(ChemotherapyAdvisor) – The US Food and Drug Administration has approved the angiogenesis inhibitor ziv-aflibercept (Zaltrap, sanofi-aventis, Bridgewater, NJ, and Regeneron Pharmaceuticals, Tarrytown, NY) injection for intravenous infusion in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), for the treatment of adults with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen.

“An improvement in median survival time was noted with the addition of Zaltrap to FOLFIRI, accompanied by an improvement in response rate and a delay in tumor progression and growth,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research in a press release.

Ziv-aflibercept, a recombinant fusion protein, acts as a soluble receptor that binds to vascular endothelial growth factor-A (VEGF-A), VEGF-B and placental growth factor (PIGF). Approval of ziv-aflibercept, following a priority review, was based on results of the phase 3 VELOUR trial of 1,226 patients randomly assigned to second-line FOLFIRI plus ziv-aflibercept 4mg/kg administered IV over 1 hour on day 1, every 2 weeks (n=614) or placebo (n=612). A total of 28% of patients previously had received bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA), considered the principal competitor to ziv-aflibercept.

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Median overall survival, the primary end point, was 13.5 months in the FOLFIRI plus ziv-aflibercept arm vs 12.06 months in the FOLFIRI plus placebo arm (HR 0.817 [95% CI 0.714–0.935]; P=0.0032), an 18% relative risk reduction. Tumor volume was reduced 20% in the combination arm vs 11% in the placebo arm.

Progression-free survival, a secondary end point, was 6.9 months in the FOLFIRI plus ziv-aflibercept arm vs 4.7 months, in the FOLFIRI plus placebo arm (HR 0.758 [95% CI 0.661–0.869]; P=0.00007), a 24% relative risk reduction. The overall response rate in the FOLFIRI plus ziv-aflibercept arm was 19.8% vs. 11.1% for FOLFIRI plus placebo (P=0.0001).

According to the FDA, ziv-aflibercept is being approved with a Boxed Warning alerting patients and health care professionals that the drug can cause severe and sometimes fatal hemorrhage, including gastrointestinal hemorrhage, as well as gastrointestinal perforation and compromised wound healing.

Most common adverse reactions (all grades, ≥20% incidence and at least 2% greater incidence for the Zaltrap/FOLFIRI regimen) were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache, according to the prescribing information.

The FDA granted Zaltrap “new molecular entity” status as “ziv-aflibercept” to differentiate it from “aflibercept,” or Eylea, which is marketed by Regeneron for wet age-related macular degeneration.

FDA Press Release

Prescribing Information

Clinicaltrials.gov Listing