Introduction

On May 29, 2013, the U. S. Food and Drug Administration (FDA) approved trametinib (MEKINIST™ tablets, GlaxoSmithKline, USA), as a single agent oral treatment for patients with non-operable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) with BRAF V600E or V600K mutations as detected by an FDA-approved test, called the THxID™ – BRAF assay from bioMérieux S.A.

Trametinib is the fourth new cancer drug approved that demonstrates an improvement in overall survival in melanoma patients.

It is not indicated for the treatment of patients who have received a prior BRAF inhibitor therapy such as dabrafenib or vemurafenib.

Clinical trial evidence for trametinib

FDA approval was based on results of the phase III METRIC trial.

METRIC trial highlights

• The approval of trametinib is based on results from the open-label, international Phase III METRIC study.
• 322 unresectable or metastatic melanoma adult patients with a BRAF V600E or V600K mutation, who had no more than one prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment, were randomised to receive trametinib or chemotherapy (dacarbazine) in a 2:1 ratio, respectively.
• Patients received either trametinib 2 mg orally once daily (n=214) or chemotherapy consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2 intravenously administered every three weeks (n= 108).
• Treatment continued until disease progression or unacceptable toxicity.
• The study demonstrated a statistically significant increase in progression-free-survival (PFS) in patients treated with trametinib, compared to chemotherapy (Hazard ratio [HR]= 0.47; [95% CI: 0.34, 0.65], p<0.0001).
• The median PFS was 4.8 months for patients taking trametinib (95% CI: 4.3, 4.9) compared to 1.5 months for chemotherapy (95% CI: 1.4, 2.7).
• Fifty-one patients (47%) crossed over from the chemotherapy arm at the time of disease progression to receive trametinib.

The most common adverse reactions (greater than or equal to 10%) of any grade in patients receiving trametinib included:

• rash (57%)
• diarrhoea (43%)
• lymphoedema (swelling of the face, arms or legs) (32%)
• dermatitis acneiform (acne-like rash) (19%)
• stomatitis (mouth sores) (15%)
• hypertension (new or worsening high blood pressure) (15%)
• abdominal pain (13%), haemorrhage (bleeding) (13%)
• dry skin (11%)
• pruritus (itching) (10%)
• paronychia (nail infection) (10%).

Key efficacy findings are summarised in the tables below.

Clinical trial evidence on the efficacy of combined dabrafenib and trematinib

• As both dabrafenib and trematinib target the MAPK pathway, combined blockade may circumvent or delay acquired resistance because of reactiva¬tion of the MAPK pathway.
• Combining the two drugs may also reduce the toxicities of each drug when given individually (especially cutaneous toxicity from dabrafenib).
• In a phase II trial patients were randomized 1:1:1 to CombiDT at a dose of dabrafenib 150 mg BID and trametinib 1 mg daily, CombiDT at a dose of dabrafenib 150 mg BID and trametinib 2 mg daily (150/2), or dabrafenib monotherapy (150 mg BID).
• BRAF/MEK inhibitor-naïve melanoma patients reported a response rate of 76% in those receiving CombiDT at the 150/2 dose, which was significantly higher than that in patients receiving dabrafenib monotherapy (54%; P = 0.026).
• The median PFS of 9.4 months in those receiving CombiDT at the 150/2 dose was significantly longer than that in the dabrafenib monotherapy arm (5.8 months; HR, 0.39; P <0.0001).
• These results are better than those reported in the previous phase III dabrafenib and trametinib monotherapy trials.
• Toxicities with this combination were generally mild.
• Notably, cutaneous toxicities such as hyperkeratosis, cutaneous squamous cell carcinoma, keratoacanthoma, and rash were greatly reduced, and there appeared to be a reduction in diarrhoea and hypertension (trametinib-related toxicities) compared with single-agent trametinib trials.
• The most common toxicity was fever, occurring in approximately 70% of patients (5% grade 3/4) of those patients receiving CombiDT at the 150/2 dose – much more frequent than with dabrafenib monotherapy.
• Two phase III trials of CombiDT are under way, comparing CombiDT at the 150/2 dose with dabrafenib and vemurafenib monotherapies.
• The results of these studies may lead to replacement of BRAF inhibitor monotherapy by combination BRAF and MEK inhibitor therapy as the first-line treatment for BRAFmut melanoma.