What Is Cobimetinib (Cotellic)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes (Initial approval date: 10 November 2015)
• Brand Name: Cotellic
• Active Ingredient Name: Cobimetinib
• Route of Administration: Oral (tablet form)
• Class: Signal Transduction Inhibitor, MEK Inhibitor
• Category: Targeted Agent
• Manufacturer: Genentech/Roche
• Turkey Distributor: Genentech
• Approved Cancer Indications:
  • Metastatic Melanoma:
    • Used in combination with vemurafenib in patients with a BRAF-V600E or V600K mutation.
  • Histiocytic Neoplasms:
    • FDA-approved for use as a single agent.

What Is Cotellic?

Cotellic, whose active ingredient is cobimetinib, is an oral MEK inhibitor used to treat metastatic melanoma with a BRAF-V600 mutation. It aims to inhibit tumor growth and slow disease progression, particularly when used in combination with vemurafenib.

What Is a MEK Inhibitor?

MEK inhibitors are drugs that target the RAS-RAF-MEK-ERK signaling pathway, which controls cell growth. This pathway becomes overactive, particularly in cancers such as melanoma with a BRAF mutation, causing uncontrolled cell growth. MEK inhibitors block the MEK1 and MEK2 proteins, halting cell division and inhibiting tumor growth.

How Does It Work?

• MEK1 and MEK2 Inhibition:
  Cobimetinib inhibits the mitogen-activated extracellular signal-regulated kinase 1 and 2 (MEK1 and MEK2) enzymes.
• Blocking ERK Pathway Activity:
  Inhibition of MEK1 and MEK2 blocks the activity of the downstream ERK pathway, preventing cellular proliferation (growth and division).
• Inhibition of Tumor Growth:
  It is particularly effective in melanoma cells with a BRAF-V600 mutation, stopping the growth and spread of cancer cells.
• Combination Therapy:
  When used in combination with vemurafenib, it blocks the signaling pathway at both the BRAF and MEK levels, increasing treatment efficacy.

FDA (US Food and Drug Administration) Approval History

• 10 November 2015:
  Cotellic (cobimetinib) received FDA approval for use in combination with vemurafenib (Zelboraf) to treat advanced melanoma.
• 1 November 2022:
  Cotellic was approved by the FDA for use as a single agent for histiocytic neoplasms.

Key Developments

• 18 February 2015:
  The FDA granted priority review status to cobimetinib. This review covered its use in combination with Zelboraf to treat melanoma.
• 14 December 2014:
  Genentech submitted a new drug application (NDA) for cobimetinib to the FDA. The application covered its use in combination with Zelboraf for melanoma.
• 1 July 2015:
  Exelixis published an update on Genentech's FDA application for cobimetinib.

Licensing in Turkey

The conditions / therapeutic indications for which Cotellic is licensed in the Republic of Turkey are stated as follows:

Therapeutic indications

• Cotellic is indicated in combination with vemurafenib until progression in patients with relapsed or metastatic malignant melanoma positive for a BRAF V600 mutation who have not previously received any RAF pathway inhibitor, have an ECOG performance score of 0 or 1, have progressed after local treatments, and cannot receive further local treatments.
• It cannot be used after progression, either as a single agent or in combination with other treatments. Cotellic is not appropriate as a single agent for this indication.

Is Cotellic Reimbursed?

The treatment settings in which Cotellic is reimbursed by Turkey's Social Security Institution (SGK) are as follows:

• SGK covers Cotellic in combination with vemurafenib until progression in patients with relapsed or metastatic malignant melanoma positive for a BRAF V600 mutation who have not previously received any RAF pathway inhibitor, have an ECOG performance score of 0 or 1, have progressed after local treatments, and cannot receive further local treatments.

What Is Cotellic's Status on the List of Off-Label Drugs Usable Without Additional TİTCK Approval?

• Stage IV Malignant Melanoma: Appropriate for use in the 1st line in disease with a BRAF V600 mutation.

Price: As of August 2025, Cotellic 20 mg tablets cost 90.833.51 TL. 

Resistance Mechanism

• Increased Expression and/or Activation of the PI3K/AKT Pathway:
  This pathway increases signals that support cell growth and survival, which may reduce the efficacy of MEK inhibitors.
• Reactivation of the MAPK Signaling Pathway:
  Reactivation of this pathway can allow tumor growth to continue by reactivating the signaling targeted by MEK inhibitors.
• Emergence of MEK2 Mutations:
  Mutations in MEK2 may limit the effects of inhibitors and allow tumor cells to grow.
• Presence of NRAS Mutations:
  NRAS mutations may cause signaling pathways to be bypassed and reduce the efficacy of MEK inhibitors.
• Increased Expression and/or Activation of the HER2-Neu Pathway:
  This pathway may contribute to resistance to MEK inhibitors by providing an alternative signaling mechanism that promotes cancer cell growth and spread.

Pharmacokinetic Properties

• Absorption
  Cobimetinib has an oral bioavailability of approximately 46%. It reaches peak plasma concentrations within 2.4 hours after oral administration. High-fat foods have been reported not to alter the rate of absorption and not to affect systemic drug exposure.
• Distribution
  Cobimetinib is 95% bound to plasma proteins. With daily dosing, steady-state blood levels are reached in approximately 9 days.
• Metabolism
  Cobimetinib is metabolized in the liver primarily through CYP3A4 oxidation. A portion of the drug is metabolized through glucuronidation. Excretion occurs mainly through feces (76%) and urine (18%). Its terminal half-life is approximately 44 hours.

Dosing Schedule

The recommended dose of cobimetinib is 60 mg once daily in a 21-day cycle. Each cycle lasts 28 days, meaning it includes a 7-day drug-free period. It may be taken with or without food during treatment.

Drug Interactions

• CYP3A4 Inducers:
  CYP3A4 inducers such as phenytoin, rifampin, and St. John's Wort may increase cobimetinib metabolism and reduce its efficacy.
• CYP3A4 Inhibitors:
  Inhibitors such as ketoconazole and erythromycin may reduce cobimetinib metabolism and increase the risk of toxicity.
• Warfarin:
  Cobimetinib may affect warfarin metabolism. PT and INR values should be monitored because of the risk of bleeding.

Precautions

• Risk of New Cancers:
  Patients should be monitored regularly during Cotellic treatment because of the increased risk of cutaneous and noncutaneous primary cancers. This risk may persist for up to 6 months after treatment ends.
• Skin Reactions:
  Reactions such as skin rashes are common. Treatment interruption or dose adjustment should be considered for moderate-to-severe reactions.
• Liver Function Tests:
  Liver function should be monitored regularly during treatment. It should be used cautiously in patients with moderate or severe hepatic impairment.
• Sun Exposure:
  Patients should protect themselves from sunlight and use sunscreen. There is a risk of photosensitivity (sensitivity to light).
• CPK Levels:
  Creatine phosphokinase (CPK) levels should be monitored regularly before and during treatment because of the risk of rhabdomyolysis.
• LVEF Monitoring:
  Cardiac monitoring should be performed before and during treatment because decreased left ventricular ejection fraction (LVEF) has been reported. Treatment may be stopped if a decrease in LVEF is detected.
• BRAF Testing:
  The presence of a BRAF-V600 mutation should be confirmed using an FDA-approved test before treatment begins.
• Renal Impairment:
  No dose adjustment is required in patients with mild or moderate renal impairment. Caution should be exercised in severe renal impairment.
• Hepatic Impairment:
  No dose adjustment is required in patients with mild hepatic impairment. However, it should be used cautiously in patients with moderate or severe hepatic impairment.
• Pregnancy and Breastfeeding:
  It is pregnancy category D. Its use during pregnancy is contraindicated. It is also not recommended for breastfeeding women.
• Vision Problems:
  Because of visual adverse effects such as serous retinopathy or retinal vein occlusion, an eye examination should be performed if changes in vision occur during treatment.
• Bleeding Risk:
  Cotellic may increase the risk of serious bleeding, such as gastrointestinal bleeding. Patients should be monitored closely for signs of bleeding.
• Hypertension and Heart Rate:
  Blood pressure and heart rate should be monitored monthly during the first year of treatment.
• Skin Toxicity:
  Treatment should be stopped or the dose reduced in the event of severe skin reactions.

Adverse Effects

• Cardiotoxicity:
  • Cardiomyopathy, decreased left ventricular ejection fraction (LVEF).
• Visual Adverse Effects:
  • Serous retinopathy, retinal vein occlusion, blurred vision.
• Skin Reactions:
  • Rash, dermatitis, hand-foot syndrome, photosensitivity.
• Gastrointestinal:
  • Diarrhea, nausea, vomiting, abdominal pain, mucositis.
• Hematological:
  • Anemia, thrombocytopenia.
• Musculoskeletal:
  • Joint pain, muscle pain, back pain.
• Infection Risk:
  • Increased risk of infection, particularly in patients with weakened immune systems.
• Rhabdomyolysis:
  • A serious complication caused by muscle tissue damage; CPK levels may increase.
• Risk of New Cancers:
  • Development of cutaneous squamous cell carcinoma, keratoacanthoma, and basal cell carcinoma.
• Hypertension