Stockholm, Sweden—In a global phase III trial, the addition of aflibercept to the standard FOLFIRI chemotherapy regimen improved progression-free survival (PFS) and overall survival (OS) in previously treated patients with metastatic colorectal cancer, Josep Tabernero, MD, of Vall D’Hebron University Hospital in Barcelona, Spain, reported at the 2011 European Multidisciplinary Cancer Congress.
“Adding aflibercept to FOLFIRI in metastatic colorectal cancer patients previously treated with oxaliplatin-based regimens resulted in OS and PFS benefits that are both statistically significant and clinically meaningful,” Tabernero said in his presentation at the Presidential Session.
Aflibercept is a new fusion protein of key domains from human vascular endothelial growth factor (VEGF) receptors 1 and 2. It blocks all VEGF-A isoforms, VEGF-B and placental growth factor (PIGF) as well, binding with high affinity.
The VELOUR study randomized 1226 patients with previously treated metastatic disease to 1-hour intravenous aflibercept (4 mg/kg) or placebo, plus FOLFIRI (folinic acid, 5-FU, oxaliplatin, irinotecan), every 2 weeks until progression.
The primary endpoint of OS was reached, with a hazard ratio [HR] of 0.82 (P
= .0032). Median OS in the intention-to-treat population was 12.1 months with FOLFIRI alone, and 12.5 months with FOLFIRI plus aflibercept.
Positive results were also observed for PFS, with a HR of 0.76 (P
= .00007). Median PFS was 4.7 with chemotherapy alone versus 6.9 months with the addition of aflibercept. Response rates were 11.1% versus 19.8%, respectively (P
= .0001), Taberno reported.All subgroups benefited, especially patients with liver-only metastases
Prespecified subgroup analyses were planned to confirm the consistency of the effect of aflibercept on OS and PFS. Investigators assessed the impact by stratification factors (performance status, prior bevacizumab treatment), and patient characteristics (age, gender, geographic region, prior hypertension, number of metastatic sites, disease confined to the liver, location of primary tumor).
“The preplanned subgroup analyses supported the consistency and robustness of the efficacy results across all domains, including prior treatment with bevacizumab,” he reported.
A significant interaction was observed between treatment arm and the presence of liver metastases only, indicating a greater treatment effect in this group of patients, as compared with patients with disease not confined to the liver or no liver disease.
Among patients with liver metastases only, mortality was reduced by 35%, compared with an 11% risk reduction among other groups. PFS followed a similar pattern. For patients with prior bevacizumab treatment who received aflibercept, median PFS was 6.7 months, and OS was 12.5 months, which did not differ from overall study results.
The incidence of grade 3-4 adverse events were as expected with the anti-VEGF class of agents, and were similar among patients with and without prior bevacizumab exposure. Grade 3-4 hypertension occurred in 16.6% and 20.5% of these groups, respectively.
“Prior treatment with bevacizumab does not appear to significantly impact the safety profile of aflibercept,” he noted.
David Kerr, MD of the University of Oxford, United Kingdom, who is also president of the European Society of Medical Oncology, called VELOUR a, “well designed and well conducted study,” in his comments at the Presidential Session. He praised the investigators for conducting a preplanned subgroup analysis with a priori
biologic rationale rather than “sifting through the data post hoc” to look for associations, but he added that the findings of subgroup analyses should always be considered hypothesis generating rather than practice changing.
However, he said the main findings from VELOUR do, “change the landscape” of the second-line treatment of advanced disease. “We have a new agent to consider for those patients who progress following frontline treatment with FOLFOX with or without bevacizumab,” he said.