The addition of a MEK inhibitor (Mekinist) to a BRAF inhibitor (Tafinlar) to decrease the ability of melanoma to reactivate the MAPK signaling, Possibly preventing or delaying the emergence of resistance.
TAFINLAR® (dabrafenib) + MEKINIST® (trametinib)
For patients with BRAF+ unresectable or metastatic melanoma.
Oral dosing with TAFINLAR + MEKINIST
Recommended dose: TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily.
First dose – Morning: TAFINLAR 150 mg (2 x 75 mg) Second dose – Evening: TAFINLAR 150 mg (2 x 75 mg).
Take MEKINIST at the same time each day with either the morning dose OR evening dose of TAFINLAR Once daily: MEKINIST 2 mg.
Both TAFINLAR and MEKINIST should be taken without food, at least 1 hour before or 2 hours after a meal
A missed dose of TAFINLAR should not be taken within 6 hours of the next dose, or a missed dose of MEKINIST within 12 hours of the next dose.
MEKINIST should be stored in the refrigerator between 36°F to 46°F.
TAFINLAR should be stored at room temperature.
Treatment with TAFINLAR + MEKINIST should continue until disease progression or unacceptable toxicity occurs
Dose Reductions for TAFINLAR toxicity: First dose reduction100 mg orally twice daily.
Second dose reduction75 mg orally twice daily.
Third dose reduction 50 mg orally twice daily.
Permanently discontinued if unable to tolerate 50 mg orally twice daily
Dose Reductions for MEKINIST:
First dose reduction1.5 mg orally once daily.
Second dose reduction 1 mg orally once daily.
Permanently discontinue if unable to tolerate 1 mg orally once daily
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 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.
New primary malignancies: basal cell carcinoma 6%, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma 10%; new primary melanoma1.9%.
Dermatologic evaluations should be done prior to initiation of therapy, every 2 months while on therapy and for up to 6 months following discontinuation of TAFINLAR.
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 compared with TAFINLAR as a single agent was 19% (40/209) vs 15% (32/211), respectively.
Gastrointestinal hemorrhage occurred in 6% of 209 patients treated with the combination compared with 3% of 211 patients treated with TAFINLAR alone.
Intracranial hemorrhage was fatal in 1.4% of 209 patients receiving the combination compared with no patients receiving TAFINLAR as a single agent.
Permanently discontinue TAFINLAR and MEKINIST for all grade 4 hemorrhagic events, and for any persistent grade 3 hemorrhagic events.
Withhold the combination for grade 3 hemorrhagic events; if improved, resume at a lower dose.
Colitis and gastrointestinal perforation, including fatal outcomes, can occur: colitis occurred in 0.6% of patients and gastrointestinal perforation occurred in 0.3% of patients, respectively.
Deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% of 209 patients treated with the combination vs 0.9% of 211 patients treated with TAFINLAR as a single agent.
Cardiomyopathy, including cardiac failure, can occur.
It is recommended to assess LVEF by an echocardiogram or a multigated acquisition (MUGA) scan before initiation of therapy, 1 month after initiation then at 2‑ to 3‑month intervals while on treatment.
Patients should be monitored for visual signs and symptoms of uveitis.
Serious skin toxicity occurs in 0.7% of patients.
Monitoring serum glucose levels upon initiation, and as clinically appropriate in patients with preexisting diabetes or hyperglycemia.
TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman.
TAFINLAR can render hormonal contraceptives ineffective.
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‑d and COMBI‑v studies, other clinically important adverse reactions observed in <10% of patients receiving the combination were pancreatitis, panniculitis, bradycardia, and rhabdomyolysis.
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 AST (59%), increased blood alkaline phosphatase (49%), increased ALT (48%), hypoalbuminemia (48%), neutropenia (46%), anemia (43%), hypophosphatemia (38%), lymphopenia (32%), hyponatremia (25%), and thrombocytopenia (21%).
The majority of resistance to BRAFF inhibitors may be due to MAPK pathway reactivation.
The above combination is approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations.
The combination of these 2 drugs targeted to different tyrosine kinases in the RAS/RAF/MEK/ERK pathway.
Cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 7% of patients treating with the above combination.
The combination of the above drugs and her increased incidence of DVT and pulmonary embolism.
Hemorrhage, including major bleeding can occur With the above combination of drugs at a rate as high as 16%.
Initial dosage Tafinlar 150 mg twice daily and Mekinist 2 mg once a day