trametinib in combination with dabrafenib is approved for the adjuvant treatment of patients with stage III melanoma with a BRAF V600 mutation after complete resection (09 2018).

Furthermore, the drug is approved for advanced or metastatic non-small cell lung cancer: Trametinib is approved in combination with dabrafenib for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC; non-small cell lung cancer) with a BRAF-V600E mutation after prior chemotherapy.

When using trametinib, the recommended dose in combination with dabrafenib is 2 mg per os 1x/day; the recommended dose of dabrafenib is 150 mg p.o. 2x/day. Trametinib and dabrafenib should be taken without food, i.e. at least one hour before and at the earliest two hours after a meal.

The combination of trametinib and dabrafenib may cause new malignancies, both cutaneous and non-cutaneous: cutaneous squamous cell carcinoma, keratoacanthomas, new primary melanoma, pyrexia: the majority of pyrexia events occurred within the first month of therapy. Pyrexia may be accompanied by severe chills, dehydration and hypotension, which in some cases may lead to acute renal failure. Furthermore, colitis, perforation of the stomach or intestine, left ventricular dysfunction, dysrhythmia, bleeding, sometimes with fatal outcome, and ophthalmological complications were observed (detachment of the retinal pigment epithelium/retinal detachment, chorioretinopathy, retinal vein occlusion). In clinical studies with trametinibine in combination with dabrafenib, exanthema occurred in about 20 - 30% of patients.

Effect of other medicines on trametinib: Trametinib is not a substrate of CYP enzymes or the transporters BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, MRP2 and MATE1. Trametinib is deacetylated via carboxylic esterases. Interactions with other drugs are rather unlikely as drug interactions competing for esterases are not described in the literature.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion in July 2017, recommending that dabrafenib in combination with trametinib be authorised. The combination therapy was approved by the U.S. Food and Drug Administration in April 2018 and by the European Commission in September 2018 for the adjuvant treatment of adult stage III melanoma patients with a BRAF V600 mutation after complete resection.

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