Aflibercept (ZALTRAP, EYLEA)

Aflibercept, sold under the brand names Eylea and Zaltrap, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. 

Aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin.

Approved for use in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen.

Ziv-aflibercept is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 that are fused to the Fc portion of the human IgG1 immunoglobulin.

Acts as a decoy receptor and presents the interaction of vascular endothelial growth factor-A and VEGF-B and placental growth factor with their receptors.

Double-blind, placebo-controlled, phase III multicenter trial enrolling 1226 patients with mCRC that progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab, were randomly allocated (1:1) to receive FOLFIRI (irinotecan 180 mg/m2 IV infusion over 90 minutes, leucovorin 400 mg/m² IV infusion over 2 hours, followed by 5-FU 400 mg/m² IV bolus, followed by 5-FU 2400 mg/m² continuous IV infusion over 46-hours) with either ziv-aflibercept or placebo (Allegra CJ et al).

In the above stiudy Ziv-aflibercept was administered at a dose of 4 mg/kg IV infusion over 1 hour prior to FOLFIRI and treatment cycles on both arms were repeated every 2 weeks.

A statistically significant improvement in OS was observed in patients receiving FOLFIRI plus ziv-aflibercept compared to those receiving FOLFIRI plus placebo, with a median Owaif 13.5 and 12.06 months for patients on the ziv-aflibercept and placebo arms, respectively, and a median progression-free survival in the ziv-aflibercept arm was 6.9 compared to 4.7 months in the placebo arm.

When added to stage chemotherapy for refractive colorectal cancer it demonstrates increased efficacy.

The most common grade 3-4 adverse reactions in the ziv-aflibercept plus FOLFIRI group were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.

Severe and sometimes fatal hemorrhages, including gastrointestinal hemorrhages, have been reported in patients receiving ziv-aflibercept.

Grade 3-4 hemorrhagic events occurred in 2.9% of patients receiving FOLFIRI plus ziv-aflibercept compared with 1.7% of those receiving FOLFIRI plus placebo.

In addition to hemorrhage, serious adverse reactions gastrointestinal perforation and compromised wound healing.

Venous thromboembolic events were also observed more frequently with ziv-aflibercept:  9% patients in the ziv-aflibercept-containing arm compared to 7% in the placebo-containing arm.

Fistula formation and reversible posterior leukoencephalopathy syndrome have also been reported in patients who received ziv-aflibercept.

Prior treatment with bevacizumab does not affect response rate or safety.

Aflibercept improved its primary endpoint of overall survival in the for second-line treatment for metastatic colorectal cancer (mCRC).

Routes of administration Intravenous, intravitreal injection

It is used for the treatment of wet macular degeneration and is administered as an intravitreal injection.

For cancer treatment, is given intravenously in combination with the other cancer drugs 5-fluorouracil and irinotecan and the adjuvant folinic acid.

Eylea is indicated for the treatment of people with visual impairment due to diabetic macular edema all stages of diabetic retinopathy.


Eylea is contraindicated in patients with infections or active inflammations of or near the eye, while Zaltrap has no contraindications.

Adverse effects:

Conjunctival hemorrhage, eye pain, cataract, vitreous detachment, floaters, and ocular hypertension.

Zaltrap has adverse effects; reduced blood cell count (leukopenia, neutropenia, thrombocytopenia), gastrointestinal disorders like diarrhoea and abdominal pain, fatigue, and hypertension.

Mechanism of action in wet macular degeneration, abnormal blood vessels grow in the choriocapillaris, a layer of capillaries in the eye, leading to blood and protein leakage below the macula.

Tumors need new blood vessels when they become larger than a few millimetres, in order to get access to oxygen and nutritive substances to facilitate further growth.

Aflibercept binds to circulating VEGFs, inhibiting  the activity of the vascular endothelial growth factor subtypes VEGF-A and VEGF-B, as well as to placental growth factor (PGF), inhibiting the growth of new blood vessels in the choriocapillaris or the tumor, respectively.

There is moderate evidence that aflibercept is significantly favored in all measured efficacy outcomes over ranibizumab and bevacizumab, after one year.

Among patients with NPDR but without center involved diabetic macular edema at four years treatment with IV aflibercept versus versus compared to initiating aflibercept  treatment only if vision threatening complications developed, resulted in significant anatomic improvement, but no improvement in visual acuity at four years.

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