曲美替尼Mekinist(trametinib)

【Function and Indications】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 and V600K mutations detected by an FDA-approved test. The combined use is based on the demonstration of durable response rates. Improvements in disease-related symptoms and overall survival for the combination of MEKINIST and dabrafenib have not been demonstrated.

Limitations of Use: MEKINIST as a single agent is not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy.

On January 10, 2014, the U.S. Food and Drug Administration (FDA) approved Mekinist (trametinib) in combination with Tafinlar (dabrafenib) for the treatment of patients with unresectable (cannot be removed surgically) and metastatic (advanced) advanced melanoma.

In May 2013, the FDA approved both drugs as single-agent treatments for patients with unresectable or metastatic melanoma. Melanoma is the most aggressive type of skin cancer and the leading cause of death from skin diseases. The National Cancer Institute estimates that in 2013, 76,690 Americans will be diagnosed with melanoma and 9,480 will die from the disease.

Mekinist and Tafinlar are used to block signals in different parts of the same molecular pathway that promote cancer cell growth. They are particularly useful as a combination therapy for melanoma patients whose tumors express gene mutations called BRAF V600E and V600K. The BRAF protein is involved in regulating normal cell growth, but in about half of melanomas from the skin, it is mutated.

[Model and Specification] Tablet: 0.5 mg

[Usage and Dosage]
(1) Confirm the presence of BRAF V600E and V600K mutations in tumor samples before starting treatment with MEKINIST.

(2) The recommended dosage regimen of MEKINIST is 2 mg orally once daily as a single agent and in combination with dabrafenib 150 mg orally twice daily. Take MEKINIST at least 1 hour before and at least 2 hours after a meal.

【Precautions】

(1) New primary malignancies, skin and non-skin: May occur when MEKINIST is used in combination with dabrafenib.

(2) Bleeding: Major bleeding events may 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 may occur in patients receiving MEKINIST in combination with dabrafenib.

(4) Cardiomyopathy: Assess LVEF before treatment, 1 month after treatment, and then every 2 to 3 months.

(5) Ocular toxicity: Perform an ophthalmological evaluation for any visual impairment. For retinal vein occlusion (RVO), permanently discontinue MEKINIST.

(6) Interstitial lung disease (ILD): Withhold MEKINIST for new and progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD and pneumonitis.

(7) Severe febrile reactions: May occur when MEKINIST is used in combination with dabrafenib.
(8) Severe skin toxicity: Monitor for skin toxicity and secondary infection. Discontinue MEKINIST for intolerable Grade 2, and Grade 3 and 4 rash that does not improve within 3 weeks despite interruption of MEKINIST.

(9) Hyperglycemia: Monitor serum glucose levels in patients with preexisting diabetes and hyperglycemia.

(10) Embryofetal toxicity: May cause fetal harm. Advise females of reproductive potential of the risk to the fetus.

[Adverse Reactions and Contraindications]

(1) The most common adverse reactions (≥20%) for MEKINIST as a single agent include rash, diarrhea, and lymphedema.

(2) The most common adverse reactions (≥20%) for MEKINIST in combination with dabrafenib include fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia.

[Contraindications] Females and males of reproductive potential: Discuss pregnancy planning and prevention with female patients. May impair fertility.

[Pregnant women use] Nursing mothers: Discontinue medication and breastfeeding. May cause fetal harm. Advise females of reproductive potential of the risk to the fetus.

[Pediatric use] Safety and effectiveness have not been established for children.

[Drug interactions]
(1) Avoid co-administration of strong inhibitors of CYP3A4 and CYP2C8 when MEKINIST is used in combination with dabrafenib.
(2) Avoid co-administration of strong inducers of CYP3A4 and CYP2C8 when MEKINIST is used in combination with dabrafenib.
(3) When MEKINIST is used in combination with dabrafenib, concomitant use of drugs that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6 may result in loss of efficacy of these drugs.