NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Pseudoprogression, True Progression and Four Subtypes:


This post is rated S for suppositions. Note: In the trial there are other additional steps that I have not included below. I've done this to focus on the matters I'm addressing as a layman.

Step 1. In the DCVAX-L trial, patients are given surgery and an initial round of chemotherapy and radiation that lasts about 6 weeks.

Step 2. The next step is deciding who gets enrolled in the main body of the study. This selection process must be completed within 4 weeks after Step 1 initial therapy is completed.

Step 2A. Within this 4 week selection window immediately after Step 1, patients with indistinguishable Pseudoprogression and/or true progression are not allowed into the main body of the study and will not be used for statistical purposes in order to request approval. Those with distinguishable true progression are excluded from the trial but may receive treatment on a compassionate basis. Those with indistinguishable pseudo/true progression are placed in a "side group" also known as the "extra arm (not the third arm)." They are outside the main body of the trial (not used for OS or PFS statistics in main body of Phase III trial). In those -- fence sitting -- patients where it can be ultimately determined they really do not have true progression, they will be selected and randomized into the trial.


All GBM patients fall into 1 of four subtypes. Classic, Neural, Proneural or Mesenchymal.

Subtype responses to Chemotherapy and Radiation.

Proneural patients typically are younger and live longer than the average of the group as a whole, but they do not respond very effectively to Chemotherapy and Radiation.

Classic patients respond fairly well to Aggressive Chemo and radiation.

Mesenchymal patients have the most aggressive cancer, but they surprisingly respond very well to Aggressive chemotherapy and radiation early on, but down the road they build up a resistance to chemotherapy treatment.

Neural patients do not respond very well to Aggressive chemotherapy, and unfortunately they do not live as long on average as the pro-neural group.

For a better understanding of the response to Aggressive chemotherapy plus radiation for these subtypes please see figure 5 in the following article. This is very important IMHO.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818769/

Subtype responses to additional therapy with DCVAX-L

Mesenchymal patients apparently have the best response to DCVAX-L treatment, and this response is synergistic to the response benefit they already received from aggressive chemotherapy and radiation. Proneural patients have little response to DCVAX-L.

It is unclear how the remaining subtypes respond to DCVAX-l additional therapy but I'll put forth some suppositions based upon prior information.

Background for suppositions:

*Dr. Linda Liau (and Dr.Kim) observed that DCVAX-L works better on patients that are stable when treatment with DCVAX-L is initiated. In other words, during that 4 week period after surgery/chemo/radiation, if there are no 'signs' of progression before DCVAX-L treatment is initiated, patients on average seem to do better.

"All patients that generated a systemic CTL response showed no MRI evidence of progressive disease at the time of vaccination [initiation]. Conversely, no patient with actively progressive disease developed statistically significant 'cytotoxicity. (which means being toxic to cancer cells)." This is really really important.

*The median time for pseudo-progression to appear after a 6 week round of radiation/chemo therapy is 4 weeks

* In a retrospective study, "early progression was confirmed in 42 patients (60%) according to Macdonald criteria and 15 patients (21%) according to RANO criteria. Pseudoprogression was identified in 10 (23.8%) or 2 (13.3%) patients in Macdonald and RANO groups, respectively. Cumulative survival of pseudoprogression group was higher than that of true progression group and not statistically different from the non-progressive disease group." This is also really really important.


Suppositions based on the above information.

I. If patients are excluded from the main body of the DCVAX-L trial that present signs of tumor progression/pseudoprogression within the first four weeks after the first round of chemo/radiation, most of those patients excluded from the trial will be those with true progression because:

A. They represent the larger percentage of patients in retrospective studies

B. Many pseudo progression patients will be included in the study anyway because the average time to pseudo progression takes a median average of 4 weeks.

2. If more pseudo-progression patients are left in the trial than real progression patients, the opportunity to demonstrate real treatment effect is significant because:

A. The real progression patients are likely to be pro-neural because:
1. The Kaplan-meier curves demonstrate those with no early response to chemotherapy and radiation are more likely to be pro-neural, and if mostly pro-neural patients are being excluded from the main body of the trial, and pro neural groups are longer lived than the group as a whole regardless of cemo/radiation/dcvax-l therapy, then the opportunity to show improvement in the remaining subgroups with less pro neural subtypes becomes more likely.

B. Remember, those with real progression at baseline in prior DCVAX-L studies had no systemic response to therapy.


What is the point here. Supposition

The point is that the inclusion/exclusion processes at the time for initiation of DCVAX treatment strongly points toward the fact that the majority of subtypes excluded were mostly in the pro-neural and neural category, and while some mesenchymal patients may have been excluded as well (because they tend to show inflammation that might be categorized as pseudo-progression), the majority of Mesenchymal patients will not demonstrate pseudo-progression at the time selection and treatment initiation starts. Moreover, those mesenchymal that do present pseudo progression are probably in the minority of their subtype.

Finally, the representation of subtypes is lore likely to appear in this order.

1. Classic -- should have the strongest representation in the actual body of the phase three DCVAX-L trial, and likely responds well to DCVAX-l.

2. Mesenchymal -- should have the second strongest representation in the actual body of the phase three trial and does respond very well to DCVAX-L.

3. Neural -- should have the third most representation (second to last) and likely does not respond as well to DCVAX-L as classic and mesenchymal. (nor does it respond as well to chemo radiation).

4. Proneural -- should have the least representation in the phase II DCVAX-L trial, and it does not respond near as well to dcvax-L (nor does it respond to chemo radiation).