In August 2012, the antiangiogenic agent ziv-aflibercept (Zaltrap) was approved for use in combination with FOLFIRI (fluorouracil, leucovorin, irinotecan) for the treatment of metastatic colorectal cancer resistant to or progressing after an oxaliplatin-containing regimen.1,2
Approval was based on a randomized, double-blind phase III study (VELOUR trial) in which 1,226 patients with metastatic colorectal cancer that had progressed during or within 6 months after oxaliplatin-based combination chemotherapy received FOLFIRI plus ziv-aflibercept (n = 612) or placebo (n = 614) every 2 weeks.2 Patients were enrolled irrespective of prior bevacizumab (Avastin) treatment. Ziv-aflibercept was given at 4 mg/kg via IV infusion over 1 hour prior to FOLFIRI.
Patients had a median age of 61 years, 59% were male, 87% were white, and 98% had ECOG performance status of 0 or 1. All had received prior oxaliplatin; 90% of patients in the ziv-aflibercept group and 89% in the placebo group had received oxaliplatin-based treatment in the advanced/metastatic disease setting. Overall, 28% had received bevacizumab in combination with oxaliplatin-based treatment. The primary endpoint was overall survival, and treatment assignment was stratified by ECOG performance status and prior exposure to bevacizumab.
The median number of treatment cycles was nine in the ziv-aflibercept group and eight in the placebo group. Median overall survival was 13.5 months in the ziv-aflibercept group vs 12.1 months in the placebo group, representing a significant 18% reduction in mortality with ziv-aflibercept (HR = 0.82, 95% CI = 0.71–0.94, P = .0032 on stratified log-rank test). Median progression-free survival was 6.9 months in the ziv-aflibercept group vs 4.7 months in the placebo group (HR = 0.76, 95% CI = 0.66–0.87, P = .00007). Overall response rates were 19.8% in the ziv-aflibercept group and 11.1% in the placebo group (P = .0001).
How It Works
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 fused to the Fc portion of human IgG1. Ziv-aflibercept acts as a soluble receptor that binds to VEGF-A, VEGF-B, and placental growth factor, thus blocking binding of these growth factors to their respective receptors and inhibiting receptor activation. This inhibition can reduce neovascularization and vascular permeability, resulting in reduced tumor angiogenesis and metastasis.
In animal studies, ziv-aflibercept inhibited the proliferation of endothelial cells and thus the growth of new blood vessels. The drug also inhibited the progression of colon tumor xenografts.
How It Is Given
Ziv-aflibercept is given at 4 mg/kg by IV infusion over 1 hour every 2 weeks in combination with FOLFIRI. It must be administered before any component of FOLFIRI on the day of treatment, and it must be administered through a 0.2-micron polyethersulfone filter.
Ziv-aflibercept should be discontinued for severe hemorrhage, gastrointestinal (GI) perforation, compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, and reversible posterior leukoencephalopathy syndrome. Treatment should be temporarily suspended before elective surgery (≥ 4 weeks prior), for recurrent or severe hypertension until controlled, and for proteinuria of 2 g/24 hours until resolved.
Treatment should be reinstituted at a dose of 2 mg/kg after hypertension is controlled and in cases of recurrent proteinuria. Treatment should not be restarted until ≥ 4 weeks after major surgery and until complete healing of the surgical wound.
In the VELOUR trial, the most common adverse events occurring in ≥ 20% of ziv-aflibercept–treated patients and with ≥ 2% greater frequency than in the placebo group were leukopenia (78% vs 72%), diarrhea (69% vs 57%), neutropenia (67% vs 57%), proteinuria (62% vs 41%), increased AST (62% vs 54%) and ALT (50% vs 39%), stomatitis (50% vs 33%), fatigue (48% vs 39%), thrombocytopenia (48% vs 35%), hypertension (41% vs 11%), decreased weight (32% vs 14%), decreased appetite (32% vs 24%), epistaxis (28% vs 7%), abdominal pain (27% vs 24%), dysphonia (25% vs 3%), increased serum creatinine (23% vs 19%), and headache (22% vs 9%).
The most common grade 3 or 4 adverse events occurring in ≥ 5% of ziv-aflibercept patients and ≥ 2% more frequently than in the placebo group were neutropenia (37% vs 30%), diarrhea (19% vs 8%), hypertension (19% vs 1.5%), leukopenia (16% vs 12%), stomatitis (13% vs 5%), fatigue (13% vs 8%), proteinuria (8% vs 1%), and asthenia (5% vs 3%).
Grade 3 or 4 hemorrhagic events occurred in 2.9% of patients in the ziv-aflibercept group compared with 1.7% of placebo patients. Arterial thromboembolic events were observed in 2.6% and 1.7% of patients, respectively, and venous thromboembolic events were observed in 9% and 7%, respectively.
Ziv-aflibercept carries a boxed warning for hemorrhage (including GI hemorrhage), GI perforation, and compromised wound healing. The drug also carries warnings/precautions for fistula formation, hypertension, arterial thromboembolic events, proteinuria, neutropenia and neutropenic complications, diarrhea and dehydration, and reversible posterior leukoencephalopathy syndrome. ■
1. U.S. Food and Drug Administration: Hematology/oncology (cancer) approvals & safety notifications. Ziv-aflibercept. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm314438.htm. Accessed August 20, 2012.
2. ZALTRAP® (ziv-aflibercept) injection for intravenous infusion prescribing information. Regeneron Pharmaceuticals, Inc/Sanofi-Aventis, US, LLC, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125418s000lbl.pdf. Accessed August 20, 2012.