The investigational agent aflibercept (Zaltrap?/AVE0005,Sanofi Aventis and Regeneron Pharmaceuticals, Inc), also known as VEGF Trap, significantly improved survival in previously treated metastatic colorectal cancer patients. Results from Pivotal Phase III VELOUR Trial, presented at the ESMO World Congress on Gastrointestinal Cancer on June 25, 2011 outlines the results. The abstract (#0-0024) was published in the June 2011 supplement to Annals of Oncology.

Worldwide, colorectal cancer is the third most commonly diagnosed cancer in males and the second most in females, with more than 1.2 million new cases diagnosed in 2008. Colorectal cancer is one of the deadliest cancers and was responsible for more than 600,000 deaths in 2008 alone. In Europe the overall survival rate is 43%, whereas in the United States it is 62%; these numbers drop considerably when the cancer spreads to distant organs. The risk of colorectal cancer increases with age ? in developed countries, more than 90% of cases are diagnosed in individuals older than age 50.

Aflibercept is an investigational angiogenesis inhibitor with a unique mechanism of action. This fusion protein binds all forms of Vascular Endothelial Growth Factor-A (VEGF-A), as well as VEGF-B and placental growth factor (PlGF), additional angiogenic growth factors that appear to play a role in tumor angiogenesis and inflammation. Aflibercept has been shown to bind VEGF-A, VEGF-B, and PlGF with higher affinity than their native receptors.

Previously treated patients
Patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin were randomized to receiveaflibercept or placebo in combination with the FOLFIRI regimen (irinotecan-5-fluorouracil-leucovorin). The addition of aflibercept to the FOLFIRI regimen significantly improved both overall survival (HR=0.817; p=0.0032) and progression-free survival (HR=0.758; p=0.00007). A similar effect was seen with aflibercept therapy whether or not patients had received prior bevacizumab therapy.

Grade 3 or 4 adverse events (AEs) that occurred with a more than 2 percent greater incidence in the aflibercept arm than in the placebo arm included diarrhea, asthenia/fatigue, stomatitis/ulceration, infections, hypertension, GI/abdominal pains, neutropenia, neutropenic complications and proteinuria. Deaths on study treatment due to AEs occurred in 2.4 percent of patients in the aflibercept arm and in 1.0 percent of patients in the placebo arm.

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“We are excited by these results and are committed to bringing this novel therapy to patients as soon as possible,” said Debasish Roychowdhury, M.D., Senior Vice President and Head, Sanofi Oncology. “We plan to submit regulatory applications for marketing approval to the U.S. Food and Drug Administration and the European Medicines Agency in the second half of the year.”

“These results highlight the potential utility of our novel anti-VEGF therapy in cancer settings where there continue to be significant medical need,” said George D. Yancopoulos, M.D., Ph.D., Chief Scientific Officer of Regeneron and President of Regeneron Research Laboratories. “We look forward to further developing ZALTRAP using innovative combinations that can help advance the management of patients with cancer.”

The VELOUR study was a multinational, randomized, double-blind trial comparing FOLFIRI in combination with either aflibercept or placebo in the treatment of patients with mCRC. The study randomized 1,226 patients with mCRC who previously had been treated with an oxaliplatin-based regimen. Approximately 30% of patients in the trial received prior bevacizumab therapy. The primary endpoint was an improvement in overall survival. Secondary endpoints included progression-free survival, response to treatment, and safety.

Clinical Development Program
Sanofi Oncology and Regeneron are collaborating on a broad oncology development program, combining the investigational agent aflibercept with common chemotherapy regimens in the treatment of patients with advanced cancers. In addition to VELOUR, the program includes one Phase III trial and one Phase II trial, both of which are fully enrolled.

The VENICE trial
The primary objective of the VENICE Phase III trial is to demonstrate an improvement of overall survival in patients treated with aflibercept versus placebo, in patients receiving docetaxel/ prednisone. The main secondary endpoints gather prostate-specific antigen (PSA) response, pain response,time to occurrence of skeletal related events and progression free survival (PFS), as well as safety, pharmacokinetics and immunogenicity. An interim analysis is expected to be conducted by an Independent Data Monitoring Committee in mid 2011. The final results are anticipated in 2012.

The AFFIRM trial
The AFFIRM trial is a Phase II study in the first-line treatment of metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX). The main objective of the study is to estimate the percentage of patients without progression of the disease at 12 months. The secondary objectives include the evaluation of response to treatment, overall survival, safety and documentation of potential immunogenicity of aflibercept. Final results are expected during the second half of 2011.

For more information:

E. Van Cutsem, et al Intravenous (IV) aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): Results of a multinational phase III trial (EFC10262-VELOUR) Abstract:O-0024. Ann Oncol (2011) 22 (suppl 5): v10-v18. doi: 10.1093/annonc/mdr285 This article appears in: ESMO 13th World Congress on Gastrointestinal Cancer 22?25 June 2011, Barcelona, Spain.

Clinical trials
– Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in theTreatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen (VELOUR) [NCT00561470]
– Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer (VENICE)
– Study of Aflibercept And Modified FOLFOX6 As First-Line Treatment In Patients With Metastatic Colorectal Cancer (AFFIRM) [NCT00851084]

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