Indications TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.
TAFINLAR, in combination with MEKINIST, is indicated for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection.
Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma. MEKINIST is not indicated for treatment of patients who have progressed on prior BRAF-inhibitor therapy.
TAFINLAR® (dabrafenib) capsules, in combination with MEKINIST® (trametinib) tablets, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test.
Limitation of Use: TAFINLAR is not indicated for the treatment of patients with wild-type BRAF melanoma. MEKINIST is not indicated for the treatment of patients who have progressed on prior BRAF-inhibitor therapy.
Cutaneous Malignancies: In the COMBI-d study in patients with unresectable or metastatic melanoma, the incidence of basal cell carcinoma in patients receiving TAFINLAR with MEKINIST was 3.3% compared with 6% of patients receiving single-agent TAFINLAR. Among the 7 patients receiving TAFINLAR with MEKINIST who developed basal cell carcinoma, 2 experienced more than 1 occurrence (range: 1 to 3). Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma, and new primary melanoma occurred in 3% and 0.5% of patients receiving TAFINLAR with MEKINIST, respectively.
In the COMBI-AD study, cuSCC and new primary melanoma occurred in 1% and <1% of patients receiving TAFINLAR with MEKINIST, respectively.
Noncutaneous Malignancies: In the COMBI-d study, noncutaneous malignancies occurred in 1.4% of patients receiving TAFINLAR with MEKINIST. In the COMBI-AD study, noncutaneous malignancies occurred in 1% of patients receiving TAFINLAR with MEKINIST. Monitor patients closely for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for monomeric G protein (RAS)-mutation–positive noncutaneous malignancies. No dose modification of MEKINIST is required for patients who develop noncutaneous malignancies.
Tumor Promotion in BRAF Wild-type Melanoma. In vitro experiments have demonstrated paradoxical activation of mitogen-activated protein kinase (MAPK) signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of therapy.
Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur. In the COMBI-d study, the incidence of hemorrhagic events in patients treated with the combination was 19% compared with 15% of patients receiving single-agent TAFINLAR. Gastrointestinal hemorrhage occurred in 6% of patients treated with the combination compared with 3% of patients receiving single-agent TAFINLAR. In the COMBI-d study, intracranial hemorrhage was fatal in 1.4% of patients receiving the combination. No fatal hemorrhagic events were observed in the COMBI-AD study.
Venous Thromboembolism. In the COMBI-d study, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of patients treated with the combination. In the COMBI-AD study, DVT and PE occurred in 2% of patients receiving TAFINLAR with MEKINIST.
Cardiomyopathy. Cardiomyopathy, including cardiac failure, can occur. In the COMBI-d study, cardiomyopathy (defined as a decrease in left ventricular ejection fraction [LVEF] ≥10% from baseline and below the institutional lower limit of normal [LLN]) occurred in 6% of patients treated with the combination and 2.9% of patients receiving single-agent TAFINLAR, and resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Development of cardiomyopathy resulted in dose interruption of TAFINLAR (4.4%) or discontinuation of TAFINLAR (1.0%) in patients receiving the combination. In patients receiving single-agent TAFINLAR, development of cardiomyopathy resulted in dose interruption, reduction, or discontinuation in 2.4%, 0.5%, and 1.0% of patients, respectively. Cardiomyopathy resolved in 10 of 12 patients receiving the combination and in 3 of 6 patients receiving single-agent TAFINLAR.
In the COMBI-AD study, cardiomyopathy, defined as a decrease in LVEF below the institutional LLN with an absolute decrease in LVEF >10% below screening, occurred in 3% of patients receiving TAFINLAR with MEKINIST and resulted in discontinuation, dose reduction, and dose interruption of TAFINLAR in 0.2%, 1.6%, and 2.1% of patients, respectively. Cardiomyopathy resolved in 12 of 14 patients receiving TAFINLAR with MEKINIST.
Interstitial Lung Disease (ILD). In clinical trials of MEKINIST as a single agent, ILD or pneumonitis occurred in 2% of patients. In the COMBI-d study, 1.0% of patients treated with the combination developed pneumonitis. In the COMBI-AD study, <1% of patients treated with the combination developed pneumonitis.
Most Common Adverse Reactions. In the COMBI-d and COMBI-v studies, the most common adverse reactions (≥20%) for the combination were pyrexia (54%), nausea (35%), rash (32%), chills (31%), diarrhea (31%), headache (30%), vomiting (27%), hypertension (26%), arthralgia (25%), peripheral edema (21%), and cough (20%). In the COMBI-d and COMBI-v studies, the most common grade 3 or 4 adverse reactions (≥2%) for the combination were hypertension (11%), pyrexia (5%), and hemorrhage (2%). In the COMBI-AD study, the most common adverse reactions (>20%) for the combination were pyrexia (63%), fatigue (59%), nausea (40%), headache (39%), rash (37%), chills (37%), diarrhea (33%), vomiting (28%), arthralgia (28%), and myalgia (20%). The most common grade 3 or 4 adverse reactions (>2%) for the combination were pyrexia (5%) and fatigue (5%).
Other Clinically Important Adverse Reactions. In the COMBI-d and COMBI-v studies, other clinically important adverse reactions observed in <10% of patients receiving the combination were pancreatitis, panniculitis, bradycardia, and rhabdomyolysis. In the COMBI-AD study, other clinically important adverse reactions observed in <20% of patients receiving the combination were blurred vision (6%), decreased ejection fraction (5%), and rhabdomyolysis (<1%).
Laboratory Abnormalities. In the COMBI-d and COMBI-v studies, treatment-emergent laboratory abnormalities occurring in ≥10% of patients receiving the combination were hyperglycemia (60%), increased aspartate aminotransferase (AST) (59%), increased blood alkaline phosphatase (49%), increased alanine aminotransferase (ALT) (48%), hypoalbuminemia (48%), neutropenia (46%), anemia (43%), hypophosphatemia (38%), lymphopenia (32%), hyponatremia (25%), and thrombocytopenia (21%). In the COMBI-AD study, treatment-emergent laboratory abnormalities occurring in >20% of patients receiving the combination were hyperglycemia (63%), increased AST (57%), increased ALT (48%), neutropenia (47%), hypophosphatemia (42%), increased blood alkaline phosphatase (38%), lymphopenia (26%), anemia (25%), and hypoalbuminemia (25%).