FDA Approval for Ziv-Aflibercept
Brand Name(s): Zaltrap®
Full prescribing information is available, including Boxed Warning, clinical trial information, safety, dosing, and use in specific populations.
On August 3, 2012, the Food and Drug Administration (FDA) approved ziv-aflibercept injection ( Zaltrap®, made by Sanofi and Regeneron Pharmaceuticals, Inc.) for use in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following treatment with an oxaliplatin‑containing regimen. Ziv-aflibercept (previously known as aflibercept) is a recombinant fusion protein that consists of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1 immunoglobulin.
This approval is based on the results of a randomized double-blind placebo-controlled global multicenter trial that enrolled patients with mCRC whose disease progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior bevacizumab.
The Phase III trial accrued 1226 patients who were randomly assigned (1:1) to receive FOLFIRI (irinotecan 180 mg/m2 intravenous [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 (N=612) or placebo (N=614). Ziv-aflibercept was administered at a dose of 4 mg/kg IV infusion over 1 hour prior to FOLFIRI. The treatment cycles on both arms were repeated every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by ECOG performance status and prior exposure to bevacizumab.
Median age of randomized patients was 61 years, 59 percent were men, and 98 percent had an ECOG performance status of 0 or 1. All patients had received prior oxaliplatin treatment. A statistically significant improvement in OS was observed in patients in the FOLFIRI plus ziv-aflibercept group compared with the FOLFIRI plus placebo group [HR 0.82 (95 percent CI: 0.71, 0.94), p=0.0032, stratified log-rank test]. The median OS was 13.5 months for patients in the ziv-aflibercept group and 12.06 months for patients in the placebo group. Median progression-free survival was 6.9 months in the ziv-aflibercept group, compared with 4.7 months in the placebo group [HR 0.76 (95 percent CI: 0.66, 0.87), p=0.00007].
The most common adverse reactions (all grades), occurring in at least 20 percent of patients in the ziv-aflibercept plus FOLFIRI group (with at least a 2 percent difference between groups), were leukopenia, diarrhea, neutropenia, proteinuria, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), stomatitis, fatigue, thrombocytopenia, hypertension, decreased weight, decreased appetite, epistaxis, abdominal pain, dysphonia, increased serum creatinine, and headache. The most common grade 3-4 adverse reactions (in at least 5 percent of patients) that were reported at a higher incidence in the ziv-aflibercept plus FOLFIRI group (with at least a 2 percent difference between groups) 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 percent of patients in the FOLFIRI plus ziv-aflibercept group compared with 1.7 percent of those in the FOLFIRI plus placebo group. A Boxed Warning on the ziv-aflibercept label notes that, in addition to hemorrhage, ziv-aflibercept can cause the serious adverse reactions gastrointestinal perforation and compromised wound healing.
Arterial thromboembolic events were observed in 1.7 percent of patients in the placebo group and 2.6 percent of patients in the ziv-aflibercept group. Venous thromboembolic events were also observed more frequently with ziv-aflibercept: 9 percent of patients in the ziv-aflibercept group, compared with 7 percent of patients in the placebo group. Fistula formation and reversible posterior leukoencephalopathy syndrome have also been reported in patients who received ziv-aflibercept.
The recommended ziv-aflibercept dose and schedule is 4 mg/kg administered as a 60-minute IV infusion every 2 weeks in combination with the FOLFIRI regimen.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.