Large Trials Completed with Zactima (ZD6474, vandetanib) in Advanced NSCLC

March 14, 2008 - 1:54 pm email to a friend

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Dr West

We’ve been following the development of a drug called Zactima (also known as ZD6474, or vandetanib) for over a year as it continues to be studied in lung cancer, and the work continues. As first discussed in my initial post on this agent, this agent actually inhibits BOTH VEGF and EGFR (in fact, the name vandetanib comes from VandE, I learned). It’s an oral tyrosine kinase inhibitor of these receptors, but it appears to inhibit VEGF at a lower dose of 100 mg daily than the 300 mg daily that block EGFR in addition to VEGF. Because of that, we presume it behaves differently depending on the dose used.

This may well be significant because the dose that has moved forward is 300 mg as a single agent, based on encouraging work at this dose compared with iressa (gefitinib) (prior post here). In contrast, a different phase II trial tested both the 100 mg and 300 mg doses with taxotere (docetaxel) compared with the same chemo alone (described here; note: this is the same as the initial post on zactima). In that trial, the lower dose appeared to be clearly better than the higher dose. My suspicion has been that this could be because the higher dose is where you block EGFR activity, which I’ve described as being potentially detrimental when giving chemo concurrently, although this remains unclear). On the basis of this early work, trials moved forward with the 300 mg dose as a single agent, and the 100 mg dose in combination with chemo).

There are four main trials evaluating zactima in advanced NSCLC, and three of them have now been completed. The first that accrued all of its intended patients is the ZEST trial that I described previously, back in November of 2007. In this study of patients with advanced NSCLC who had received one or two lines of prior chemotherapy, zactima was compared head to head with tarceva (erlotinib). We haven’t hear any results from that study. The other major single agent trial of zactima is called the ZEPHYR trial (Zactima Efficacy trial for NSCLC Patients with HistorY of EGFR and chemo-Resistance — a rather forced if clever acronym: “nobody leaves this room until we come up with a great name for this trial!”), which is directly comparing zactima to a placebo in patients who have already been on an EGFR inhibitor like tarceva or iressa:

(click on image to enlarge)

This trial is still in the process of enrolling a target of 930 patients (more information here)., The sites are outsde of the US, because of the great difficulty in enrolling American patients on placebo-controlled trials.

The news this week (press release here) was that two other large trials with zactima have also been completed. The larger one, called ZODIAC (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer), another tortured acronym in the name of cleverness, apparently reached its target of 1380 second line advanced NSCLC who were randomized to receive either taxotere alone or the ame chemo with zactima at 100 mg per day:

This was obviously based on the favorable results from the smaller phase II trial completed a couple of years ago. However, US-based oncologists have largely switched from taxotere to alimta (pemetrexed) as the preferred second line chemo agent in advanced NSCLC. In response to this reality, the sponsor company (AstraZeneca) also ran a smaller (but still respectably sized) has coducted a smaller but still respectably sized randomized trial called ZEAL (Zactima Efficacy with Alimta in Lung cancer), in which second-line advanced NSCLC patients receive alimta alone or with Zactima:

Both of these combination trials are now completed, but the press release tells us that we can’t expect any more information until later this year. I doubt that these trials that have only completed accrual in the last 3-4 months will have enough follow-up information to present anything at ASCO in late May/early June, so it may be another press release or possibly at a large lung cancer meeting in Chicago in November that we’ll learn more.

It’s interesting that all of these trials except the one comparing zactima to placebo are using progression-free survival as their primary endpoint. This presumes that patients may receive later treatments that will help them, thereby diluting the effects of the treatment being studied. However, it’s not clear whether the FDA, oncologists, and/or patients will consider a new treatment to be particularly beneficial if it improves the progression-free survival (PFS) but doesn’t change overall survival. If these large trials show an improvement in PFS by just 6 weeks and no benefit in survival, it’s not clear that zactma would be approved and become commercially available. Another potential challenge is the work that Dr. John Heymach has shown at some recent meetings that suggests that the benefit of zactima with taxotere appears to possibly be limited to women and not be seen at all in men. That work is preliminary, but we’ll need to learn more.

I’ll keep you posted as new information comes in. If you have questions or comments, particularly on how valuable you think it would be (or not at all) to have a delay in progression but not an improvement in survival with a new agent like zactima, let us know. It’s actually a tribute to the growing number of new treatments for advanced NSCLC that people think we can dilute the benefits of second line or even third line treatment with a new agent from later therapies, but it’s a new question for us.

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