Abstract
The second biologic VEGF inhibitor approved by the U.S. Food and Drug Administration offers modest survival improvement.
People who have metastatic colon cancer and have experienced tumor progression following first-line chemotherapy have a new option: in August, the U.S. Food and Drug Administration (FDA) approved the intravenous VEGF inhibitor Zaltrap (ziv-aflibercept; Sanofi/Regeneron).
The agency approved Zaltrap for use in combination with leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI) in patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen with or without bevacizumab (Avastin; Genentech/Roche).
Zaltrap is only the second biologic VEGF inhibitor to gain FDA approval. Unlike Avastin, which is a monoclonal antibody that binds exclusively to VEGF-A, Zaltrap is a recombinant fusion protein that acts as a soluble decoy receptor and binds to VEGF-A, VEGF-B, and placental growth factor. It is a specially adapted variant of Regeneron's Eylea (aflibercept), which is used to treat neovascular age-related macular degeneration.
“It's a good thing to have another player out there with some different properties but that's still very selective, and combinable,” says Donald McDonald, MD, PhD, professor of anatomy at the University of California/San Francisco and an angiogenesis researcher who was not involved with the development or testing of Zaltrap. “The small-molecule tyrosine kinase inhibitors are not readily combinable with other anticancer drugs because of additive toxicities.”
The FDA's approval was based on a multinational, randomized, double-blind phase III trial that compared FOLFIRI in combination with either Zaltrap or placebo in colon cancer patients who previously had been treated with an oxaliplatin-containing regimen. Twenty-eight percent of participants also received prior Avastin therapy. The response rate was 19.8% for Zaltrap plus FOLFIRI and 11.1% for FOLFIRI alone. Adding Zaltrap increased median survival from 12.1 months to 13.5 months.
“These are modest improvements,” points out Tanios Bekaii-Saab, MD, an assistant professor of oncology and pharmacology at Ohio State University. He notes that in the patients who received Avastin in first-line therapy, the improvement in survival drops from 1.5 months to only 0.8 to 0.9 months.
The trial revealed some instances of more severe toxicities and side effects with Zaltrap than have been seen in Avastin studies. McDonald says this may coincide with increased efficacy, because Zaltrap binds to additional angiogenesis factors. Both McDonald and Bakaii-Saab emphasize that it's impossible to judge differences between the 2 drugs, because this was not a head-to-head study.
“I think in the long run, angiogenesis inhibitors are going to be an important contributor to cancer therapy,” says McDonald. “I don't think we're there yet, and that's why the data are less than what was hoped for.”
Bakaii-Saab suggests that such inhibitors will improve their utility as researchers find positive predictors for which patients are most likely to respond to them. He is involved in a phase II study of metastatic colon cancer using Zaltrap in combination with 5-fluorouracil, leucovorin, and oxaliplatin in first-line therapy. “We're trying to understand whether we can find a personalized approach to selecting patients the drugs will work for,” he says. “Right now, I'm exposing a lot of patients to toxic drugs that benefit only a few.”
