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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Posted on June 11, 2009 at 8:36 am
Dr. West: Thank you for both your kind words and for taking my post seriously. I’m going to answer a few of your points, though I feel the battle is somewhat unfair. After all, you only got your medical training at Harvard Medical School, while I’ve been the beneficiary of learning about medical stuff across the whole entire Internet!
1. Thanks for clearing up the question about the dosing of Zactima in the ZODICAC and ZEAL trials. That makes a lot more sense to me now. One question: if the dose of Zactima used in those trials “is enough to block angiogenic activity but probably not block the EGFR pathway”, then I’d be curious to know whether prior Avastin impacted results in those trials. Was that reported at all?
2. We actually largely agree on the conclusion. As Dr. West puts it, “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.” The only difference is that I would give presumption to Zactima until then (although by the time the decision is made the results of the ZEPHYR trial will probably be available), and I probably wouldn’t impose a 95% confidence requirement on that trial given the trend in the evidence from the other three trials.
3. To a large extent, I would agree with Dr. West that a survival benefit is the key endpoint. However, I would not focus just on median survival. If a drug has no benefit in median survival but it does improve long-term survival rates, that is a good drug. So, for instance, what do the survival curves say about 2-year surival rates in the Zactima plus Alimta arm of the ZEAL trial (versus 2-year survival rates in the placebo plus Alimta arm)? And the same for the ZODIAC trial? I don’t know the answers, but those are key questions. One of the things that has excited so many about Tarceva is not that it extends median survival by 2 months but that it provides some patients with years of progression-free survival.
4. Finally, the cost question is clearly an important one, but I think it’s a bit of a red herring in this case. Assuming that the monthly cost of Zactima is similar to (or a little higher than) that of Tarceva, that’s an awful lot for a prescription drug in pill form, but it’s comparable to some of the cheaper IV chemo drugs. For instance, if one were to give Zactima to a good performance-status patient as third or fourth-line therapy (not that I’m thinking of anyone in particular) instead of Gemzar or Navelbine, it would only produce an extra cost if it produced a survival benefit. If it didn’t produce a survival benefit, then the patient would receive treatments of equal cost for an equal time. And the cost comparison really would be moot compared to a drug like Alimta (not to mention that it appears to be more effective for squamous cell patients than Alimta).
Just some thoughts. Now back to trying to learn to be a rocket scientist via the Internet!–Neil