Lung Cancer / Mesothelioma
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Loading ...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.
Posted in: Anti-angiogenic agents, Current Clinical Trials, Epidermal growth factor receptor (EGFR)-based therapies, Lung Cancer, Multikinase inhibitors, Non-Small Cell Lung Cancer (NSCLC), Second-line treatment, Stage IV/Advanced/Metastatic NSCLC, Targeted therapies, Third-line therapy and beyond, Treatment
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Once again, great job in explaining heavy technical stuff to the masses. Thank you.
Would it make sense that Zactima following Iressa would work better because it does more than iressa (the anti-agiogenic component)? WHereas switching the other way, one might be getting a less effective drug in part two…
Also, has this drug been compared to Avastin + Tarceva?
And would the success for it in Japan have to do with the fact that the Japanesse already respond well to EGFR-inhibitors?
Just trying to make sense of it all…
Katie
katiekeating
Katie,
All of your ideas are good thoughts, but I wouldn’t get hung up on trying to make sense of such small amounts of evidence. One or two patients happening to do well or poorly can change how the results look overall in such small studies, which is why we so strongly favor larger trials, where we expect random chance is drowned out by the real truth of the situation.
I do think a comparison of zactima vs. tarceva and avastin is apt, but hasn’t been done yet, and it isn’t on the books yet either.
And yes, I think that we are learning more about the fundamental differences between Japanese and US-based or European populations, particularly with regard to EGFR. However, they didn’t test for EGFR mutation in the phase I zactima trial, so right now it’s an intriguing idea, but we haven’t got enough information to say more than that.
-Dr. West
Dr. West,
Thanks for the great information! How do you go about finding such useful information? Do you search it yourself or have a research librarian helping you?
Is anyone looking at a combination of low dose Zactima (low EGFR but higher angiogenesis) with Tarceva (with strong EGFR properties)? I wonder if scientifically this combo may make sense for patients who may be losing steam with Tarceva? Just a thought…
Happy holidays,
Prem
prem
Right now I’m doing it myself. My job is to be a medical oncologist focusing on lung cancer, and I lecture and collect slides and other figures on these subjects. I can cover the same topics when speaking with other physicians that I use talking with patients and families about what is new and exciting in the field.
That said, I’m cutting down on my clinic time somewhat so that I can spend more time researching and writing and really doing justice to the project. I am going to be seeking some educational grant support to allow me to take the extra time to really provide timely information here.
At the time, there are no studies looking at a combination of Zactima and Tarceva. I think there are a lot of potential combinations to consider, but I probably wouldn’t pursue two agents that both act as EGFR tyrosine kinase inhibitors. I doubt they would be very additive, but we just don’t know.
-Dr. West
Dr. West:
I find it interesting that you talk about both Sutent and ZD6474. I have been in both Clinical Studies. I was in the ZD6474 vs Iressa Study back in December 2003 to January 2004. I was pulled from the study as I developed a shift in my EKG. The study was opened and it was discovered that I was on ZD6474. The good news, the ZD6474, in just 6 weeks, stabilized the tumors in my liver. Earlier in 2003, was when I had my first recurrence which was the cause for me to Stage IV. I was in the ABT-510 Study with Carbo/Taxol from May to September 2003. Throughout all of 2004, I remained stable and was being scanned every month at the request of Astra Zeneca with Joan Schiller concurring.
In January 2005, the monthly scan detected new tumor growth in the RLL. Dr. Schiller decided that we would wait and watch. By March the primary tumor had doubled in size. At that point, Dr. Schiller suggested the Phase I Sutent study, which included 6-3 week cycles of Taxotere. By September 2005, the tumors had stabilized and I finished the Taxotere in late October. I continued on the Sutent until March 22, 2006, when a CT scan revealed that I had a new tumor in my liver. This was at my last appointment with Dr. Schiller at University of Wisconsin, and March 22nd was her last clinic day at UW. We had planned a low key appointment and then sit and talk for awhile, but that was not to be because of the new recurrence.
Dr. Schiller’s last official act, with me as her patient, was to write the prescription for Tarceva. I was then transferred to the care of Anne Traynor.
In July 2006 Dr. Traynor took me off the Tarceva because of shortness of breath. She then put me in the Sorafinib Study, which I originally started August 1, 2006. We, however, overlooked the fact that I was Renitidine and I experienced a severe drug interaction with nausea and vomiting. I was taken off the Sorafinib and the Renitidine until August 22, when Dr. Traynor and I decided to try again. This time everything worked and now I am in the Randomized phase. It is suspected that I have been randomized to Sorafinib as the liver tumor has regressed and I have a severe foot rash on both feet.
So here you are writing about studies that I am very familar with.
I greatly appreciate your input at LCA Survivors Community.
Dave Grant
Co-Director, LCA Survivors Community
Dave Grant
Dr. West–is there a chart anywhere that lists all these therapies, and gives a little summary information about them? Something like–name, MKI, angiogenetic, in stage II trials, etc. It just seems if there were some simple reference chart it would be easier to keep them straight!
sally
Not that I know of, but I’ll try to dig around and see if I can find anything that fits the bill.
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