1 INDICATIONS AND USAGE
1.1 BRAF V600E or V600K Mutation-Positive Unresectable or Metastatic Melanoma
MEKINIST® is indicated, as a single agent or 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 [see Clinical Studies (14.1)].
1.2 BRAF V600E Mutation-Positive Metastatic NSCLC
MEKINIST is indicated, in combination with dabrafenib, for the treatment of patients with metastatic nonsmall cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test [see Clinical Studies (14.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
- Melanoma
Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at:
http://www.fda.gov/CompanionDiagnostics.
- NSCLC
Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with MEKINIST and dabrafenib [see Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of BRAF V600E mutations in NSCLC is available at:
http://www.fda.gov/CompanionDiagnostics.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Metastatic, BRAF V600E Mutation-Positive NSCLC
12 CLINICAL PHARMACOLOGY
12.1 Mechanis m 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 cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutationpositive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.
14 CLINICAL STUDIES
14.1 BRAF V600E or V600K Mutation-Pos itive Unres ectable or Metas tatic Melanoma
14.2 BRAF V600E Mutation-Pos itive Metas tatic Non-Small Cell Lung Cancer (NSCLC)