NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Three studies show adding Avastin to Lomustine in rGBM or TMZ in nGBM increases the chance of death for patients under 50 years of age, and yet it is approved in combination with Lomustine to treat rGBM, and this, according to Genentech's/Roche's own approval study for rGBM increases the risk of death by 61% in that patient population.

Yet the FDA/Roche/Genentech do not provide a blackbox warning regarding this subgroup.

AVII77 Saturday, 02/17/18 09:56:04 AM
Re: flipper44 post# 158470 0
Post # of 158561
Quote:

Bears have sure been quiet since I brought this up. -- flipper

Flipper, please do not read anything into my silence. This is not my job (contrary to popular opinion)....

Having said that, you certainly made an interesting observation about Avastin and age.

You said:

If one is under 50 years of age, for rGBM, the chance of dying at any given time, if Avastin is added to lomustine, increases 61%. Apparently. JMHO.

So everyone knows, you were referring to the Forest Plot in the Supplemental Appendix (of the trial used to convert Avastin from AA to Full Approval in rGBM). The top portion of that Forest plot is below:
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I had not noticed that before. The FDA would not typically use a subgroup analysis for a claim of efficacy, but I have seen them take subgroup analysis like this and use it to restrict the label.

Anyway, I looked into this further to see if there was evidence this was a spurious finding (as often happens on these subgroup analysis).

I was surprised to actually find something to support this finding.
This 2008 paper Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma notes:

We evaluated other variables that might have an effect on clinical outcome. KPS at the time of enrollment and the number of prior chemotherapy regimens had no effect on PFS. Age had a major effect, although opposite to what has been generally reported in glioma trials. The median PFS for patients with a median age of 53 years or older was 30 weeks versus a median PFS of 11 weeks for younger patients (log-rank test P < .001).

This wasn't a randomized trial so they couldn't say Avastin harmed younger rGBM patients, but they certainly noted the older patients did better than younger.

They go on to speculate:

Finally, it is of interest that older patients in our study had a significantly longer PFS than younger patients, in contrast to the observation in most trials of cytotoxic agents. These findings may reflect statistical variance secondary to small patient numbers. Alternatively, bevacizumab may potentially have greater activity in the biologic subtype of gliomas more commonly found in older patients.

When you combine those two trials with the nGBM Figure I shared (that led to this whole discussion), it sure looks like younger GBM patients do worse with Avastin (or Avastin doesn't help younger people).

So yeah, that is interesting. I figured I'd check the new Label for Avastin. No mention of it there.