A Look at 7 VEGF Inhibitors Currently in Development

The success of bevacizumab in the clinic and the marketplace has helped spur pharmaceutical industry interest in pursuing a variety of angiogenic cancer-fighting agents.

In fact, nearly 250 drugs linked to approximately 180 different molecular and pathway targets are in various stages of development, according to Research and Markets, an analysis company based in Dublin, Ireland.

While many agents ultimately falter, there are at least 7 drugs specifically targeting vascular endothelial growth factor (VEGF) in later-stage clinical trials that have been the subject of presentations at oncology conferences in recent months.

Here is a look at those drugs:

Axitinib—Pfizer Inc filed a new drug application with the FDA in June seeking approval for the drug as a treatment for advanced renal cell carcinoma (RCC). It selectively inhibits VEGF receptors 1,2, and 3. The submission is based on phase III data from the AXIS 1032 trial demonstrating a statistically significant advance in progression-free survival (PFS) compared with sorafenib.

Cabozantinib (formerly XL184)—Exelixis Inc plans to submit a rolling application with the FDA this year in medullary thyroid cancer, after reporting top-line phase III data from the EXAM trial. The drug, which inhibits both the VEGF and MET pathways, also is being investigated as treatment for patients with castrate-resistant prostate cancer (CRPC) and ovarian cancer.

Aflibercept (Zaltrap)—Sanofi-aventis and Regeneron Pharmaceuticals, Inc are developing the VEGF Trap agent, which is a fusion protein that binds all forms of VEGF-A as well as placental growth factor. VELOUR phase III trial results indicated that adding aflibercept to a standard FOLFIRI chemotherapy regimen improved PFS and overall survival in patients with previously treated metastatic CRPC. The drug also is being investigated as combination first-line treatment both in prostate and colorectal cancers.

Brivanib (BMS-582664)—Bristol-Myers Squibb is investigating this dual inhibitor of VEGF and fibroblast growth factor signaling in soft-tissue sarcomas and hepatocellular carcinoma. Phase II data indicate a significant improvement in PFS versus placebo for patients with unresectable soft-tissue sarcomas and no other treatment options.

Tivozanib (AV-951)—The drug demonstrated median PFS of 11.7 months among 272 patients with advanced RCC who participated in a phase II trial. The small molecule tyrosine kinase inhibitor of VEGF receptors 1,2, and 3 also is being compared with sorafenib for patients with RCC in a randomized phase III trial. AVEO Pharmaceuticals, Inc and Astellas Pharma Inc are collaborating on development.

Ramucirumab (IMC-1121B)—Eli Lilly and Company is investigating the agent, which binds to the extracellular domain of VEGF receptor 2, as a single agent or in combination therapy in liver, gastric, colorectal, non—small cell lung, and breast cancers. There are 6 phase III trials in progress, with the first new drug filing forecast by 2014.

Motesanib—Results of the phase III MONET1 study in advanced non—small cell lung cancer were disappointing for this agent, which selectively inhibits VEGF receptors 1,2, and 3 as well as plateletderived growth factor receptor and stem-cell factor receptor. The drug failed to improve overall survival when added to carboplatin/ paclitaxel compared with chemotherapy alone. Amgen, Millennium: The Takeda Oncology Company, and Takeda Pharmaceutical Company Limited are collaborating on the research.