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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

The Benefit of Zactima: Damning with Faint Praise

Please Note: New Treatments Have Emerged Since this Original Post
Author
Howard (Jack) West, MD

Member Neil Berch just wrote a nice summary of the four large randomized clinical trials being done with Zactima (vandetanib), an oral targeted therapy that can block both the VEGF (angiogenic) and EGFR pathways. In fact, the name vandetanib comes from blocking V and E. In the single agent studies, one comparing Zactima to Tarceva (erlotinib) and the other to a placebo (in patients with advanced NSCLC previously treated with an EGFR inhibitor like Tarceva), the Zactima dose was 300 mg, which is a dose thought to block both pathways. In the chemotherapy trials, the daily dose of Zactima was 100 mg, which the lab work would suggests is enough to block angiogenic activity but probably not block the EGFR pathway. Why? A prior, preliminary trial of the chemo agent Taxotere (docetaxel) with either placebo or Zactima at 100 mg or 300 mg daily actually demonstrated clearly better results with Zactima at the lower dose, a finding that I suspect may be because blocking the EGFR pathway while also giving chemotherapy could well be detrimental. In any event, we can't presume that a higher dose would lead to better results with chemo in the current large trials.

Neil's post describes the highlights of the 3 trials that have been presented, and I don't really think the facts are debatable: 1) When added to Taxotere as second line therapy for advanced NSCLC, Zactima led to a rather modest but statistically significant improvement in progression-free survival (PFS), a very modest and non-significant trend favoring overall survival (OS), a significant improvement in response rate (RR), and a modest but significant delay in worsening of cancer-related symptoms. As Neil summarized, some symptoms were worse with Zactima (rash, diarrhea, high blood pressure), and some were actually less with it (nausea, vomiting, anemia), the latter for reasons we can't explain. 2) When added to Alimta (pemetrexed) in a trial of the same design, Zactima led to a more modest and non-significant improvement in PFS, a modest and non-significant trend favoring OS, a significant improvement in RR, and a modest but significant delay in worsening of cancer-related symptoms. Again, some symptoms were worse with zactima, and some were diminished, the same trend as with Taxotere. 3) Compared head to head with Tarceva in previously treated patients with advanced NSCLC, Zactima performed remarkably similarly but was associated with a higher frequency of moderate to severe side effects. 4) No real clinically or molecularly defined subgroup was found that did convincingly better or worse with Zactima. I think Neil and I agree on these issues. I would say that the differences are really in where these results take us. I concur that Zactima is very marginally beneficial. So marginal that it hasn't been shown to improve survival for anyone. And while Neil is right that it performed comparably to Tarceva, it hasn't been shown at all that it will improve outcomes for patients without EGFR mutations, at least not significantly more than Tarceva. We've seen evidence that Tarceva can improve survival far more broadly than in the 10% or so of North American patients who have an EGFR mutation. You could argue that if Zactima's benefit isn't seen disproportionately in that group, then it's in other patients. But so far we're just surmising that this benefit is spread very thinly among a large group of other patients, at least until we can identify a subpopulation who benefits a lot with Zactima (and the three studies didn't find any such group). I'll say that if the ZEPHYR trial of Zactima vs. Placebo in EGFR inhibitor-treated patients is positive for a survival benefit, that would seal it for me. Otherwise, I agree with Neil that there's nothing to recommend Zactima over Tarceva, an agent with the same activity and a more favorable side effect profile. The benefit of Zactima added to chemo is, in my mind, very similar between the two chemo trials, and very marginal for both. I agree with Neil that there isn't a need to worship at the alter of statistical significance -- I don't care much whether the PFS benefit is a little above or a little below the threshold p-value of 0.05 that defines statistical significance. What I do care about is that there wasn't an OS benefit, and I think the other variables are very soft supporting points. It's of some value that the response rate is a few percentage points higher with Zactima, and it's good to see a few patients develop worsening of cancer-related symptoms more slowly, but is that really enough? We can't help but argue from our own perspective, but we have a limited number of resources, and it's hard to envision a treatment with less value, assuming that Zactima won't be free (and I'm going to make the leap of presuming that it won't be free). While many patients with NSCLC who might have the hope of being beneficiaries of this marginally helpful approach would want to have it available, would they consider it valuable enough to pay a 40% co-pay on it? Or is this something that should be made available as long as someone else is footing the bill? The problem is that if that money is coming from a pot that isn't covering something else, you're making a value judgment, and I don't think Zactima stacks up well in any medical benefit value judgment without a survival benefit. I agree with Neil that the NSCLC world needs more bullets for the arsenal. I just think it's a problem when what we're really debating is a spitball, and likely an expensive one at that.

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