ALITRAMETINIB ALIDABRAFENIB Trametinib Tablets 2mg Dabrafenib Capsules 75mg

[Product Name]: Trametinib + Dabrafenib

[English Name]: Trametinib and Dabrafenib

[Specifications]: Trametinib 2 mg × 30 tablets/box

Dabrafenib 75 mg × 120 capsules/box

[Manufacturer]: Lao United Pharmaceutical Group Co., Ltd.

Dabrafenib Approval Number (Lao National Drug Administration): 10 L 1222/24

Trametinib Approval Number (Lao National Drug Administration): 11 L 1256/24

Dabrafenib and Trametinib act like a pair of twins; they are typically employed in combination therapy to combat cancer.

Currently, FDA-approved indications for this combination include: melanoma, small cell lung cancer, and thyroid cancer.

Dabrafenib and Trametinib target different kinases within the serine/threonine kinase family—specifically BRAF and MEK1/2, respectively—within the RAS/RAF/MEK/ERK pathway. This pathway is implicated in non-small cell lung cancer (NSCLC) and melanoma, as well as other forms of cancer.

Mutations in the KRAS gene are currently considered among the most challenging genetic mutations to treat globally. In the context of lung cancer, patients harboring KRAS mutations tend to show a poor response to TKI (tyrosine kinase inhibitor) medications. Furthermore, the development of targeted therapies specifically directed at the KRAS mutation site presents significant technical challenges. Consequently, the treatment strategy for patients with KRAS mutations often begins by blocking the downstream signaling cascade (the RAS-RAF-MEK-ERK-MAPK pathway); in this regard, MEK inhibitors serve as ideal therapeutic agents for KRAS-mutated lung cancer. Trametinib is a MEK1/2 inhibitor that primarily exerts its therapeutic effect by acting on MEK proteins, thereby modulating the MAPK pathway and inhibiting cellular proliferation. Since MEK acts as a downstream signal transduction protein relative to RAS and RAF, Trametinib may also prove effective against cancers harboring RAS or RAF mutations. The U.S. FDA has approved Trametinib for the treatment of unresectable or metastatic melanoma harboring BRAF V600E or V600K mutations, as well as for use in combination with Dabrafenib for the treatment of metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. [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 cell proliferation. BRAF V600E mutations lead to constitutive activation of the BRAF pathway, which includes MEK1 and MEK2. Trametinib inhibits the growth of BRAF V600-mutant melanoma cells *in vitro* and *in vivo*.

Trametinib and dabrafenib target two distinct tyrosine kinases in the RAS/RAF/MEK/ERK pathway. In comparison to either drug used alone, the combination of trametinib and dabrafenib resulted in greater inhibition of BRAF V600-mutant melanoma cell lines *in vitro* and prolonged inhibition of tumor growth in BRAF V600-mutant melanoma xenografts.

[Indications and Usage]

TRAMETINIB 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, as detected by an FDA-approved test. The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutations.

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

[Dosage and Administration]

(1) Confirm the presence of BRAF V600E and V600K mutations in tumor specimens prior to initiating treatment with TRAMETINIB.

(2) The recommended dosage regimen for TRAMETINIB is 2 mg orally once daily as a single agent, and in combination with dabrafenib 150 mg orally twice daily.

Take TRAMETINIB at least 1 hour before a meal or at least 2 hours after a meal. [Contraindications] None.

[Warnings and Precautions]

(1) New Primary Malignancies (Cutaneous and Non-cutaneous): May occur when TRAMETINIB is used in combination with dabrafenib. Monitor patients for new malignancies prior to initiating treatment, during treatment, and following the discontinuation of combination therapy.

(2) Hemorrhage: Major hemorrhagic events may occur in patients receiving TRAMETINIB in combination with dabrafenib. Monitor for signs and symptoms of hemorrhage.

(3) Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism may occur in patients receiving TRAMETINIB in combination with dabrafenib.

(4) Cardiomyopathy: Assess Left Ventricular Ejection Fraction (LVEF) prior to treatment, one month after initiating treatment, and subsequently every 2 to 3 months thereafter.

(5) Ocular Toxicity: Conduct an ophthalmologic evaluation for any visual disturbances. Permanently discontinue TRAMETINIB in cases of Retinal Vein Occlusion (RVO).

(6) Interstitial Lung Disease (ILD): Withhold TRAMETINIB in the presence of new or progressive, unexplained pulmonary symptoms. Permanently discontinue TRAMETINIB in cases of treatment-related ILD or pneumonitis.

(7) Severe Febrile Reactions: May occur when TRAMETINIB is used in combination with dabrafenib.

(8) Severe Cutaneous Toxicity: Monitor for cutaneous toxicity and secondary infections. Discontinue treatment if Grade 2 rash is intolerable, or if Grade 3 or 4 rash does not improve within 3 weeks despite withholding TRAMETINIB.

(9) Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.

(10) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential regarding the potential risk to the fetus. [Adverse Reactions]

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

(2) The most common adverse reactions (≥20%) associated with TRAMETINIB 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.

[Drug Interactions]

(1) When TRAMETINIB is used in combination with dabrafenib, avoid the concomitant administration of strong inhibitors of CYP3A4 and CYP2C8.

(2) When TRAMETINIB is used in combination with dabrafenib, avoid the concomitant administration of strong inducers of CYP3A4 and CYP2C8.

(3) When TRAMETINIB is used in combination with dabrafenib, the concomitant use of drugs that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6 may result in a loss of therapeutic efficacy for these drugs.

[Use in Specific Populations]

(1) Nursing Mothers: Discontinue the drug or discontinue nursing.

(2) Females and Males of Reproductive Potential: Counsel female patients regarding pregnancy planning and prevention. May impair fertility.