Of course, one would agree that there are other explanations and perhaps mine is a bit disingenuous. I do not mean to necessarily convey the idea that NWBO has failed in the overall trial---just perhaps in the primary and secondary endpoints. Perhaps the results are nothing to write home about and it represents a quandary in analysis and communication to investors and the market at large. Allow me to explain.
I am going to speculate but here is what I think is going on. From what we know, not necessarily with certainty but with fairly good odds, DC VAX appears to work over all sub groups of nGBM to varying degrees. I would guess that DC VAX works very well for mesenchymal and methylated MGMT. I do not know what the correlation is between Mesenchymal and MGMT is but I would guess, as a whole, that this broad grouping comprises about 30%-40% of the clinical trial pool. I would posit that approximately 2/3rds are in the early TX group and the balance in pure placebo and the X-over groups.
Mesenchymal(NF) and methylated MGMT may express themselves in different ways. Mesenchymal is immunogenic meaning that the micro tumour environment is less suppressive and therefore more responsive to Temodar and DC VAX. The methylation promoter associated with MGMT interferes with the cellular repair mechanism. DC VAX appears to work well with this overall group.
In addition, there is some correlation between classical(EGFRviii) and methylated MGMT. The efficacy, to some extent, might be significant for a portion of patients in this group. Wrt to the other two groups, pro-neural and neural, there may be little to no effect and it is thought that some small selected pro-neural group may respond to the vaccine. However, wrt to these latter two groups, I would surmise that the efficacy is relatively de minimis.
Accordingly, I think that, overall, about 40% of the patient pool would respond very well to DC VAX. As to the balance, DC VAX may have relatively less to no effect at all.
Thus, the rather modest blinded mOS of 23.1 months from surgery and not randomisation, in and of itself, does not tell the whole story. It could very well mean that the vaccine works quite well in a relatively large sub-set but not so well for the balance. The long tail that we see developing pertains to the groupings where the vaccine is quite effective. And LP is continuing the trial to ensure plateauing and a dramatic slowing of the eventing rate. I believe that she is quite correct that the most important factor in evaluating immunological approaches is the tail. If it is quite significant and for a relatively large sub-group, this may serve to assure broad approval, leaving it up to doctors and their patients to decide whether to take the vaccine as part of their therapy rather than leaving it up to regulatory fiat.
With respect to PFS, we are all in the dark, as no data has been revealed even though we have reached the so-called trigger event back in February, 2017. Perhaps due to pseudo-progression confoundment, which LP has stated, if I recall correctly, was not an issue, the data has not been available simply due to the need for further analysis. However, the foregoing may well indicate that there is nothing to write home about with respect to the PFS end point. Further analysis may be needed to ascertain whether PFS extension is seen in some groups versus others and to what extent. In addition, while PFS eventing extension may not be significant, slowing progression dramatically after eventing as the immunological approach begins to take hold in time may possibly be happening. That is a good thing. We won't know until all the fine analysis takes place after unblinding.
Certainly, we would have been more comfortable with a blinded mOS of, say, 28 or 30 months versus 23 months. Perhaps the mOS will shift more to the right with the spring refresh. If it does, I think it will shift in 1/10ths of months rather than a month or two. I don't think there will be significant improvement.
Accordingly, unless top line numbers are remarkable for the trial as a whole, their revelation may not be meaningful without explanation. If the numbers show, for example, that they are overall marginal, their publication could give a completely misguided perception and Wall Street, with its limited attention span and understanding, turn what is good news into bad. Therefore, LP and company need to be very careful in their analysis, presentation and how they communicate to the market at large. This may be why LP is banking on a home run tail. It neutralises and significantly overcomes what may seem to be negative but is rather good news with proper explanation.
Finally, I have to believe that the 2018 spring refresh is it. LP, due to financial, investor and competitive pressures, surely realises that the trial cannot continue with more expense and now largely diminishing, if no, returns. LP understands that NWBO is a commercial and not research institution at this point. There is little if anything to be gained with yet another data collection and indeterminate continuation of the trial. It is time for data lock. JMHO.
