As introduced in the last post, ZD6474, or Zactima, is a pill that blocks tumor blood supply and at higher doses (in the 300 mg per day range) also blocks EGFR. This mutli-targeted therapy has shown some intriguing activity when combined with chemo, and today I'll focus on the research that gave it as a single agent and where it has led us in terms of current trials.

As I mentioned in my previous post, an early phase I trial just trying to establish an optimal dose showed some activity zactima as a single-agent, as 4 of 9 patients with NSCLC in a Japanese trial showed significant tumor shrinkage on zactima. From there, Dr. Ron Natale at Cedars-Sinai Medical Center in Los Angeles led a randomized phase II trial (abstract here) that compared zactima as a single agent at the higher dose of 300 mg by mouth per day, pretty close to the maximal feasible dose, to iressa at 250 mg by mouth daily. The trial was designed to allow cross-over to the other drug after patients experienced either progression or problematic side effects. So the design was as shown here:

(click to enlarge)

There were a total of 168 patients, previously treated with one or two prior lines of therapy, and patients with treated brain metastases were allowed to enroll. They found that the time to disease progression was about 30% longer in the people who received zactima compared with the iressa recipients, 11 vs. 8 weeks. The response rates were modest for both groups but higher for zactima (8%) than iressa (1%, which is pretty disappointing, frankly). From the "waterfall plot", you can see that there are clearly more people with some degree of tumor shrinkage on zactima than on iressa. A waterfall plot shows the overall change in tumor volume from all measured tumors on a scan, and bars going upward above the horizonal line indicate overall growth, while bars going downward indicate overall shrikage. So the closer the "waterfall" is to the left, the more shrinkage vs. progression there was on a certain treatment. Here's the plot ffor zactima vs. iressa in the first part of the trial (before cross-over):

After progression or side effect problems, patients could cross over to the other drug. However, many patients declined rapidly or otherwise didn't continue on the trial, so only 29 patients went on to iressa after zactima, of whom there was a single response and a stable disease rate of 24%. Of the 37 patients who received zactima after iressa, there were no objective responses, but the stable disease/disease control rate was 43%.

The overall survival was not significantly different between the two groups. This is not especially surprising, since both groups had the potential to receive the benefits of each drug. However, it was a bit surprising to see that the trend in survival was actually in favor of the folks who received Iressa first, then switched to Zactima, given that the rest of the activity measures favored the early Zactima recipients, and fewer than half of the patients on the Iressa first arm received Zactima at all. The survival curves are shown here:

Lastly, there's the issue of side effects. Basically, they were pretty similar, with rash seen in about half, diarrhea seen more commonly with zactima, about a third of patients with nausea, and about 20% of patients on zactima developing asymptomatic EKG changes (changes in the electrical system of the heart). This last one is certainly something that AstraZeneca, the company that makes zactima, is following closely, and we need to take seriously, but fortunately we really haven't seen serious cardiac complications on zactima to this point. Other side effects were pretty infrequent. For a drug that has anti-angiogenic activity, we really haven't seen serious bleeding complications on zactima.

At the end of the day, what can we say about this trial? It has a lot of promising leads, such as the improvement in progression-free survival on zactima compared with iressa. Too bad iressa didn't beat placebo on a clinical trial, so that's not as exciting as being superior to a more active drug. And then there's the issue of the survival actually being a bit better (numerically, not statistically) in the folks who received iressa first and then went on zactima. Finally, none of the results was remarkable, with all of the response rates in single digits and the survival numbers OK, but not inspiring.

So there are no conclusions to take to the bank, but Zactima warrants further study. AstraZeneca has started a larger phase III randomized trial comparing Zactima to Tarceva, which has been shown to improve survival in the previously treated advanced NSCLC setting, unlike Iressa. This trial (AZ Trial 57 info here) is just getting started, and another one for patients who have already received Iressa or Tarceva is testing Zactima vs. a placebo (AZ Trial 44 info here). We'll get a good sense of what this drug has to offer from these larger trials that are just getting started.