JustObserving,
Thanks very much for the Merrill info. A few thoughts:
Secondly, it appears the Zevalin causes more neutropenia
than Coulter's Bexxar. However IDEC uses a more
stringent definition of neutropenia than Coulter. If a
patient's neutrophil count falls below 500/ml, IDPH called
this neutropenia, whereas Coulter used a limit of 100/ml
for neutropenia.
It is true that in the past, Coulter has (inexplicably?) reported neutropenia using a limit of 100/ml (if you look at ASCO abstracts for the last couple of years you will see it reported this way). I say "inexplicably" because I've spent a little more time lately studying the NCI Common Toxicity Criteria (see an earlier post of mine on this thread), and it looks like the standard for grade 4 neutropenia has been 500/ml for some time now (perhaps someone here might know why Coulter might have had a legitimate reason for reporting 100/ml?).
At any rate, the Merrill analyst failed to note that in the ASH abstracts just published, Coulter has (finally?) reported some neutropenia data based on 500/ml, so IDEC no longer uses a more stringent definition than Coulter (that ASH abstract from Coulter was copied to this thread, Message 11979032 - note the "ANC < 500 cells/mm3 = 17%" reported there). In the limited data that we have seen reported this way so far, we saw that Bex's 17% neutropenia still bested the 23% reported for Zev, although there are some differences in the pt populations involved, and I'm not sure if the 17% vs. 23% would be considered statistically significant.
As I mentioned in my prior post, while the Bex hematological toxicity still seems to edge that of Zevalin based on the limited data we have at this point, I was disappointed that we didn't see a wider safety margin for Bex, probably because I never took a closer look at the ANC standard (<100) reported in the past by the Coulter researchers. Looks like a lot more data will be required now before a clear winner on this count will emerge. Which makes me wonder whether the FDA foot-dragging on Bexxar application stems perhaps from a desire on their part to be able to evaluate Bex and Zev data more or less at the same time, kind of staging more of a "bake-off" between the two.
Also from Merrill:
In addition, Zevalin was dosed to the point where patients started to develop neutropenia in-order to maximize the therapeutic benefit.
This is true but somewhat irrelevant, Bex dosage was arrived at in the same manner. This can be seen from the full text journal article on Bex phaseI/II (see J CLIN ONCOL 14(7):1974-81 1996, Kaminski MS), in the section titled "Evaluation of Toxicity". So this certainly explains why we see 17 - 23% of pts with grade 4 neutropenia in these studies, but the important point is not why, instead it is whether one treatment will be shown to be superior to the other when the respective treatment benefits are weighed against the respective adverse events. If one of the contestants emerges with an inferior profile, it won't matter that the researchers intended to have a certain amount of neutropenia or some other adverse event.
Finally, from the Merrill analyst,
Furthermore, with the availability of Neupogen, neutropenia is no longer a major clinical concern.
Sure, this may be less of a clinical concern nowadays, but that doesn't mean that this adverse event is any less of a concern to the FDA (or thought leaders in the field) when evaluating competing therapies, IMO. The FDA is supremely concerned with safety, and is charged with making some pretty fine distinctions in this area, approving safer therapies over less safe ones. Folks seem to forget sometimes that this is a horserace, a therapy which typically requires less support from additional drugs like Neupogen for the same clinical benefit will be generally favored, IMO.
Thanks again for the Merrill stuff!
Gordon |
