What Is Zaltrap (Aflibercept)? FDA Approval, Turkish Authorization, and Reimbursement

• FDA Approved: Yes (initial approval: August 3, 2012)
• Pack Name: Zaltrap
• Active Ingredient: Aflibercept
• Administration: Intravenous infusion
• Class: VEGF (vascular endothelial growth factor) inhibitor
• Category: Targeted agent
• Manufacturer: Regeneron/Sanofi-Aventis
• Distribution in Turkey: Sanofi Türkiye
• Approved Cancers:
  • Metastatic colorectal cancer (used with FOLFIRI in patients whose disease has progressed after oxaliplatin-based treatment).

What Is Zaltrap (Aflibercept)?

Zaltrap, containing aflibercept, is an intravenous VEGF inhibitor used to treat metastatic colorectal cancer. Particularly in combination with FOLFIRI chemotherapy, it aims to inhibit tumor growth and metastatic spread in patients who do not respond to oxaliplatin-based treatment.

What Is a VEGF Inhibitor?

VEGF inhibitors target vascular endothelial growth factors (VEGF), blocking tumors' ability to form blood vessels. This restricts the tumor's access to oxygen and nutrients, thereby stopping cancer-cell growth.

How Does It Work?

Aflibercept is a recombinant fusion protein that binds VEGF-A, VEGF-B, and PlGF (placental growth factor) ligands, producing the following effects:

• Blocking VEGF Receptors:
  • Prevents VEGF ligands from binding to receptors, inhibiting VEGF-related signaling pathways.
• Suppressing Angiogenesis:
  • Stops tumors from forming new blood vessels, reducing intratumoral pressure and regulating blood flow.
• Reducing Tumor Blood Flow:
  • Limits the tumor's access to blood, oxygen, and nutrients.
• Antitumor Effect:
  • Prevents tumor growth and metastasis.

These mechanisms make Zaltrap an effective option in VEGF-mediated tumors such as metastatic colorectal cancer.

FDA (United States Food and Drug Administration) Approval History

• April 5, 2012:
  • Sanofi and Regeneron announced regulatory and clinical updates for Zaltrap (aflibercept).
• August 3, 2012:
  • The FDA approved Zaltrap for patients with metastatic colorectal cancer.

Authorization in Turkey

Zaltrap's licensed therapeutic indications in Turkey are stated as follows:

Therapeutic Indications

In patients with RAS wild-type metastatic colorectal cancer who received first-line oxaliplatin-based treatment combined with anti-EGFR therapy and subsequently progressed, use with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) is indicated until progression.

It must not be used in patients with RAS wild-type metastatic colorectal cancer who received any anti-VEGF therapy with first-line oxaliplatin-based treatment and subsequently progressed.

In patients with RAS-mutant metastatic colorectal cancer who received first-line oxaliplatin-based treatment and subsequently progressed, use with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) is indicated until progression.

Is Zaltrap Reimbursed?

The Turkish Social Security Institution (SGK) reimburses Zaltrap in the following treatment settings:

SGK covers use until progression with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in patients with RAS wild-type metastatic colorectal cancer who received first-line oxaliplatin-based treatment combined with anti-EGFR therapy and subsequently progressed.

It must not be used in patients with RAS wild-type metastatic colorectal cancer who received any anti-VEGF therapy with first-line oxaliplatin-based treatment and subsequently progressed.

SGK covers use with irinotecan/5-fluorouracil/folinic acid (FOLFIRI) in patients with RAS-mutant metastatic colorectal cancer who received first-line oxaliplatin-based treatment and subsequently progressed.

Price: Zaltrap 100 mg 1x4 ml vial: 12873.66 TL; Zaltrap 200 mg 1x 8 ml vial: 25637.07 TL. 

Resistance Mechanisms

Cancer cells can develop resistance through various mechanisms that overcome Zaltrap's effects. These include:

• Increased Expression/Activity of the IL6/STAT3 Signaling Pathway:
  • IL6 and STAT3 form part of a signaling pathway associated with cell growth and survival. Increased activity activates alternative VEGF-independent angiogenic pathways, limiting Zaltrap's effects.
• Increased Expression of Proangiogenic Factor Ligands:
  • bFGF (Basic Fibroblast Growth Factor): Tumor cells may increase bFGF levels to support new blood vessel formation.
  • HGF (Hepatocyte Growth Factor): Another factor supporting tumor growth and metastasis. Increased levels of these ligands may reduce the effect of VEGF suppression.
• Increased Expression of Ang-2 (Angiopoietin-2):
  • Ang-2 is a protein involved in blood vessel remodeling and new vessel formation. Ang-2 expression may limit Zaltrap's effects on tumor blood vessels.
• Recruitment of Bone Marrow–Derived Cells:
  • Bone marrow–derived cells can rebuild tumor vessels by overcoming dependence on VEGF signaling.
  • These cells support neovascularization and tumor angiogenesis despite VEGF suppression, reducing treatment effectiveness.

Pharmacokinetic Properties

• Absorption 
  • Because aflibercept is administered intravenously (IV), it does not undergo gastrointestinal absorption. Its bioavailability is 100% because it is delivered directly into systemic circulation.
• Distribution
  • Aflibercept's distribution in the body has not been fully characterized. The time to steady state is approximately 14 days.
• Metabolism
  • Aflibercept metabolism has not been fully characterized. The elimination half-life of free aflibercept is approximately 6 days, and clearance through the liver or kidneys is thought to be minimal. Its tissue half-life is not well characterized.
• Dosing Interval
  • The recommended dose is 4 mg/kg by intravenous infusion every 2 weeks.
  • An alternative regimen is 6 mg/kg by intravenous infusion every 3 weeks.

Drug Interactions

No significant or well-defined drug interaction has been reported for Zaltrap (aflibercept).

Precautions

• Risk of Arterial Thromboembolic Events:
  • Zaltrap may increase the risk of arterial thromboembolic events such as myocardial infarction, angina, and stroke. This is considered a "black box warning."
• Serious Bleeding Complications:
  • Serious bleeding may occur, including gastrointestinal bleeding, hemoptysis, and postprocedural hemorrhage. Patients should be informed of this risk and monitored during treatment.
• Gastrointestinal Perforation:
  • The medicine may cause gastrointestinal perforation, which can be fatal. Particular care is needed in patients with a history of invasive surgery.
• Wound-Healing Problems:
  • Zaltrap can delay wound healing. Treatment should be stopped before surgery and not restarted until healing is complete.
• Fistula Formation:
  • Fistulas have been observed in the gastrointestinal tract or other sites during treatment. These should be monitored carefully.
• Proteinuria and Nephrotic Syndrome:
  • Zaltrap can cause proteinuria (protein loss in urine) and nephrotic syndrome. Urinary protein levels should be checked regularly during treatment.
• Hypertension:
  • Hypertension may occur in 40% of patients and can be controlled with antihypertensive medicines. Treatment should be stopped if a hypertensive crisis develops.
• Risk of Serious Infection:
  • Zaltrap may have immunosuppressive effects such as neutropenia. Complete blood counts should be checked regularly because of the risk of febrile neutropenia.
• RPLS (Reversible Posterior Leukoencephalopathy Syndrome):
  • Zaltrap can cause RPLS, a rare condition involving headache, seizures, lethargy, confusion, vision loss, and other neurological symptoms. MRI is required for diagnosis.
• Pregnancy and Breastfeeding:
  • Zaltrap is pregnancy category C. Use during pregnancy should be avoided, and it must not be administered while breastfeeding.

Side Effects

• Gastrointestinal Perforation and Wound-Healing Complications:
  • Bowel perforation or severe delays in wound healing may occur.
• Bleeding Complications:
  • Serious and life-threatening intracranial or pulmonary bleeding may occur rarely.
• Arterial Thromboembolic Events:
  • The risk of arterial thromboembolic events such as myocardial infarction, angina, and stroke may increase.
• Hypertension:
  • Hypertension occurs in 40% of patients. Grade 3 hypertension has been reported in 20%. It can generally be controlled with antihypertensive medicines.
• Myelosuppression:
  • Myelosuppression with neutropenia may occur. Febrile neutropenia occurs in 4% of patients.
• Gastrointestinal Toxicities:
  • Gastrointestinal side effects such as diarrhea and mucositis have been reported.
• Proteinuria and Nephrotic Syndrome:
  • Proteinuria has occurred in up to 10% of patients. Treatment should be stopped if nephrotic syndrome develops.
• Central Nervous System Events:
  • These occur rarely and involve headache, seizures, lethargy, confusion, vision loss, and other neurological symptoms. Magnetic resonance imaging (MRI) is required for diagnosis.