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Ziv-aflibercept yields encouraging results in metastatic colorectal cancer
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The addition of ziv-aflibercept to infusional FOLFIRI improved survival in a cohort of patients with metastatic colorectal cancer.
All eligible patients had previously been treated with oxaliplatin, and some had previously received bevacizumab (Avastin, Genentech).
In the current study, 612 patients received ziv-aflibercept (Zaltrap, Sanofi-Aventis) intravenously at 4 mg/kg, and 614 patients received placebo. The regimens were given with FOLFIRI every 2 weeks until disease progression or unacceptable toxicity.
OS served as the primary outcome measure.
Eric Van Cutsem, MD, PhD, head of digestive oncology and professor of medicine at University Hospital Gasthuisberg in Leuven, Belgium, and colleagues observed a significant improvement in OS among patients assigned to the study drug (HR=0.817; 95.34% CI, 0.713-0.937). Median survival was 13.5 months in the ziv-aflibercept group and 12.06 months in the placebo group.
Patients assigned to ziv-aflibercept also demonstrated improved PFS (6.9 months vs. 4.67 months; HR=0.758; 95% CI, 0.661-0.869).
The survival outcomes remained consistent across analyses of prespecified subgroups, including those patients previously treated with bevacizumab.
The researchers observed a 19.8% response rate (95% CI, 16.4-23.2) among patients assigned to ziv-aflibercept group compared with an 11.1% rate (95% CI, 8.5-13.8) among those assigned to placebo (P=.0001).
Patients assigned to the study drug reported anti-VEGF effects and increased incidence of chemotherapy-related toxicities.
“[Aflibercept] is the first agent to demonstrate a survival benefit in patients previously treated with an oxaliplatin-based regimen who are being treated with FOLFIRI for their metastatic disease,” Van Cutsem and colleagues wrote. “Aflibercept plus FOLFIRI may provide a new therapeutic option for the treatment of metastatic colorectal cancer in patients previously treated with oxaliplatin.”
Perspective
Back to TopDale R. Shepard, MD, PhD, FACP
This trial by Van Cutsem and colleagues shows improved OS in patients with metastatic colorectal cancer who received FOLFIRI and aflibercept compared with FOLFIRI alone as second-line therapy. These results are encouraging, somewhat predictable, and again show the relatively modest benefit of targeted biologic agents in this disease. The importance of the VEGF pathway in this disease has been established with bevacizumab, which targets the VEGFA receptor. Aflibercept traps the VEGF ligand and blocks activation of VEGFA, VEGFB and placental growth factor (PGF) receptors. There was an increase in median OS from 12.06 months to 13.5 months, an increase in median PFS, and an increase in response rate from 11.1% to 19.8%.
The 1.5-month increase in median OS is similar to the 1.4-month increase in median OS seen by addition of bevacizumab to second-line therapy in the recent TML trial (Arnold D. Abstract #CRA3503. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago). The use of a placebo in the comparator arm of this trial is understandable based on when the trial was written, but it leaves unanswered questions. Importantly, does the additional inhibition of the VEGFB and placental growth factor receptors really matter? As an agent that can differentiate itself from bevacizumab, does it? As we have more pressure to use therapies that provide value to the patient and the health care system, the actual benefits of biological therapies must be examined.
Although the VEGF pathway is considered an important target, the increase in median OS was only about 10% more than chemotherapy alone, and at a significant increase in cost. Further, only an additional 8.7% of patients responded to therapy, with fewer than 20% of all patients responding. While scientifically sound, the additional inhibition of VEGFB and PGF receptors had a negligible clinical effect. So this trial is encouraging with activity of another agent for treating metastatic colorectal cancer, but discouraging in that the relative benefit is small. The true benefit will be capitalizing on the additional inhibition of VEGFB and PGF receptors and determining which patients should receive this antibody.
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