It's been a while since there was anything to discuss about Zactima (vandetanib), an oral targeted therapy being investigated by AstraZeneca that has the potential to inhibit both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF), key targets of two important pathways in cancer treatment. They launched a total of four large trials looking at the activity of Zactima added to second line chemo, or compared head to head with the FDA-approved EGFR inhibitor Tarceva (erlotinib) in one trial or placebo in another trial. We learned some preliminary results of first three trials more than a year ago, and more complete information was presented at the American Society for Clinical Oncology (ASCO) meeting in early June of 2009. Those results overall indicated that Zactima could provide a modest but real improvement in progression-free survival (PFS) but no real improvement in overall survival (OS) when added to standard second line chemotherapy (statistically significant difference in PFS in a larger trial with Taxotere (docetaxel), and a similar magnitude of improvement in PFS but not reaching statistical significance in a smaller, less "well-powered" (to show a statistically significant difference) trial adding Zactima to Alimta (pemetrexed). The head to head comparison of Zactima to Tarceva showed equivalent activity.

Overall, the evidence showed some activity for Zactima, but it was debatable whether the balance of results was positive enough to consider it a worthy addition to our current treatments. In fact, we had a debate, of sorts, on the GRACE website, where GRACE board member and lung cancer patient Neil Berch argued in favor of it being approved, while I argued that the results weren't positive enough to make as compelling a case as we'd hope to see. We both agreed that a subsequent finding of a survival benefit from Zactima compared with placebo in NSCLC patients previously treated with an EGFR inhibitor like Tarceva would provide a clear and clinically meaningful benefit, though the trial testing this, known as ZEPHYR, had not had its results reported yet.

Several months ago, we received notice that AstraZeneca had withdrawn its application for FDA approval of Zactima, though without much elaboration. Now, buried within the AZ annual report is a very brief mention of negative results from the anxiously awaited and very important ZEPHYR trial:

During December 2009, the phase III ZETA and ZEPHYR trials were analysed. The ZETA trial met its primary endpoint of improving progression-free survival in patients with advanced medullary thyroid cancer. The ZEPHYR trial did not meet its primary endpoint of prolonging overall survival in patients with advanced lung cancer who had previously received EGFR inhibitor therapy. Full results of these two trials will be presented at medical congresses during 2010.

I expect that we should learn details of this work at ASCO, 2010 this coming June. In the meantime, it's a disappointing setback that would lead us to speculate that this agent will probably be abandoned in lung cancer, at least unless or until we can identify which patients are the ones who benefit more or less with it.