At the end of 2006 I reviewed a drug called vandetanib, or Zactima, which is being developed for treatment of advanced NSCLC (intro post here). It’s a multi-targeted agent, also referred to as a multi-kinase inhibitor: as a single drug it can block both the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) receptor. It can therefore potentially have activity similar to tarceva (EGFR inhibitor) and avastin (VEGF inhibitor, anti-angiogenic agent) all in one pill.
Sure, but does it work? Well, it clearly has some activity, and I described some of this single-agent work in a prior post, which described a randomized phase II trial of zactima compared with iressa, now off the market in the US because iressa did not beat a placebo for survival in a large trial of previously treated, refractory patients with advanced NSCLC.
In the years since that earlier trial was developed, tarceva has become an established treatment for chemo-pretreated patients with advanced NSCLC, while iressa has become more of a historical footnote, to the chagrin of AstraZeneca (AZ), who make iressa in addition to zactima. To answer a more contemporary question, AZ developed the ZEST (Zactima Efficacy Study vs. Tarceva) trial, comparing zactima to tarceva head to head:
(Click on image to enlarge)
Today, AZ issued a press release reporting that they have completed accrual of this trial that enrolled over 1100 patients with previously treated advanced NSCLC, directly comparing the multi-targeted oral agent zactima to the established single agent tarceva. Progression-free survival is the primary endpoint, which is an earlier endpoint to determine than overall survival. Although the company didn’t mention a timeline for reporting results, it should be possible for them to submit the latest available data to ASCO in time for this to be an important presentation at the ASCO 2008 meeting in early June. While I would consider overall survival to be a more important variable than progression-free survival (how beneficial is it if you went 4-6 more weeks before coming off of a certain treatment but didn’t end up living any longer?), if the trial shows that zactima is superior to tarceva, it could lead to FDA approval for another drug in lung cancer.
In addition to this single-agent trial of zactima against tarceva, AZ is running other important trials comparing zactima to supportive care alone, and combinations of zactima with either taxotere or alimta compared with the same chemo alone.
More to come on this agent.
posted by Dr. West @ 11:07 pm link to this post
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December 1st, 2007 at 9:50 am
Questions (one out of practical interest, some for a scholarly paper I’m working on):
1. Is there any early sense that Zactima might be effective (or is likely to be completely ineffective) following a decent run with Tarceva?
2. To become FDA-approved, should Zactima have to beat Tarceva (the reigning champion) or should it have to beat best supportive care (which is another of the current phase III trials–not totally accrued yet)?
3. What to do if (and this is a hypothetical) Zactima is overall inferior to Tarceva but is superior to Tarceva in some major subgroup (like current smokers)?
–Neil
December 2nd, 2007 at 6:21 pm
Neil,
The trial in question obviously won’t speak to the issue of zactima after tarceva, but I think the closest thing we have is the results of the trial by Natale and colleagues (detailed in my earlier post on zactima) in which there was planned crossover from iressa to zactima after progression, or vice versa. The results weren’t especially encouraging for that setting, in my estimation. I’d presume that zactima after tarceva would be a remarkably similar situation.
It’s very hard to really predict what FDA will do. I think Zactima will be in a much better position if it’s superior to tarceva. It could be that zactima would be approved as another option in the previously treated setting, but that’s gets harder as we have more agents approved in previously treated patients. It appears to me that FDA has less stringent requirements when there are very few options, and less inclination to approve lateral moves when there are several comparable options.
Again, not knowing what FDA will really do, I’d be surprised to see an approval based on an unplanned subset analysis, but perhaps in a planned subset analysis. I’m not sure of details with regard to whether ZEST is including prospectively definted subset analyses.
-Dr. West