Novel Kinase Inhibitor Combination Approved for Advanced Melanoma



The United States FDA has approved​​ the​​ kinase inhibitor​​ combination​​ encorafenib​​ (Braftovi™)​​ and​​ binimetinib​​ (Mektovi™) for the treatment of​​ advanced melanoma​​ with V600E/K​​ BRAF​​ mutations.

-​​ June 27th, 2018




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~  ​​ ​​​​ 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.




Adverse Events

  • 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. ​​ 



by​​ pharmacologyreview