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Guidance for Initiating a Targeted Combination Treatment for BRAF Mutation-Positive Stage III or Advanced Melanoma

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What do you need to take into consideration to start patients with BRAF V600E or V600K mutation-positive stage III or advanced melanoma on a targeted combination treatment option?

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  • Overview

    Before starting patients on TAFINLAR® (dabrafenib) capsules + MEKINIST® (trametinib) tablets, what screening and monitoring recommendations are important for patients with BRAF V600E or V600K mutation-positive stage III or advanced melanoma? Grace Cherry, RN, MSN, NP, and Suzanne McGettigan, MSN, share guidance on initiating treatment with TAFINLAR + MEKINIST.

    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.

  • Important Safety Information

    • Across clinical trials of TAFINLAR® (dabrafenib) capsules administered with MEKINIST® (trametinib) tablets (“the combination”), the incidence of cutaneous squamous cell carcinomas (cuSCCs), including keratoacanthomas, occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and <1% of patients, respectively. Perform dermatologic evaluations prior to initiation of the combination, every 2 months while on therapy, and for up to 6 months following discontinuation. Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of monomeric G protein (RAS) through mutation or other mechanisms. Across clinical trials of TAFINLAR monotherapy and the combination, noncutaneous malignancies occurred in 1% of patients. Monitor patients receiving the combination for signs or symptoms of noncutaneous malignancies. Permanently discontinue TAFINLAR for RAS-mutation-positive noncutaneous malignancies. No dose modification is required for MEKINIST in patients who develop noncutaneous malignancies.

    • TAFINLAR can cause paradoxical tumor growth in patients with BRAF wild-type tumors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of therapy.

    • Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with the combination. Fatal cases have been reported.

    • Across clinical trials of the combination, hemorrhagic events occurred in 17% of patients. Gastrointestinal hemorrhage occurred in 3% of patients who received the combination. Intracranial hemorrhage occurred in 0.6% of patients who received the combination. Fatal hemorrhage occurred in 0.5% of patients who received the combination. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

    • Colitis and gastrointestinal perforation, including fatal outcomes, can occur. Across clinical trials of the combination, colitis occurred in <1% of patients and gastrointestinal perforation occurred in <1% of patients.

    • Across clinical trials of the combination, deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients. Advise patients to seek medical care immediately if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling.

    • Cardiomyopathy, including cardiac failure, can occur. Across clinical trials of the combination, 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. Development of cardiomyopathy resulted in dose interruption or discontinuation of TAFINLAR in 3% and <1% of patients, respectively, and in 3% and <1% of patients receiving MEKINIST, respectively.
      Cardiomyopathy resolved in 45 of 50 patients who received the combination.

    • Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of the combination, 1 month after initiation, and then at 2- to 3-month intervals while on treatment.

    • Ocular toxicities, including retinal vein occlusion (RVO), retinal pigment epithelial detachment, and uveitis can occur. There were no cases of RVO across clinical trials of the combination; uveitis occurred in 2% of patients treated with the combination across trials. RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

    • Interstitial lung disease/pneumonitis occurred in 1% of patients across trials of the combination.

    • Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure, can occur. Across clinical trials of the combination, fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration, or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in <1% of patients.

    • Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with the combination. Across clinical trials of the combination, other serious skin toxicity occurred in <1% of patients. Monitor for new or worsening serious skin reactions.

    • Across clinical trials of the combination, 15% of patients with a history of diabetes required more intensive hypoglycemic therapy. Grade 3 and grade 4 hyperglycemia occurred in 2% of patients. Monitor serum glucose levels upon initiation and as clinically appropriate in patients with preexisting diabetes or hyperglycemia. Initiate or optimize antihyperglycemic medications as clinically indicated.

    • Monitor patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as TAFINLAR confers a potential risk of hemolytic anemia in these patients.

    • TAFINLAR and MEKINIST can cause fetal harm when administered to a pregnant woman.

    • 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%). 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%).

    • 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%), rhabdomyolysis (<1%), and sarcoidosis (<1%).

    • 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%).

    Please see full Prescribing Information for TAFINLAR and full Prescribing Information for MEKINIST.


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Schedule20 Oct 2021
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