We really do not know what LL meant. I believe you are incorrect when you claim that she referred to early enrollees versus late enrollees. Rather she was referring to early vaccinations versus later vaccinations as a result to crossovers upon eventing and comparing the two. In fact, it may be that there is no significant separation which is good for patients but not so good for the trial.
When she said that patients are living longer than expected, what does this mean? Does it also refer to the non-crossovers? Perhaps as an overall group, patients are living longer than expected but this could also include the non-crossovers which are about 14% or about 46 patients. She would not know about these patients. And what is she comparing this expectation to? The usual 15-17 months mOS? She probably did not mean long tail or 36 months at the time she made the statement. WRT to M+, the comparator was 21.7 months mOS and blended was 34.7 months. Looks good with the comparator chosen for the article. But......there are studies that have SOC at 29 months or even 34 months. Are these outliers? We have unconfirmed ideas what comparators will be chosen and those selected will be extremely important to success or failure of the trial.
So, you can now see that long tail/36 months is extremely important and the reason why LP and the SAB are dragging the trial out:
1. Most probably, due to pseudo-progression, I believe that even with adjudication, the primary end-point of the trial will be missed. Does this threaten success if other sign posts are positive? In my opinion, no. Firstly, OS is the gold standard and PFS is used as a surrogate. By now, NWBO has enough data for OS and long tail. What is more important is the "distance" between progression eventing and OS. Secondly, even though there may be earlier PFS eventing than expected, it may be that as the vaccine effects begin to take hold even after progression eventing, the rate of progression is slowed and in some cases, perhaps to zero. So, failure in the PFS primary end-point is not a killer to trial success. But it certainly is a concern, especially if other markers are not significantly positive.
2. WRT to OS, it appears that this is more promising especially when you look at bended numbers both for M-(19.8 months) and M+(34.7 months). So, paraphrasing the words of Dr. Ashkans, the vaccine appears to help across all groups to a greater or lesser degree. Much more so wrt to M+ than M-. However, success is largely dependent upon the comparator used. If it is a combination of crossovers plus non-crossovers as control, there may be confoundment and extended survival. We just don't know. Further, there are studies that show control to exceed the commonly referred to the overall 15-17 months more commonly quoted. The success in M+ which appears to be made up of predominantly pro-neural seems to contradict Dr. Prins'/LL's earlier findings that pro-neural seems little or not affected at all by the vaccine and chemo/rad due to its being less immunogenic than say mesenchymal which is found in M- and was found to be a better responder to the vaccine in earlier studies. So, in summary, there are question marks wrt to OS as the secondary end-point.
3. Thus, one can easily understand the focus on 36 months and long tail out to 60 months and beyond. LP stressed, in so many words, that this is the new gold standard for immunological therapies like DC VAX L and that this is the criterion that investors should be focused upon. If 1 and 2 above are not successful, mixed or ambiguous, 36 months/long tail need to be home runs. These probably need to be in any event. There is no second chance. Once they unblind, they either hit it out of the park or it is over. Forget D. They want it to be undeniable(note LG remark on April 27, 2018) on at least the 36/longtail not only for reg approvals but for QALY/ insurance purposes as well---and not to mention relatively quick reg approvals. A lot is at stake here. It is digital. There is no in between. Thus, the odds may be that the trial drags out beyond November and into next year. Neither good for investors(more dilution, uncertainty and pps devastation) nor patients(obvious if it works). November is a critical month. Can LP/LG hide an accounting at the ASM assuming they don't delay it indeterminately? JMHO.
AI
