Aflibercept (ZALTRAP)

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.

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