ZALTRAP APPROVED IN EUROPE 

Aflibercept (Zaltrap, Regeneron/Sanofi) has been approved in Europe for use in the treatment of metastatic colorectal cancer.

The indication is for use in combination with the conventional FOLFIRI regimen (irinotecan, 5-fluorouracil, leucovorin) for the second-line treatment of patients who have progressed on an oxaliplatin-containing regimen.

The same indication was approved in the United States in August 2012.

The European approval is based on the phase 3 VELOUR (Aflibercept vs Placebo in Metastatic Colorectal Cancer After Failure of an Oxaliplatin-Based Regimen) trial (J Clin Oncol. 2012;30:3499-3506).

In the 1226 VELOUR patients, the addition of aflibercept to the FOLFIRI regimen significantly improved both overall and progression-free survival. Median overall survival improved from 12.06 to 13.50 months (hazard ratio [HR], 0.917; P = .0032); progression-free survival improved from 4.67 to 6.90 months (HR, 0.758; P = .00007).

This is the first and only agent to demonstrate a statistically significant improvement in a phase 3 trial of patients previously treated with an oxaliplatin-based regimen who are being treated with FOLFIRI for their metastatic disease, said lead VELOUR investigator Eric Van Cutsem, MD, PhD, from University Hospitals in Leuven, Belgium. "Aflibercept is an important addition to the metastatic colorectal cancer treatment landscape, and it helps to fill a critical treatment gap," he said in a statement.

However, this trial has been criticized for not including bevacizumab (Avastin, Genentech/Roche), which is a standard addition to chemotherapy in metastatic colorectal cancer. Of the 1226 patients participating in the VELOUR trial, only 28% had previously received bevacizumab therapy, and the control group of the study was FOLFORI alone, rather than FOLFORI plus bevacizumab, which is now a common second-line treatment option.

Would aflibercept have shown a benefit if an antiangiogenic agent was used in the control group, or "is this a 'me-too' drug?" Alok Khorana, MD, associate professor and vice-chief of hematology/oncology at the James P. Wilmot Cancer Center, University of Rochester, New York, asks in his October 18, 2012OncNotes blog posting on Medscape.

Aflibercept and bevacizumab are angiogenesis inhibitors, but they have slightly different mechanisms of action.

Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF)-A.

Aflibercept is a novel fusion protein that acts like a sponge to mop up circulating VEGF. It has been described in the scientific literature as a "VEGF trap." It inhibits VEGF-A, VEGF-B, and placental growth factor, so has a broader mechanism of action than currently available agents, according to the manufacturer.

Outrage Over High Cost

In addition to this scientific controversy, there has been outrage in the United States over the high cost of aflibercept.

The Memorial Sloan-Kettering Cancer Center refused to add it to its formulary. In an op-ed piecepublished October 14, 2012 in the New York Times, experts report that aflibercept "has proved to be no better than a similar medicine we already have for advanced colorectal cancer, while its price — at $11,063 on average for a month of treatment — is more than twice as high. In most industries something that offers no advantage over its competitors and yet sells for twice the price would never even get on the market."

This publicity led the manufacturer to offer a 50% discount on the drug, which is unprecedented, Dr. Khorana writes in his November 8, 2012 OncNotes blog posting.