Hi Doc:
On the whole, I agree with your comments. Further, from the info out there, I am swayed that the odds are favourable for FDA approvals. I would agree that PFS, although a primary end point, is not an as important as other metrics such as OS and particularly the long tail.
If PFS fails to meet the end point, I don't think that is curtains for the trial. After all it is a surrogate for the OS gold standard. More importantly, immunological therapies like DC VAX L take time to manifest their efficacy and demonstrate it at the long end. Indeed, I would think measuring the interval between progression and the death event would be more meaningful. I believe that even though there may be earlier progression, I think that as the treatment begins to take hold, it acts to slow the rate of progression and even in some cases reduce it to zero, thus extending OS and the building of the long tail.
However, there are some unanswered anomalies, at least to my mind. For example, in prior studies, Prins and Liau found that the vaccine worked especially well in MES which is a large sub-molecular group categorised in the major group as per the JTM of M-(unmethylated) and where MES constitutes anywhere between 30%~50% of all nGBM. This was because MES is a more heterogenous and immunogenic sub-group. On the other hand, they found that the vaccine had little to no effect upon pro-neural which appears to predominantly compose M+(methylated). Apparently, this sub-molecular group is characterised by methylization interfering with cancerous cell repair mechanisms allowing longer survival. From the JTM data, it appears that blended results show very significant survival as compared to historical controls. This may suggest that DC VAX L indeed works on this sub-molecular group in contra-distinction to earlier findings. Further, even in the M- group, the vaccine appears to be working perhaps due to its MES composition, but not nearly as well as the M+ group. In fact the blended results for this M- group at the OS 36 milestone shows 14.1% survival(which is about a 20% improvement over 2017 data reported in the JTM). One would think that this group would survive at least as well if not better than the M+ group. Why isn't that the apparent case? M- is also composed of classical which makes up about 25%~30% of nGBM characterised by the mutation EGFRviii and the focus of the failed CLDX trial and which seems to respond to chemo/rad and to some extent DC VAX L. Neural is less than 10% of this population and may not respond at all. Perhaps these latter molecular sub-groupings act to pull down the supposedly superior results wrt MES thus pulling down overall M- performance at the OS 36 milestone. In addition, we need to understand the composition of the long tail. Is it a one trick pony composed of predominantly M+? We don't really know, at least at this point, what the MOA may be to explain these and other possible anomalies. Hopefully, unblinding and analysis will shed some favourable light on all this. JMHO.
