NorthWest Biotherapeutics Inc (NWBO)

[AVII77]

regarding ccnu/lomustine, I was told by AVII that treatment with TMZ alone resulted in a mPFS of 16.7 months. I just looked through a number of publications whose mPFS for patients with methylated MGMT who were treated with RT and temozolomide ranged between about 9.6-14 months.

This German trial with a mPFS of 16.7 months represents the longest time between enrollment and PFS that I came across.

It is important how endpoints are determined (ascertained).

Survival is easy.

Determining progression is not so straightforward.

In a randomized trial, what's most important is that whatever method you use to determine an endpoint, like progression, is equally applied for both arms.

When making a cross-trial comparison it is important to understand the methods of determining progression.

Below are different flavors of PFS assessment:

1 Macdonald Criteria
2. Macdonald plus Flair (DCVac Ph3 Trial)
3. RANO
4. Modified RANO (The German Trial)
5. iRANO

The Germans "Modified" RANO to made it more like iRANO. Specifically, progressions (except for obvious clinical progressions) require confirmation if they occur with 24 weeks of primary treatment.

RANO is similar except the period for confirmation is limited to the first 12 weeks.

And of course, for anyone who was here 2 years ago, you will remember the board debate about Macdonald and Macdonald plus Flair, where I asserted (and still assert) progressions do not require confirmation for either. Others disagreed. No surprise there.

Then you have smaller trials where individual investigators add their own twist. For example, Dr. Liau's assessment of progression for some patients in the earlier trials was: "we elected to watch and it kinda went away" (essentially RANO, modified RANO or iRANO but not Macdonald, or Macdonald plus Flair).

Dr. Bosch was quoted as saying that psPD has wreaked havoc on GBM trials (not a direct quote - but the "wreaked havoc" is what he is reported to have said). That "havoc" is brought about by assessing progression and prompts the evolution of the ascertainment methods noted above.

The point is, when you compare OS between trials you have to be cognizant of differences in patient populations (enrollment criteria).

When you compare PFS between trials, you not only need to consider differences in patient populations but also methods used for ascertainment of PFS.