2014年4月25日，葛兰素史克（GSK）黑色素瘤药物Mekinist（trametinib）获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）的积极意见。CHMP建议批准Mekinist作为一种单药疗法，用于携带BRAF V600突变（V600E或V600K）的不可切除性或转移性黑色素瘤成人患者的治疗。Mekinist不适用于既往接受过BRAF抑制剂疗法的患者的治疗。在接受Mekinist治疗前，患者必须经过一款伴侣诊断试剂盒（THxID-BRAF）检测证实存在BRAF V600突变。
CHMP的积极意见，是基于一项随机、开放标签III期研究和一项非随机II期研究的数据。III期研究在322例携带BRAF V600突变（V600E和V600K）的黑色素瘤患者中开展，将trametinib单药疗法与化疗进行了对比。II期研究在在97例携带BRAF V600突变的黑色素瘤患者中开展，研究中将患者分为2组：BRAF抑制剂经治组和BRAF抑制剂初治组。
关于Mekinist（trametinib）：
Mekinist是首个MEK抑制剂，靶向于MAPK信号通路，该通路调节细胞的正常生长和死亡，包括皮肤细胞，在转移性黑色素瘤中发挥着关键作用。
Mekinist已获FDA和澳大利亚批准，作为单药疗法或与黑色素瘤药物Tafinlar（dabrafenib）联合用药。此外，加拿大也已批准Mekinist作为一种单药疗法。
Tafinlar是GSK开发的另一种黑色素瘤药物，该药是一种BRAF抑制剂，适用于携带BRAF V600E突变的手术不可切除性或转移性黑色素瘤成人患者的治疗，该药不适用于野生型BRAF黑色素瘤患者的治疗。   
CHMP的积极意见是药物在欧盟上市前的最后一个监管步骤。欧盟委员会（EC）预计将于2014年第二季度做出最终审查决定。
转移性黑色素瘤中，约有一半携带BRAF突变，该异常突变能促使黑色素瘤生长和扩散。其中，BRAF V600E突变和BRAF V600K突变分别约占转移性黑色素瘤所有BRAF V600突变的85%和10%.
PRESCRIBING HIGHLIGHTS:  Please see package insert for additional information and possible updates to ensure safe and effective use of this medication. The authors make no claims of the accuracy of the information contained herein; and these suggested doses are not a substitute for clinical judgment. Neither GlobalRPh Inc. nor any other party involved in the preparation of this program shall be liable for any special, consequential, or exemplary damages resulting in whole or part from any user's use of or reliance upon this material. Please read the disclaimer carefully BEFORE accessing or using this site. BY ACCESSING OR USING THIS SITE, YOU AGREE TO BE BOUND BY THE TERMS AND CONDITIONS SET FORTH IN THE DISCLAIMER.  
WARNINGS  
See warnings and precautions below.
DESCRIPTION  
MEKINIST (trametinib) tablets, for oral use
Initial U.S. Approval: 2013
Trametinib dimethyl sulfoxide is a kinase inhibitor.
Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media.
MEKINIST (trametinib) tablets are supplied as 0.5-mg, 1-mg, and 2-mg tablets for oral administration. Each 0.5-mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2-mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent.
CLINICAL PHARMACOLOGY: 
Mechanism of Action:
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.
Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.
INDICATIONS AND USAGE:
MEKINIST is a kinase inhibitor indicated as a single agent and in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. The use in combination is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with dabrafenib.
Limitation of use: MEKINIST as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy.
CONTRAINDICATIONS 
None.
PRECAUTIONS 
WARNINGS AND PRECAUTIONS:
1.New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is used in combination with dabrafenib. Monitor patients for new malignancies prior to initiation of therapy while on therapy, and following discontinuation of the combination treatment.
2.Hemorrhage: Major hemorrhagic events can occur in patients receiving MEKINIST in combination with dabrafenib. Monitor for signs and symptoms of bleeding.
3.Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur in patients receiving MEKINIST in combination with dabrafenib.
4.Cardiomyopathy: Assess LVEF before treatment, after one month of treatment, then every 2 to 3 months thereafter.
5.Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. For Retinal Vein Occlusion (RVO), permanently discontinue MEKINIST.
6.Interstitial Lung Disease (ILD): Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis.
7.Serious Febrile Reactions can occur when MEKINIST is used in combination with dabrafenib.
8.Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST.
9.Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.
10.Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus. 
ADVERSE REACTIONS
Most common adverse reactions (20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema.
Most common adverse reactions (20%) for MEKINIST in combination with dabrafenib include pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Avoid concurrent administration of strong inhibitors of CYP3A4 or CYP2C8 when MEKINIST is used in combination with dabrafenib.
Avoid concurrent administration of strong inducers of CYP3A4 or CYP2C8 when MEKINIST is used in combination with dabrafenib.
Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents when MEKINIST is used in combination with dabrafenib.
USE IN SPECIFIC POPULATIONS
•Nursing Mothers: Discontinue drug or nursing.
•Females and Males of Reproductive Potential: Counsel female patients on pregnancy planning and prevention. May impair fertility.
See PACKAGE INSERT for PATIENT COUNSELING INFORMATION and Medication Guide. 
DOSAGE AND ADMINISTRATION:
 Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST.
The recommended dosage regimens of MEKINIST are 2 mg orally once daily as a single agent or in combination with dabrafenib 150 mg orally twice daily. Take MEKINIST at least 1 hour before or at least 2 hours after a meal.
HOW SUPPLIED 
DOSAGE FORMS AND STRENGTHS
Tablets: 0.5 mg, 1 mg, and 2 mg.
REFERENCE
Package insert data:   [Accessed: Jan 2014].
GlaxoSmithKline
Research Triangle Park, NC 27709
Revised: January 2014
MEKINIST is a registered trademark of the GlaxoSmithKline group of companies.
©2014, GlaxoSmithKline group of companies. All rights reserved