VANDETANIB NOT AS EFFECTIVE AS WE EXPECTED

Posted By: H. Jack West, Oncology, Medical, 01:05AM Jun 11

Medical Director, Thoracic Onc, Swedish Cancer Inst, Seattle, WA

Though many may already be familiar with vandetanib, I'll briefly summarize that vandetanib is an oral targeted therapy that can block both the VEGF and EGFR pathways (in fact, the name vandetanib comes from inhibiting V and E). In the recent single agent studies, one comparing vandetanib to erlotinib ("ZEST" trial) and the other to a placebo in patients with advanced NSCLC previously treated with an oral EGFR inhibitor ("ZEPHYR"), the vandetanib dose was 300 mg, which is a dose thought to block both pathways. In the chemotherapy trials, the daily dose of vandetanib was 100 mg, which preclinical work suggests is enough to block angiogenic activity but probably not inhibit the EGFR pathway. Why the lower dose with chemo? A prior randomized phase II trial of docetaxel with either placebo or Zactima at 100 mg or 300 mg daily actually demonstrated clearly superior results for the docetaxel/vandetanib 100 mg dose, a finding that I suspect may be because it's detrimental to block the EGFR pathway while giving concurrent chemotherapy (many trials negative, with suggestion of deleterious effect).

At this year's ASCO, we saw results of three of the four large trials conducted with vandetanib in advanced NSCLC:

1) When added to docetaxel as second line therapy for advanced NSCLC ("ZODIAC" trial), vandetanib led to a rather modest but statistically significant improvement in PFS, a very modest and non-significant trend favoring OS, a significant improvement in RR, and a modest but statistically significant delay in worsening of cancer-related symptoms. Interestingly, 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 pemetrexed in the "ZEAL" 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 docetaxel.

3) Compared head to head with erlotinib in previously treated patients with advanced NSCLC, vandetanib performed remarkably similarly but was associated with a higher frequency of moderate to severe side effects (40% vs. 50% grade 3/4 adverse effects).

4) No real clinically or molecularly defined subgroup was found that did convincingly better or worse with vandetanib.

My overall impression is that vandetanib is very marginally beneficial, so marginal that it hasn't been shown to improve survival for anyone. The one remaining trial that we haven't learned about is the ZEPHYR trial of vandetanib vs. placebo in EGFR inhibitor-treated patients; if that shows a survival benefit, I think it will make a far more compelling argument for using vandtanib. Otherwise, I don't believe that there's any to recommend vandetanib over erlotinib, an agent with the same activity and a (slightly) more favorable side effect profile.

The benefit of vandetanib added to chemo is, in my mind, very similar between the two chemo trials, and very marginal for both. Though the larger trial with docetaxel is "positive" for a PFS benefit while the smaller pemetrexed trial is technically "negative" for PFS benefit, I don't see a need to worship at the alter of statistical significance -- the results are similarly unimpressive. Importantly, there wasn't an OS benefit, and I think the other variables are very soft supporting points.

Overall, though these studies do demonstrate that vandetanib has some activity in patients with advanced NSCLC, the fact is that we have a limited number of resources. For me, it's hard to envision a treatment with less value, assuming thatvandetanib will be priced aggressively, likely far exceeding its benefit.