Signs that progression-free survival data would not be sufficient to support approval of Zactima (vandetanib) in advanced non-small cell lung cancer led AstraZeneca to pull the regulatory submissions for the drug, the firm announced Oct. 28.

The tyrosine kinase inhibitor was filed for review with both FDA and the Europeans Medicines Agency in June, for use in combination with chemotherapy to treat advanced NSCLC.

But, AstraZeneca reported, "preliminary feedback" from regulatory agencies indicated that PFS was not a sufficient primary endpoint for approval in this setting. That initial response, combined with "an updated analysis that demonstrated no overall survival advantage when vandetanib was added to chemotherapy," left the application with little support.

The drug has been plagued with lackluster data throughout development. AstraZeneca ran a wide-ranging clinical program, with five named Phase III trials. The first two were failures for vandetanib, where the drug did not meet the PFS endpoint versus pemetrexed (in ZEAL) or erlotinib (in ZEST). The third trial showed some benefit versus docetaxel in ZODIAC, presented at the American Society of Clinical Oncology annual meeting ( Also see "ASCO IN BRIEF" - Pink Sheet, 1 June, 2009. ).

But a median 4.0 month vs. 3.2 month PFS benefit (though statistically significant) is not a robust basis for approval, and FDA's oncology office has been clear that PFS findings must be clinically - as well as statistically - meaningful (Also see "FDA Will Revisit Appropriate Use Of PFS Endpoints At Advisory Committee" - Pink Sheet, 16 September, 2009.).

AstraZeneca may be more willing to back away from vandetanib due to its experience with another lung cancer drug. Iressa (gefitinib). Iressa was approved based on early signs of PFS, but AstraZeneca had to deal with the repercussions when it was later found to lack a survival benefit. Although Iressa eventually found an appropriate niche, identifying that subpopulation was a lengthy and expensive process that the firm does not appear eager to replicate.

AstraZeneca is holding off on a complete dismissal of vandetanib, however. The firm's release notes that the drug was clinically active in the chemo combination, and the company plans to complete the Phase III program, "which will give a more complete view of vandetanib efficacy in different clinical settings."

The ongoing trials use monotherapy, and one is in a different setting. Results from ZEPHYR in patients with advanced NSCLC who have previously received an EGFR inhibitor and from ZETA in advanced medullary thyroid cancer are expected in late 2009 or early 2010.

The announcement came on the eve of AstraZeneca's third quarter earnings release. So far, analysts have not had tremendous reaction to the news, as Zactima was not expected to be a major addition to the firm's bottom line, and the negative results were already stacking up.

- Mary Jo Laffler (m.laffler@elsevier.com)

AstraZeneca Takes Hint From Regulators In Pulling Zactima Applications

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