Essentially, if NWBO had had the luxury of looking for that elusive "rational" "cutoff point" for methylated status that the Germans used in the CCNU/Lomustine February 2019 Lancet article, the DCVax-L trial would never be over. Never.
In other words, if instead of being content with the diluted 47% pool of methylated they got (get what you get and you don't throw a fit), had NWBO said, "you know, I just don't think some of those are methylated enough for my liking, let's set the cutoff point to something more purely methylated, so, let's drop a third of the low methylated from our trial and ramp it up with higher methylated." Well, the Germans were able to do just that in the Lomustine trial, because they were only running a methylated trial, but NWBO didn't have that luxury, they had to make the call and pick their baskets.
If NWBO had set the cutoff so that only really pure methylated made the trial (like the CCNU trial did) then there would not be this huge delta between methylated and unmethylated survival that the DCVax-L trial achieved. There wouldn't be this high ratio of methylated patients. Why? Because the unmethylated basket would have been filled up with low methylated as well.
Back to my point. Let's take a generic cutoff on a scale of one to ten. Let's say the Germans used 5 and up for their cutoff, but NWBO only used 3 and up.
When you go back through the literature, you can find a few case studies that literally show the sliding impact of methylation ratio per tumor on OS.
Had NWBO, with DCVax-L, used the 5 and up "rational" cutoff, their pool would have been even higher than just cutting out the 3s and 4s, because the reality is they would have filled those missing patients with 5s, 6s, 7s, 8s, 9s, and 10s. The trial would have literally never reached enough events to trigger completion, because, imo, of DCVax-L's long term tail impact. The tail would have grown too thick and too long.
Germany, ironically, used their CCNU trial (Lancet Feb 2019) to accumulate supermen methylated responders. That's primarily why their SOC arm did better than other (historical and contemporary) SOC arms. Extent of original surgery, on the other hand, tends to only provide synergy only up to around 24 months or so and starts to have tapering effects.
Instead, what happened, is NWBO had to simply take what was thrown at them and place them in unmethylated or methylated baskets. Even with a lower cutoff for methylated, the tail is really strong. So strong that half way through the trial they had to broaden the absolute lymphocyte count inclusion parameter.
If instead of doing that, they had the luxury to increase the cutoff for methylation acceptance, the trial would have never reached anything near its event horizon.
Respect Risk. Conduct Your Own Due Diligence. Manage your assets wisely. Diversify.
