Trametinib in metastatic melanoma

Abstract

The treatment of metastatic melanoma is rapidly changing. In 2002, the BRAF mutation was described in over 50% of melanomas and led to the first BRAF inhibitor, vemurafenib, being approved for clinical use in 2011. Clinical responses are often rapid but duration of response is limited due to the development of resistance. MEK is the next downstream target from BRAF in the MAP kinase pathway. Trametinib was the first MEK inhibitor to be approved for clinical use in 2013. Preclinical studies demonstrated a delay in resistance and a reduction in cutaneous toxicity by combined BRAF and MEK inhibition. Here, we review the rationale for clinical development of trametinib and give an update on recent clinical trials of trametinib alone and in combination with braf inhibition in melanoma.

Keywords:

• BRAF inhibitor
• medical oncology
• MEK inhibitor
• melanoma
• trametinib

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The MAPK pathway is important in targeting treatments in melanoma. BRAF mutations are present in 40–60% of patients with cutaneous melanoma and have proven to be effective targets in metastatic melanoma. However, resistance frequently develops after 5–7 months and hence other targets have been developed.

• MEK inhibitors have shown overall survival and progression-free survival benefit in BRAF mutant melanoma. They can delay onset of resistance and reduce cutaneous skin toxicity, mainly cutaneous squamous cell carcinoma, and keratocanthoma.

• Trametinib (GSK1120212) is a reversible, selective allosteric inhibitor of MEK 1 and MEK 2 activation and kinase activity, with a half-maximum inhibitory concentration (IC₅₀) of 0.7–0.9 nmol/l. It is the first MEK inhibitor to reach clinical practice.

• Trametinib is approved for BRAF-mutant metastatic melanoma in patients who have not been previously treated with a BRAF inhibitor, as a single agent and in combination with dabrafenib.

• Trials with the combination of a BRAF inhibitor and MEK inhibitor have been conducted. Dabrafenib, a BRAF inhibitor and trametinib have shown major improvements in response rates and progression-free survival (Combi-D). The main toxicity with combination treatment has been pyrexia, which is often self-limiting. Other common adverse effects (all grades) are diarrhea (24%), hypertension (22%), peripheral edema (14%), and increased LFTs (alanine transferase 11%; aspartate aminotransferase 11%).

• The COMBI-V trial has shown improvements in OS in favor of the dabrafenib and trametinib arm versus vemurafenib.

• The treatment algorithm for metastatic melanoma is continuing to develop and current recommendations will need to be updated with the evolution of new evidence.