FDA Approves Aflibercept for Metastastic Colorectal Cancer

The FDA announced that aflibercept (Zaltrap, Sanofi & Regeneron) has been approved to treat metastatic colorectal cancer (mCRC) when given in combination with the FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regimen.

This approval marks the first time the aflibercept injection has been approved to treat any form of cancer. While being explored in a number of different tumor types, the only other approval that the drug has received thus far is for age-related macular degeneration under the brand name Eylea.

The approval is for patients with mCRC whose tumors are resistant or has progressed after they have received an oxaliplatin-based chemotherapy regimen.

“This approval demonstrates the benefits of adding a biological agent, Zaltrap, to a commonly used chemotherapy drug regimen, FOLFIRI,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “An improvement in median survival time was noted with the addition of Zaltrap to FOLFIRI, accompanied by an improvement in response rate and a delay in tumor progression and growth.”

Aflibercept is a dual vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF) inhibitor. VEGF-A and PIGF are proteins that promote angiogenesis, or the growth of blood vessels in tumors. Inhibiting their production halts the formation of new blood vessels that supply blood to the tumors.

The approval was based largely on the results of the phase III VELOUR trial. In that study, 1226 patients with previously treated mCRC were randomized to receive 1-hour intravenous aflibercept (4 mg/kg) or a placebo, plus FOLFIRI every two weeks until disease progression.

In the intention-to-treat population, the median overall survival (OS), the study’s primary endpoint, was 13.5 months in the group that received FOLFIRI plus aflibercept compared to 12.1 months in the FOLFIRI alone group (HR=0.82, P = .0032). Progression-free survival (PFS) also improved with the addition of aflibercept, with a median PFS of 6.9 months observed in patients who received FOLFIRI plus aflibercept compared to 4.7 months in those who received FOLFIRI alone. The overall response rates were 19.8% in the aflibercept arm and 11.1% in the control arm (P = .0001).

Sub-analyses of the VELOUR study presented at the American Society of Clinical Oncology (ASCO) meeting in June further confirmed the effectiveness of aflibercept in certain subgroups of patients. One sub-analysis found that prior use of bevacizumab, another angiogenesis inhibitor, did not have any impact on OS or PFS, with all patients receiving aflibercept performing better than those who did not. In another analysis, a logistical function was used to determine that there was a mean OS benefit of using the combination of aflibercept and FOLFIRI of at least 2.9 months, compared to the 1.4 month survival difference observed when comparing median OS between the two arms of the study.

Aflibercept, also known as AVE0005 or VEGF trap, is being explored in a number of tumor types. Clinical trials testing the drug in patients with non-small cell lung cancer and ovarian cancer have been completed. Another trial testing aflibercept was recently announced for mCRC patients, this time testing the efficacy of the drug when given in combination with the FOLFOX6 chemotherapy regimen.