What is Mekinist (trametinib)?

What is Mekinist (Trametinib)?

Mekinist (trametinib) is an FDA-approved oral MEK1 and MEK2 inhibitor used primarily in combination with dabrafenib for treating BRAF V600E/K mutation-positive melanoma, working downstream of BRAF in the MAPK signaling pathway to block cancer cell proliferation. 1

Mechanism of Action

• Trametinib specifically binds to and inhibits MEK1 and MEK2, which are signaling molecules downstream of BRAF in the MAPK (mitogen-activated protein kinase) pathway 2
• This dual MEK inhibition blocks growth factor-mediated cell signaling and cellular proliferation in BRAF-mutated cancers 3
• When combined with dabrafenib (a BRAF inhibitor), it provides dual blockade of the MAPK pathway, which regulates cellular proliferation, differentiation, survival, and apoptosis 1

FDA-Approved Indications

• Primary indication: BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, both as monotherapy and in combination with dabrafenib 2, 3
• The combination therapy is now FDA-approved in the adjuvant setting for resected stage III melanoma with BRAF V600 mutations 2
• Standard dosing: trametinib 2 mg orally once daily in combination with dabrafenib 150 mg twice daily 1, 4

Clinical Efficacy

• Combination therapy (dabrafenib + trametinib) is superior to BRAF inhibitor monotherapy, demonstrating improved response rates, progression-free survival (PFS), and overall survival (OS) 2, 5
• As monotherapy, trametinib showed modest efficacy with a 22% response rate compared to 8% with chemotherapy, but this was lower than BRAF inhibitor monotherapy (48-53% response rates) 2
• Trametinib monotherapy failed to induce objective responses in patients previously treated with BRAF inhibitors, making it unsuitable for this population 2
• The combination prolonged median survival by approximately 6-8 months compared to vemurafenib or dabrafenib monotherapy 5, 6

Key Toxicity Profile

Common Adverse Effects

• Most frequent side effects include rash, diarrhea, peripheral edema, and fatigue 7, 4
• When combined with dabrafenib, pyrexia (fever) and nausea become prominent, with fever sometimes requiring drug interruption and antipyretics 2, 7
• Acneiform papulopustular eruptions and paronychia occur with MEK inhibition, similar to EGFR inhibitor toxicity 2

Serious Toxicities Requiring Monitoring

• Serous retinopathy (reversible) is the most notable ocular toxicity, requiring mandatory ophthalmologic surveillance 8
• Life-threatening complications include heart failure, deep vein thrombosis, bleeding (including intracranial hemorrhage), neutropenia, and gastrointestinal perforation 6
• Pneumonitis and retinal disorders also occur 6

Required Monitoring Protocol

• Mandatory pretreatment ophthalmologic examination with dilated fundoscopy before initiating trametinib 8
• Recheck ophthalmologic examination at 2-3 weeks after initiation to catch early serous retinopathy 8
• Ongoing ophthalmologic surveillance every 3-4 months during the first year of treatment 8
• Dabrafenib monotherapy has minimal ocular toxicity, but the combination requires the same monitoring as trametinib alone 8

Advantages of Combination Therapy Over Monotherapy

• Combination therapy reduces cutaneous toxicities compared to BRAF inhibitor monotherapy 2
• Fewer skin-related adverse events (cutaneous squamous cell carcinomas, keratoacanthomas, hyperkeratosis, hand-foot syndrome) occur with combination therapy due to reduced paradoxical MAPK pathway activation 2, 5
• Combination therapy attenuates or reverses many BRAF inhibitor side effects, though it introduces MEK-specific toxicities like acneiform eruptions 2

Important Clinical Caveats

• Trametinib is NOT indicated for patients who progressed on prior BRAF inhibitor therapy due to poor response and possible cross-resistance 2, 4
• Single-agent trametinib can only be used in patients intolerant to BRAF inhibitors, not those who progressed on them 2
• BRAF V600 mutation must be documented by FDA-approved or CLIA-approved testing before initiating therapy 2
• Unlike cytotoxic chemotherapy, trametinib works through specific molecular targeting, resulting in a distinct side effect profile rather than general cell toxicity 1

Management of Common Side Effects

• Acneiform eruptions can be managed with topical steroid ointments, topical or oral antibiotics (tetracyclines or cephalexins), and dilute bleach soaks 2
• Severe papulopustular eruptions may require isotretinib or drug cessation 2
• Most adverse events are mild to moderate in severity and generally manageable with dose interruptions, supportive care, and/or dose reductions 5, 7
• Pyrexia associated with dabrafenib should be managed by drug discontinuation and antipyretics (acetaminophen and/or NSAIDs) 2