FDA approves ziv-aflibercept for metastatic colorectal cancer

Andrew H. Ko, MD, MD

Besides monoclonal antibodies, such as bevacizumab (Avastin, Genentech), and oral tyrosine kinase inhibitors, such as sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer and Onyx Pharmaceuticals), we now have in aflibercept an additional novel therapeutic strategy to inhibit vascular endothelial growth factor (VEGF) signaling in solid tumors. Commonly referred to as “VEGF trap,” this drug is a recombinant fusion protein comprised of domains from VEGF receptors 1 and 2 fused to the constant region of the human antibody IgG. In effect, it acts as a decoy receptor by “trapping” circulating VEGF ligand, thus preventing it from binding to cell surface receptors.

The effectiveness of aflibercept was demonstrated when combined with FOLFIRI in patients receiving second-line treatment for metastatic colorectal cancer. Perhaps of greatest clinical significance with this agent was the improvement observed in PFS compared with chemotherapy alone. Importantly, this benefit was maintained in patients who had received bevacizumab as part of their first-line oxaliplatin-based chemotherapy regimen, although the magnitude of benefit was attenuated in this subset.

The value of continuing an anti-angiogenic strategy beyond the front-line setting also was confirmed recently in another study presented at the 2012 ASCO Annual Meeting. The TML trial demonstrated that patients who received bevacizumab as part of their first-line treatment who continued on bevacizumab in the second-line setting did better than those who did not (Arnold D. Abstract #CRA3503). Thus, treating oncologists whose patients with metastatic colorectal cancer progress following a FOLFOX-plus-bevacizumab regimen as first-line therapy may now consider either using aflibercept, continuing with bevacizumab second line, or — in patients with KRAS-wild type tumors — introducing an EGFR monoclonal antibody at that point. Although this uncertainty may lead to some confusion — and possibly spark further debate on pharmacoeconomics and the rising costs of health care — more therapeutic options in the long run can only be considered a positive development.

David H. Ilson, MD, PhD, MD, PhD

The demonstration of improving the effectiveness of second line chemotherapy with the addition of a VEGF targeted agent in advanced colorectal cancer marks a significant advance in the treatment of this disease. It validates prior trials indicating the effectiveness of anti-VEGF therapy in second line chemotherapy, as previously shown for bevacizumab in combination with FOLFOX. The trial results also  indicate that continuation of VEGF suppression into a second line of chemotherapy, even after prior bevacizumab, improves response, progression free, and overall survival. Aflibercept represents an important addition to the therapeutic options for a patient with advanced colorectal cancer. Approval of this agent will engender trials in earlier stages of this disease and other solid tumor malignancies.