The U.S. Food and Drug Administration (FDA) approved ZALTRAP? (ziv-aflibercept, Sanofi and Regeneron Pharmaceuticals, Inc) Injection for Intravenous Infusion, in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen.
“Colorectal cancer is one of the deadliest cancers and is responsible for more than half a million deaths globally each year,” said Debasish Roychowdhury, M.D., Senior Vice President and Head, Sanofi Oncology. “We want to make aflibercept available as soon as possible to patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen.”
“There are limited treatment options for metastatic colorectal cancer patients who are resistant to or whose disease has progressed after an oxaliplatin-containing regimen,” said Edith Mitchell, M.D., Clinical Professor of Medicine and Medical Oncology at Jefferson Medical College of Thomas Jefferson University and an investigator of the VELOUR pivotal study. “The approval of aflibercept in combination with a FOLFIRI chemotherapy regimen offers another treatment option and is welcome news for metastatic colorectal patients and their physicians.”
Vascular Endothelial Growth Factor-A
Aflibercept is a recombinant fusion protein, which acts as a soluble receptor that binds to Vascular Endothelial Growth Factor-A (VEGF-A), VEGF-B and placental growth factor (PIGF). Inhibition of these factors can result in decreased neovascularization and decreased vascular permeability.
The aflibercept approval was based on data from the pivotal Phase III VELOUR trial, a multinational, randomized, double-blind trial comparing FOLFIRI in combination with either aflibercept or placebo in the treatment of patients with mCRC. The study randomized 1,226 patients with mCRC who previously had been treated with an oxaliplatin-containing regimen. Twenty-eight percent of patients in the study received prior bevacizumab therapy. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, overall response rate, and safety.
Meeting unmet needs
“The approval of the novel angiogenesis inhibitor aflibercept provides a new option to address the unmet medical need in this patient population,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Research Laboratories. “However, there continues to be a need to develop new cancer therapies. Regeneron and Sanofi continue to devote resources to finding novel investigational treatments and combinations.”
The VELOUR trial showed that in patients previously treated with an oxaliplatin containing regimen, adding aflibercept to FOLFIRI significantly improved median survival from 12.06 months to 13.50 months (HR=0.817 (95% CI 0.714 to 0.935; p=0.0032), an 18 percent relative risk reduction. A significant improvement in progression-free survival from 4.67 months to 6.90 months (HR=0.758 95% CI 0.661 to 0.869; p=0.00007), a 24% relative risk reduction, was also observed. The overall response rate in the aflibercept plus FOLFIRI arm was 19.8% vs. 11.1% for FOLFIRI (p=0.0001).
Adverse events
The most common adverse reactions (all grades, ?20% incidence) reported at a higher incidence (2% or greater between-arm difference) in the aflibercept/FOLFIRI arm, in order of decreasing frequency, 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. The most common Grade 3-4 adverse reactions (?5%) reported at a higher incidence (2% or greater between-arm difference) in the aflibercept/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
Priority Review
Aflibercept was approved following a Priority Review by the FDA. A priority review is a designation given to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. Marketing authorization applications for aflibercept are also under review by the European Medicines Agency (EMA) and other regulatory agencies worldwide.
For more Information
– Aflibercept Significantly Improved Survival in Previously Treated Metastatic Colorectal Cancer; Onco’Zine, June 25, 2011.
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