This is an easy call. In the two combined studies, Zactima had a positive impact (though not always statistically signficant). In the comparison with the amazing Tarceva, it broke even. Unless there is evidence that prior exposure to Tarceva reduces the effectiveness of Zactima, then Zactima is another effective treatment that should be available.

And, I would argue that the Zactima vs. placebo study is superfluous. Zactima has already “tied” Tarceva, and Tarceva beat placebo convincingly.

Especially if there are subgroup advantages (and even more so than if they are different from those for other drugs), Zactima should be available–NOW!–Neil

Neil,

Your points are well taken, although this doesn’t address the possibility that zactima may not be effective in patients who have already received an EGFR inhibitor. For instance, iressa is an agent with some activity, and that actually has been shown to be equivalent to taxotere in the INTEREST trial that randomized second line advanced NSCLC patients to chemo vs. iressa. But I genuinely feel that iressa doesn’t offer anything that patients can’t get from tarceva. My overall interpretation of the data is that it’s essentially a less active version of tarceva, so I don’t miss not having it in the US — I could just use lower doses of tarceva to get the effects of iressa.

It’s certainly possible that zactima offers some added value, but if it’s just a lateral move, I don’t know that we need another variant on the EGFR inhibitor theme. The FDA is more inclined to approve treatments that offer an established incremental benefit, which I think would be quite convincing if it improves survival compared to placebo, particularly in recipients of prior tarceva.

The other issue is that only about 50-60% of patients in the US receive second line therapy, about 30-40% of patients receive third line therapy, and under 20% receive fourth line therapy. So while I would enthusiastically welcome a wider array of options for lung cancer, the reality is that it’s only a minority who can avail themselves of more than a couple of lines of treatment.

-Dr. West

Dr. West: Your points are well-taken as well. Two quick responses:
1. That still translates to around 50,000 lung cancer patients per year getting third-line therapy and 30,000 getting fourth-line. These numbers are more than those that get first-line therapy for most of other cancers.

2. Your point about prior EGFR therapy (”…although this doesn’t address the possibility that zactima may not be effective in patients who have already received an EGFR inhibitor.”) is actually the same as the one I made in my comment (”Unless there is evidence that prior exposure to Tarceva reduces the effectiveness of Zactima, then Zactima is another effective treatment that should be available.”) It is also an empirical question that we should be able to answer (without actual data, I’m at a major disadvantage in this discussion, as I cannot even begin to understand the argument about the biology, which would be about whether Zactima SHOULD be less effective in those who have already had Tarceva).

Unfortunately, the three studies that you summarize cannot help answer the empirical question. The two chemo-Zactima combination studies seem unlikely to have many patients who had first-line Tarceva (and those wouldn’t be representative anyway), so they’re no help. And the Zactima vs. Tarceva study was randomized and would have excluded patients with prior Tarceva. The study that would help answer the question would be the ZEPHYR study (Zactima vs. placebo). A subgroup analysis comparing those with prior EGFR inhibitors (primarily Tarceva) with others would answer that key question. Indeed, as I just now looked it up on clinicaltrials.gov, it appears that a requirement for the ZEPHYR study is previous exposure to an EGFR inhibitor. If I have the right study, then we will soon get the answer to our question.–Neil

I feel patients currently on Tarceva would be very interested in knowing the effectiveness of Zactima in patients who have already received an EGFR inhibitor. My mom is on Tarceva now, so I pay a special attention to posts related to “what after Tarceva?” in forums. I have seen many people asking this question and some people specifically mentioned that they are keeping an eye on Zactima.

Neil and zhufumama,

I agree completely that zactima would/will represent a very meaningful improvement if it shows activity after prior EGFR inhibitor. And yes, the ZEPHYR trial should directly answer that question, since it does in fact require patients to have received prior EGFR inhibitor therapy (and I believe also allows prior avastin but not oral anti-VEGF therapies). My understanding is that ZEPHYR has completed accrual but that results aren’t expected to be reported until the second half of 2009. Unfortunately, I think we’ll need to keep waiting on this question of what to do after tarceva for a while longer. I believe that Bayer/Onyx, who are developing sorafenib (nexavar), are also carefully considering testing this agent as a 3rd or 4th line treatment vs. placebo, similar to ZEPHYR. They may have decided to move forward with this plan, but I don’t think they’ve got anything going at this time, so I expect we’ll be left grappling with just our judgment until at least late 2009.

-Dr. West