Results from the Phase III VITAL trial evaluating the investigational agent aflibercept (VEGF Trap; Sanofi-aventis Oncology and Regeneron) for the second-line treatment of non-small cell lung cancer (NSCLC) showed that adding aflibercept to the chemotherapy drug docetaxel did not meet the pre-specified criteria for the primary endpoint of improvement in overall survival compared with a regimen of docetaxel plus placebo (HR=1.01, CI: 0.868 to 1.174).

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 (PIGF), 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 natural receptors.

A leading cause of cancer-related death
According to the World Health Organization, lung cancer is the leading cause of cancer-related deaths among men and women (1.4 million in 2008) world-wide. [1] Lung cancer is classified as either small cell or non-small cell (most common form).[2] Non-small cell lung cancer typically grows at a slower rate than small cell lung cancer.[3]

The VITAL study was a multinational, randomized, double-blind trial comparing aflibercept versus placebo in combination with docetaxel patients with locally advanced or metastatic non-squamous NSCLC who have failed one platinum-based therapy. The study enrolled 913 patients who were randomized to receive intravenous (IV) docetaxel 75 mg/m2 plus either IV placebo or IV aflibercept 6 mg/kg every three weeks until disease progression, unacceptable toxicity, patient’s refusal or further treatment. The primary objective of the study was to demonstrate improvement in overall survival with the combination of aflibercept and docetaxel compared with placebo and docetaxel.


Trial results
The addition of aflibercept to docetaxel demonstrated activity as measured by key secondary endpoints of the study: progression free survival (PFS) (HR=0.82, CI: 0.716 to 0.937) and an overall objective response rate (ORR) of 23.3% in the aflibercept arm compared to 8.9% in the placebo arm.

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The treatment emergent adverse events (AEs) on the aflibercept arm with an incidence that was 10 percent greater than the control arm were stomatitis, weight decrease, hypertension, epistaxis and dysphonia. Grade 3 or 4 AEs that occurred at a frequency of at least 5 percent in patients who received aflibercept were fatigue, stomatitis, disease progression, hypertension, febrile neutropenia, dyspnea, neutropenia, and asthenia. AEs leading to treatment discontinuation occurred in 27.2% of patients in the aflibercept arm compared to 14.6% in the placebo arm. The types and frequencies of AEs reported in the aflibercept treatment arm were generally consistent with those reported in previous studies with anti-VEGF agents. Sanofi-Aventis and Regeneron Pharmaceuticals will conduct a detailed analysis of the efficacy and safety results of the VITAL study. Full results will be presented at an upcoming medical meeting.

Challenging difficult to treat cancers
“Bringing new and innovative cancer therapies to patients can be incredibly challenging, especially in difficult-to-treat cancers such as second-line non-small cell lung cancer,” said Debasish Roychowdhury, SVP and Head of Global Oncology Division, Sanofi-Aventis. “Our Phase III trials of aflibercept in metastatic colorectal cancer and hormone-refractory metastatic prostate cancer are underway to determine the clinical potential of aflibercept for patients with these advanced cancers.”

Ongoing trials
The companies 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 VITAL, the program includes two Phase III trials and one Phase II trial, all of which are fully enrolled:
? VELOUR: Second-line treatment for metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) (Phase III). Final results are anticipated during the first half of 2011.
? VENICE: First-line treatment for hormone-refractory metastatic prostate cancer in combination with docetaxel and prednisone (Phase III). An interim analysis is expected to be conducted by an Independent Data Monitoring Committee in mid 2011; final results are anticipated in 2012.
? AFFIRM: First-line treatment in metastatic colorectal cancer in combination with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) (Phase II). Final results are expected during the second half of 2011.

[1] World Health Organization Index. Last accessed February 7, 2011.
[2] American Cancer Society. Cancer Facts & Figures 2010. Atlanta: American Cancer Society; 2010.
[3] American Lung Association. Understanding lung cancer . Last accessed February 3, 2011.

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