NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Regarding the Progression versus PsPD discussion, and how it is applied in this trial:

I'd suggest we just take it down to the protocol, because the assessment criteria contained in it is what really counts here. IMO, it doesn't matter what the RANO criteria states in general, only how and when it applies to this specific trial.


WITH COMPLETE RESECTION - at original site

A new measurable tumor at the site of the resected tumor in which the longest diameter is equal to or greater than 1cm in at least one dimension.

With RANO, it states it must be visible on two or more axial slices
https://radiopaedia.org/articles/rano-criteria-for-glioblastoma

To be honest, I'm not sure what one dimension means here. But

(note: no mention of *** T2/FLAIR *** used for this measurement)

So if the suspected tumor is in the original site, and it’s greater than 1cm, and is visible in at least one dimension… that’s it. If it’s not defined by those 3 criteria:
again…
1. in same site as original tumor
2. greater than 1 cm
3. visible in at least one dimension
… it is not deemed progression and treatment continues to the next MRI.

Actual protocol statement:

Progression, calculated from the nadir tumor burden (i.e. post operative, Baseline, or
Baseline 2), is defined as one of the following:

• In the case of complete resection during primary therapy: a new measurable tumor
at the site of the resected tumor, defined as a mass with a longest diameter equal to
or greater than 1 cm in at least one dimension. If progression is not defined by these
studies, treatment may proceed and determinations made at the next scheduled
MRI.

WITH INCOMPLETE RESECTION - at original site
If there is a 25% increase in the residual tumor that is at least 1 cm greater than it started, and is measured by MRI and compared to post operative MRI scans, baseline MRI scans, or baseline 2 (baseline 2 is for psPD) MRI scans and deemed attributable to tumor growth, it’s considered progression.

(note: no mention of *** T2/FLAIR *** used for this measurement)

To recap…
25% increase in residual tumor than it was at post operative, baseline, or baseline 2 MRIs
or
1 cm greater than it was at post operative, baseline, or baseline 2 MRIs
it’s deemed as progression.

Actual protocol statement:

In the case of incomplete resection during primary therapy: a 25% increase or
greater in the residual tumor if the recurrent portion of the tumor is at least 1 cm or
greater in its longest diameter, measured by MRI and confirmed by scans above as
attributable to tumor growth;

Interestingly… for both complete and incomplete resection… IF radiographic criteria for progression have not been met, surgical resection can be done to confirm progression, or rule it out.

Actual protocol statement:

If resection is indicated for recurrent disease, while radiographic criteria for
progression have not been met: surgical resection, subsequently confirmed as
progressive GBM by Pathology at the clinical site and to be confirmed by
independent pathology;

PROGRESSION - AT NEW SITE
The tumor must be measured as 1 cm or more in at least one dimension and confirmed by post operative, baseline, or baseline 2 MRIs

Actual protocol statement:

Appearance of any new lesion/site at least 1 cm in at least one dimension or greater
measured by MRI and confirmed by scans above;

WHEN T2/FLAIR IMAGES ARE CONSIDERED
Note: this is the only time T2/FLAIRs are mentioned, and this is where the 2010 or 2011 RANO documented is footnoted (I can't tell which year it is). The link is available below.


Actual protocol statement:

Unequivocal progression of non-measurable disease (either non-enhancing disease
seen only on T2/FLAIR images or enhancing disease not meeting size criteria for
measurability), such that there is confidence that tumor growth has occurred;4

#4 footnote references this RANO article - and again, only for this criteria.
4 Radbruch et al. 2010: Neuro Oncol. 2011 Dec 6.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266385/

That reads - to me anyway - that T2/FLAIR is used ONLY WHEN…
The progression is unequivocal and yet not measurable.

This phrasing is really quite awkward to me. I have to wonder how progrogression can be unequivocal while at the same time, it’s not measurable. It almost seems a contradiction.

So what exactly does “enhancing versus non-enhancing” mean?

Wow… okay just a quick google on this shows a lot of people posting their answers as to what this means.

https://www.researchgate.net/post/What_are_the_differences_between_enhancing_and_nonenhancing_lesions_in_MRI

http://www.medhelp.org/posts/Multiple-Sclerosis/Difference-between-enhancing-and-non-enhancing-lesions/show/1348347

https://www.reddit.com/r/medicalschool/comments/3tfzvv/eli5_enhancing_vs_nonenhancing_lesions/

So what that tells me is that there is probably a lot of play in what enhancement means, and what the lack of it means. Which means, it’s in the eyes of the radiologist examining it.

And the next section of that portion of the protocol states,

enhancing disease not meeting size criteria for measurability

which to me means that when enhancing disease is NOT meeting the size criteria of this protocol - 1cm or 25% increase in size.

But when you remove the parenthesized portion of this criteria, it reads…

Unequivocal progression of non-measurable disease, such that there is confidence that tumor growth has occurred;

Which makes me think that depending upon the read of one radiologist, or two, or three, this section is at the mercy of read of the radiologists. At this point, it is determined by the "confidence" of the radiologist.

And when you consider that is was the same set of radiologists that determined that the 25 indeterminate patients were originally rapid progressors, and now Linda Liau thinks the majority of them were actually pseudo progressors…


…I’d suggest that there seems a fair amount of

**mind changing**

as to what these MRI scans are indicating

both AT the time they were assessed

and

OVER time

...meaning, what was the assessment criteria these radiologist were applying to what seem to be subjective MRI readings from 2010 through to 2016? Especially as it was applied to enhancements and non-enhancements?

What this all indicates to me is that interpreting these scans IS NOT so black and white as one might think. And these radiologists are bound to follow the specific trial protocol here.

When one considers how the assessment criteria on how to read immuno-oncology scans is ever-evolving, it also indicates to me that PFS events was and is at the mercy of the expertise of the radiologists that read and are reading the scans, as well as the time period then and now when they were actually reading the scans.

So I am not going to pretend that I know what enhancement and non-enhancement means let alone looks like; or if an MRI scan shows a new tumor, or a 25% increase, etc. I'm just going off the fact that the criteria has been evolving, and that one radiologist's enhancement may be another radiologist's non-enhancement, that the protocol only specifies RANO when applying it to those enhancing and non-enhancing images (maybe that's the only time it should apply - I really don't know), and finally, that the same radiologist group that read the Info Arm scans, read the Main Arm scans. And it seems they were not sure how to interpret 25 of 55 patients when they read their scans. And I guess their T2/FLAIRs.