Encorafenib & Binimetinib
~ Encorafenib (Braftovi™) & Binimetinib (Mektovi™) ~
Encorafenib and binimetinib have been approved in combination for the treatment of unresectable or metastatic melanoma with V600E or V600K BRAF mutations. The presence of these mutations can be established with a companion test kit (THxID BRAF Kit by bioMérieux).
Encorafenib and binimetinib are both kinase inhibitors that target the RAS/RAF/ERK/MEK signaling pathway. In neoplastic cells, mutations at the V600 position in the BRAF protein can lead to a constitutively active enzyme, increased BRAF, ERK, MEK signaling, and uncontrolled cell proliferation.
Encorafenib directly inhibits wildtype BRAF and BRAF V600E (and other kinases).
Binimetinib reversibly inhibits the downstream kinase mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2.
Co-administration of encorafenib and binimetinib results in greater antiproliferative activity in-vitro and in mouse models than administration of either drug alone.
Administration and Dosing
Confirm presence of V600E/K mutations in tumor specimens before initiating therapy. The recommended dosing is 45 mg PO BID binimetinib in combination with 450 mg PO QD encorafenib to be given until disease progression or drug toxicities become intolerable. Dose adjustment should be considered in patients with hepatic impairment, or if co-administration with CYP3A4 inhibitors/inducers cannot be avoided.
New Malignancy, usually cutaneous (encorafenib label warning, >2% in combination clinical trials, >5% in single-agent trials)
Cardiomyopathy (binimetinib label warning, > 5% in clinical trials)
VTE & PE (binimetinib label warning, > 5% in clinical trials)
Ocular Toxicity (binimetinib & encorafenib label warnings, 20% in clinical trials)
Interstitial Lung Disease (binimetinib label warning, binimetinib, < 1% in clinical trials)
Hepatotoxicity (binimetinib label warning, > 5% in clinical trials)
Rhabdomyolysis (binimetinib label warning, > 50% elevated CPK in clinical trials)
Hemorrhage (binimetinib & encorafenib label warnings, > 15% in clinical trials)
QT Prolongation (encorafenib label warning, <1% w/ QTc > 500 ms in clinical trials)
Fetal Toxicity (binimetinib & encorafenib label warning, > 5% in clinical trials)
GI Distress (> 25% in clinical trials)
Fatigue (> 25% in clinical trials)
Pyrexia (> 15% in clinical trials)
Peripheral Edema (> 10% in clinical trials)
Rash (> 20% in clinical trials)
Hypertension (> 10% in clinical trials)
Anemia (> 30% in clinical trials)
Leukopenia (> 10% in clinical trials)
Contraindications & DDI
CYP3A4 Substrate (avoid CYP3A4 inducers and inhibitors if possible)
Avoid co-administration with agents that prolong QT interval
Avoid in pregnancy
~ Evidence-Basis ~
Encorafenib + binimetinib combination therapy for advanced melanoma with BRAF mutations was approved based on the results of one phase III clinical trial:
Trial 1, COLUMBUS: Randomized, phase III, open-label, comparator-controlled, 577 total participants. 192 patients with BRAF V600 mutation-positive metastatic or non-resectable melanoma treated with encorafenib + binimetinib combination therapy for median duration of 12 months (until disease progression or d/c due to drug toxicity). The median progression free survival in the combination therapy arm was 14.9 months compared with 7.3 months in the vemurafenib arm. Combination therapy also outperformed the encorafenib-only group.
~ What is Melanoma? ~
Melanoma is a malignant neoplasm of melanocytes, neural crest-derived cells responsible for producing the pigment melanin. Most melanomas are cutaneous-type (melanoma accounts for approximately 1% of all skin cancer cases), although ocular melanomas are diagnosed in 2,500 adults in the United States every year. Melanoma is the deadliest skin cancer, with a 5-year survival rate of less than 30% following distant metastasis. Risk factors for melanoma include sun exposure, multiple nevi, family history, and immunosuppression.