What Is Binimetinib (Mektovi)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA-Approved: Yes (First Approval Date: 27 June 2018)
• Brand Name: Mektovi 
• Active Ingredient: Binimetinib
• Route of Administration: Oral, tablet
• Class: Signal Transduction Inhibitor, BRAF inhibitor (more specifically, a MEK inhibitor)
• Category: Targeted Agent
• Manufacturer: Array BioPharma
• Distribution in Turkey: Pierre Fabre İlaç A.Ş.
• Approved Cancers:
  • Metastatic Melanoma: With encorafenib for unresectable or metastatic melanoma with a BRAF-V600E/K mutation (2018).
  • Metastatic Non-Small Cell Lung Cancer (NSCLC): With encorafenib for metastatic NSCLC with a BRAF-V600E mutation (2023).

What Is Binimetinib?

Mektovi, containing binimetinib, is a targeted cancer drug that particularly targets cells with genetic alterations such as a BRAF-V600E mutation. It reversibly inhibits mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2), which support cell growth and proliferation.

NOTE: Encorafenib and binimetinib are used together for certain cancers, particularly BRAF V600E mutation-positive melanoma, because the combination suppresses signaling more effectively by targeting both BRAF and MEK pathways. This synergy reduces the risk of cancer cell resistance and improves treatment efficacy. 

How Does It Work?

• It reversibly inhibits mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and kinase 2 (MEK2).
• It suppresses cellular proliferation by inhibiting downstream regulators of the extracellular signal-regulated kinase (ERK) pathway.
• It inhibits the growth of BRAF-V600 mutation-positive melanomas, such as those with V600E.
• Binimetinib plus encorafenib increases growth inhibition in both in vitro and in vivo BRAF mutation-positive models, including melanoma and colorectal cancer.

The image above shows intracellular signaling pathways and the effects of various inhibitors on them. Beginning with the EGFR receptor, it details critical cellular pathways such as RAS-RAF-MEK-ERK and PI3K-AKT-mTOR after signals are received at the cell surface.

• BRAF inhibitors (encorafenib, vemurafenib, dabrafenib) and MEK inhibitors (binimetinib, trametinib) aim to halt cell proliferation by targeting the RAS-RAF-MEK-ERK pathway.
• EGFR inhibitors (cetuximab, panitumumab) and PI3K inhibitors (alpelisib, inavolisib) inhibit different points in signaling.

Suppressing these pathways with various drugs is therefore used to change gene expression and stop cancer cell growth and proliferation.

FDA (US Food and Drug Administration) Approval History

1. 11 October 2023: The FDA approved Braftovi (encorafenib) plus Mektovi (binimetinib) for metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.
2. 27 June 2018: The FDA approved Braftovi (encorafenib) plus Mektovi (binimetinib) for BRAF mutations in patients with unresectable or metastatic melanoma.

Licensing in Turkey

The conditions / therapeutic indications for which binimetinib is licensed in Turkey are stated as follows:

Therapeutic Indications:

Mektovi is indicated in patients who have not previously received any RAF pathway inhibitor, have an ECOG performance score of 0-1, and have locally relapsed or metastatic disease progressing after local treatments that cannot be repeated, with BRAF V600E mutation-positive malignant melanoma, for use with encorafenib until progression.

Is Mektovi Reimbursed?

Mektovi is not yet reimbursed in Turkey. Although licensed by the Ministry of Health, it has not yet entered the Turkish market. If it is a treatment option required for a patient, a medical oncologist can issue a prescription and report for an application to the Turkish Pharmacists' Association (TEB). The drug may then be imported for that patient. It is on TEB's overseas drug list.

Price: Mektovi 15 mg 84 tablets cost 81.820.38 TL. 

Resistance Mechanism

• Increased expression or activation of the PI3K/AKT pathway.
• Reactivation of the MAPK signaling pathway.
• Development of MEK2 mutations.
• Presence of NRAS mutations.
• Increased expression or activation of the HER2-neu pathway.

Pharmacokinetic Properties

Absorption

• Oral bioavailability is approximately 50%.
• Peak plasma concentration is reached 1.6 hours after oral administration.
• High-fat foods do not affect maximum concentration (Cmax) or area under the curve (AUC).

Distribution

• Plasma protein binding is 97%.

Metabolism

• It is metabolized in the liver through UGT1A1 glucuronidation. Other pathways include N-dealkylation, amide hydrolysis, and loss of ethanediol from the side chain.
• An active metabolite, M3, is produced in the liver through CYP1A2 and CYP2C19 and accounts for approximately 9% of binimetinib exposure.
• The drug is largely excreted through the hepatobiliary route (62%). Approximately 31% of the dose is excreted through the kidneys.

Half-Life

• Mean terminal half-life: 3.5 hours.

Dosage

• Metastatic Melanoma:
  45 mg twice daily (PO), with encorafenib.
• Metastatic Colorectal Cancer:
  45 mg twice daily (PO), with encorafenib and cetuximab.

Precautions

1. Cardiac Monitoring (LVEF Assessment)

   • Left ventricular ejection fraction (LVEF) should be assessed before treatment, 1 month after initiation, and every 3 months thereafter.
   • Treatment should be interrupted if LVEF decreases by 10% from baseline. If dysfunction does not recover within 4 weeks or symptomatic cardiomyopathy develops, treatment should be permanently discontinued.

2. No Dose Adjustment for Mild Hepatic Impairment

   • In moderate or severe hepatic impairment, the dose should be reduced to 30 mg twice daily.

3. No Dose Adjustment for Renal Impairment

   • Dose reduction is not required in mild, moderate, or severe renal impairment.

4. Counseling About Visual Impairment Risk

   • Patients should be warned about possible visual impairment, such as blurred vision, during treatment. Regular eye examinations should monitor for serious conditions such as serous retinopathy or retinal vein occlusion.

5. Monitoring for Bleeding

   • Patients should be monitored carefully for bleeding during and after treatment. Prompt intervention is required if symptoms such as rectal bleeding occur.

6. Risk of Developing New Cancers

   • The risk of new cutaneous and noncutaneous primary cancers may increase during treatment. Patients should be monitored closely because this risk may persist for up to 6 months after treatment ends.

7. Liver Function Test Monitoring

   • Liver function tests should be performed periodically during treatment to help manage hepatotoxicity risk.

8. Sun Protection

   • Patients should avoid sunlight exposure and take precautions to protect their skin. This is essential to preventing skin toxicity.

9. Muscle Enzyme Monitoring (CPK Assessment)

   • Creatine phosphokinase (CPK) levels should be monitored regularly during treatment because of the risk of rhabdomyolysis (muscle breakdown). Treatment should be interrupted if signs of rhabdomyolysis appear.

10. Use of an FDA-Approved BRAF Test

    • An FDA-approved diagnostic test should confirm the presence of BRAF-V600E or V600K mutations to ensure the drug is given only to suitable patients.

11. Embryo-Fetal Toxicity Risk

    • Women of childbearing potential should use effective contraception because of the drug's adverse effects on the fetus. Pregnancy should be avoided during treatment and for at least 30 days after the last dose. Breastfeeding should also be avoided during treatment and for 3 days after the last dose.

12. Toxicity Risks Affecting Blood and Muscle Tissue

    • Serious adverse effects such as bleeding complications, hematological toxicity, and rhabdomyolysis may occur during treatment. Appropriate clinical monitoring is needed to manage these toxicities.

Adverse Effects

Reported adverse effects, from most to least common, are:

1. Cardiac Toxicity: Cardiomyopathy and left ventricular dysfunction.
2. Ocular Toxicity: Visual impairment, retinal detachment, and retinal vein occlusion.
3. Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain.
4. Skin Toxicity: Rash, dermatitis.
5. Hepatotoxicity: Elevated liver function tests (ALT, AST).
6. Bleeding Complications: Rectal bleeding, hematochezia.
7. Venous Thromboembolic Events: Deep vein thrombosis and pulmonary embolism.
8. Rhabdomyolysis: Increased CPK levels.
9. Interstitial Lung Disease.