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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Three Major Trials With Zactima (Vandetanib) Reported
Thu, 11/20/2008 - 18:06
Please Note: While this is Still Excellent Background Info, New Treatments and Procedures Have Emerged Since this Original Post
Author
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

As a general rule, companies don't sit on great news with their drugs. Without any insider knowledge, this was my concern about why we hadn't heard anything about the results of three major lung cancer trials with the agent Zactima (vandetanib), which I had written a post about 8 months ago (see prior post about these trials with Zactima, an oral agent that inhibits both VEGF, a major mediator of angiogenesis, and the EGFR pathway). The recent lung cancer meeting in Chicago would have been the opportunity to present the results, but that meeting passed, and then some rather tepid results (here) were just reported less than a week after the meeting ended. Go figure... To review, zactima has activity in NSCLC, as reviewed in my first post on the agent. The four large trials that were launched include the following comparisons in previously treated patients with advanced NSCLC: 1) second line treatment with taxotere (docetaxel) alone vs. docetaxel/zactima, a large phase III trial (ZODIAC) 2) second line treatment with alimta (pemetrexed) alone vs. alimta/zactima, a large phase II randomized trial ZEAL) 3) second or third line treatment with zactima vs. tarceva (erlotinib), a large phase III trial (ZEST) 4) zactima vs. placebo in previously treated patients, a large phase III trial (ZEPHYR)

The early report described results from the first three trials, since the last has taken longer to accrue (again, we know that placebo-controlled trials are very slow to accrue in the US, and probably increasingly so outside of the US as well now). We learned that the response rates in the two trials of chemo +/- zactima were higher with the combination, but that overall survival trended positive but wasn't significantly better in either trial. Progression-free survival (PFS), which was the primary endpoint in the larger ZODIAC trial with taxotere, was significantly better with zactima on the taxotere trial but just trended toward positive in the alimta trial. Many clinicians had expressed some concern that even if PFS was significantly better in both, an absence of an overall survival benefit would really leave us questioning the value of the agent and whether the FDA will/would approve it. In the trial that directly compares zactima to tarceva head to head, we learned that zactima wasn't significantly better in any efficacy parameters, but it did show equivalent efficacy in an analysis of "non-inferiority" -- so it could officially be considered a tie. And there were reportedly no significant side effect issues, although we'll really need to see the full data. It's fair to say that this wasn't a home run, but there were certainly some positive leads. It's encouraging to see improved response rates and progression-free survival with chemo, even if OS wasn't clearly better. It's possible that we'll learn that some subgroups fared much better with zactima than others. And if zactima performs comparably to tarceva, the latter is an agent that we've been happy to have in our arsenal and part of the short list of agents that has been shown to improve survival significantly in previously treated patients. The FDA could decide that there are too few agents right now for previously treated patients, especially since both taxotere and alimta are both approved as first line therapies in advanced NSCLC, leaving us with very limited choices for patients who received one of these agents previously. In addition, alimta is not active in patients with squamous cancers, so the list of active options for the 30% of patients with squamous NSCLC is even shorter. Any new agent with activity is welcome. And if the ZEPHYR trial comparing zactima to placebo actually shows a survival benefit, I think this will bolster the argument that this agent has really earned its place. The entire lung cancer community would welcome any new active drugs in this setting.

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