The U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee today announced that it approves AstraZeneca’s investigational drug, vandetanib (Zactima, also known as ZD6474 or AZD6474), for the treatment of patients with unresectable (non-operable) locally advanced or metastatic medullary thyroid cancer (MTC).
The American Cancer Society estimates that more than 44,000 new cases of thyroid cancer will be diagnosed in the United States in 2010. MTC accounts for four percent of all thyroid cancers. There are currently no approved treatment options for patients with advanced MTC. The five-year survival rates in patients with MTC that has spread to nearby organs (Stage III) and other parts of the body (Stage IV) are 81% and 28%, respectively.
The Advisory Committee was asked to discuss whether the indication should be limited to patients with progressive, symptomatic MTC. They were also asked to comment on whether there are any other subgroups that may be appropriate for treatment with vandetanib in light of the risk-benefit profile. The Committee was not asked to vote on this issue. The Committee was asked to vote on whether, assuming there is a population in which the risk-benefit profile is acceptable, additional doses of vandetanib should be evaluated as a post-approval study requirement to determine the optimal dose. The Committee acknowledged that there are patients with MTC in which the risk-benefit profile of vandetanib was acceptable, and voted 10 to 0 in favor of a post-approval study requirement to evaluate other doses.
“Patients with advanced medullary thyroid cancer face an unmet medical need since there is no medicine approved to treat this disease. Based on the clinical trial results we have seen with vandetanib, we believe it has the potential to provide appropriate patients and their doctors with an important treatment option,” said Dr. Howard Hutchinson, Chief Medical Officer, AstraZeneca. “We look forward to continuing to work with the FDA as it evaluates the Advisory Committee recommendation and completes its review of the application.”
The review by the Advisory Committee, part of the FDA’s evaluation of the New Drug Application submitted for vandetanib, is based on the results of ZETA (Zactima Efficacy in Thyroid cancer Assessment) -study, a Phase III, double-blind, placebo-controlled study.
The ZETA study randomized 331 patients with unresectable locally advanced or metastatic MTC to oral, once-daily vandetanib 300mg or placebo. Results from ZETA showed that treatment with vandetanib significantly extended progression-free survival, the primary endpoint of the study, in patients with advanced MTC. In ZETA, vandetanib demonstrated a 54% reduction in the rate of progression compared to placebo (HR=0.46, p=0.0001). The incidence of protocol-defined QTc prolongation in the vandetanib arm was 8% compared to 0% for placebo. The most common adverse events (incidence >25%) associated with vandetanib in the ZETA study included diarrhea, rash, nausea, hypertension and headache. In the randomized phase of the ZETA study, 12% of vandetanib patients discontinued due to an adverse event compared to 3% of placebo patients. The safety profile of vandetanib in this study was similar to what has been previously observed in other studies of vandetanib in medullary thyroid and non-small cell lung cancer.
The ZETA study was designed to evaluate the safety and efficacy of vandetanib compared to placebo in patients with unresectable locally advanced or metastatic MTC.
Vandetanib is an orally bioavailable 4-anilinoquinazoline and selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGF2), thereby blocking VEGF-stimulated endothelial cell proliferation and migration and reducing tumor vessel permeability. This agent also blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that mediates tumor cell proliferation and migration and angiogenesis.
AstraZeneca filed the US regulatory submission for vandetanib in the second half of 2010. The FDA granted priority review status for the NDA and set a Prescription Drug User Fee Act (PDUFA) action date of January 7, 2011. AstraZeneca is consulting with regulatory authorities on a proposed trade name. Vandetanib is also currently under regulatory review by the European Medicines Agency (EMA).
The FDA frequently convenes advisory committee meetings to obtain independent expert guidance and recommendations on clinical matters. While the FDA is not required to follow this guidance, the agency takes the advice into consideration when rendering its final decisions on pending applications and other public health matters.
Unrelated to this application and the recommendation made by the FDA, in October 2009, AstraZeneca officially withdrew its European application for a marketing authorisation for vandetanib, for use in combination with chemotherapy, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received anticancer treatment. At the time of the withdrawal, the drug was under review by the European Committee for Medicinal Products for Human Use (CHMP).
– An Efficacy Study Comparing ZD6474 to Placebo in Medullary Thyroid Cancer (NCT00410761)
– A Targeted Phase I/II Trial of ZD6474 (Vandetanib; ZACTIMA) Plus the Proteasome Inhibitor, Bortezomib (Velcade?), in Adults With Solid Tumors With a Focus on Hereditary or Sporadic, Locally Advanced or Metastatic Medullary Thyroid Cancer (NCT00923247)