Replies to post #217827 on NorthWest Biotherapeutics Inc (NWBO)

[sukus]

Really great analysis Senti. Thanks. You are one of great contributors!

[sukus]

We longs witness the bear attack almost constantly. One of their fiercest argumenta is that DCVax-L trial failed on its primary end point which is PFS target.

Senti dived deep into the data, analyzed them and rebutted the bear argument.

Her analysis confirmed potentially a homerun on PFS.

Note educated guess was used to come up with the PFS number.

[flipper44]

Nice post. One thing I'd point out is that they likely reached 248 a little earlier than February 2016, because they changed the primary completion date from October to November 2016. Then Linda Liau spoke in December 2016, with her slide that could easily be read to say all control had PFS evented by then. If one looks at this tricky time period, I think they had patients that were not yet confirmed PFS, so they waited until February 2017 to say they had passed the 248 PFS marker. Remembering that once confirmed, the event is backdated to the original date the progression was first documented.

It is reasonable to believe control had all PFS evented by December 2016, because the second half of the trial not only removed early psPD, but it broadened the inclusion levels for absolute lymphocyte count per patient -- meaning sicker patients on average entered the trial. In fact, from the European website, it appeared that the only real threshold on absolute lymphocyte count, was imposed prior to leakapheresis. Meaning that after chemoradiation, those patients would have had even lower absolute lymphocyte count when entering the trial.

That's why, way back when, a couple months or so before Dr. Liau spoke in December 2016, it was becoming clear to me that nearly all of the control group should have PFS evented by then. I really didn't think 100%, but I thought it was getting close. UCLA's December chart however seemed to infer all control had PFS evented.

As you rightly point out, the difference would have to be DCVax-L if that were the case.

If some DMC were witnessing this rapid PFS eventing in the control group much earlier in real time, say a year after Germany had entered the trial, aka: July 2015, (two years after the UK entered the trial) a safety check might have determined it just wasn't fair to place people on placebo anymore, well, they'd also be looking at OS eventing as well.

Linda Liau, however, in October 2015, would only be seeing the PFS eventing start increasing on the lower end. She wouldn't realize how rapidly in one group (probably placebo), if that were the case, and OS would not have yet been greatly impacted yet from the possible European dichotomy.

[RJL1998]

Excellent post Senti, thank you.

[doingmybest]

sentiment stocks,

Thx for this PFS analysis. I don't focus much on PFS only because I think it is more informational at this point and a technicality. That being said it certainly does grease the skids for simpler presentation to the market when you can say you met primary and not have to go into justifying details with secondary and tertiary data pieces. Headlines go better with NWBO Meets Primary and Secondary Endpoints with Unprecedented GBM Results.

[Kam8]

Great post

[marzan]

very convincing logic, senti the greatest! Thanks a million!! I will have to call my minions again today to keep loading more shares. The way you explained it makes perfect sense. Yes we have the PFS home run, no doubt about it, imo. I want to go back and read Bosche's SA article on the PFS subject again. Go NWBO!

[eagle8]

Great post sentiment.

Thank you.

GLTU

[Doc logic]

sentiment_stocks,

Great use of deductive reasoning. Excellent post so now please put up that cute curtsy again. Lol. Best wishes.

[meirluc]

With respect to PFS success or failure, I believe that it is simple to calculate that methylated MGMT (met+) succeeded spectacularly while the fate of unmethylated MGMT (met-) is still up in the air.

This seems quite simple. Of the 87 post 36 months survivors whose methylated status is known, about 64 are met+ GBM (49.1% of 131) and about 23 are met- GBM (14.3% of 162). That is a ratio of 2.78:1.00 in favor of the met+ contingent. If this survival pattern is reflected by the PFS pattern of the 83 patients who were still PFS around 11/16, we would have about 61 met+ and 22 met- patients who were still PFS about 33 months after midpoint surgery (which I estimate at about 2/14).

That means that about 61 or about 47% of the 131 met+ patients had still not progressed 33 months post surgery. Most all of the 61 met+ patients and a few Met+ who had already progressed before 11/15 most likely made up the 64 met+ post 36 months survivors. This suggests that the mPFS of the met+ contingent is likely to be excellent.

Since only about 23 of the 162 met-patients reached 36 months alive, it is much harder to estimate the mPFS of met-.

What I am trying to say is that perhaps we are making a mistake by trying AD NAUSEA to estimate the mPFS for the whole trial instead of looking at the two major patient groups separately.

Note: I have not considered LTFU which may somewhat modify this rosy picture. However I believe that even 11 LTFU are not going to change my optimistic outlook.

[survivor1x]

I can see us comparing OS as these are objective numbers. I have a harder time wrapping my head around estimating PFS. Out of those 83, most likely at least 3 where control. So I will definitely give you 80. The other 40 well that is tougher but still manageable. But I can still provide a hypothesis in which 50% of the patients saw no improvement in PFS and we still had 83 that had not evented yet. Although too me it is unlikely

Note I am in no way stating that PFS has failed only that it is harder to certainly guarantee that it hasn't compared to OS while still blinded even with 2/3 guaranteed to not have evented. I have much more certainty with a figure like 36 month percentage survival based on the enrollment curves and the expected survival (at 12, 24 36, 48 60) compared to how many were alive at a certain point in the trial--when you work these numbers there were too many patients alive at certain point in the trial for it be just by chance. PFS could be similar to OS in that there could be a larger portion of patients just beyond the "median" that this drug shows an improvement in. Median is just 1 data point. It is 1 of the primary endpoints on this trial but more and more the median taken out of context in an IO trial where 30-40% of patients are living "A VERY LONG TIME" is an imperfect measure by itself. It doesn't give a complete picture especially when median was designed for drugs that have expected proportional hazards or semi proportional hazards(Some form of a mostly straight- line what ever the trajectory/steepness). Meaning a median measure doesn't expect a leveling of for a large portion of patients after the median. It assumes it will continue for the most part like it already has. It appears that with DCVAX that straight line is only early on and an ever increasingly flat curve starts to happen. How does the median account for the hockey stick blade that occurs most likely beyond the median-the answer is it doesn't? It is still an important data point but the painful waiting we have all endured will allow a full data set to almost 4 and 5 years to be measured.

This long term follow up- along with all of the work they have done identifying the bio markers and commonality among patients (long-term responders and non responders) will speed up any future solid tumor trials. Imagine knowing early on who will benefit the most and screening for those patients and even the vaccine itself after it is prepared. Imagine how quickly that will show benefit over SOC. It may narrow the field of patients to treat, but will expand it at the same time by treating the tumor type, not tumor location. They could look for specific bio markers across all solid tumors and have an all comers trial like direct ph1.