NorthWest Biotherapeutics Inc (NWBO)

[Galzus Research]

OS is absolutely the gold standard endpoint in oncology. But there are a lot of things to say about this. It's not night and day simple as proposed here.

There are 2 notable situations where you can make a reasonable argument that OS is not the most critical endpoint. I say "reasonable argument" because this is a controversial topic. So it's not gospel, just food for thought:

1) When patients live a long time with a fairly good prognosis, the long-term follow-up for a primary endpoint of OS can be really challenging and costly (ie, interventions in early-stage cancers). In these situations, surrogates like response rate (especially path CR) or disease-free survival can be of value to inform care and might be more feasible than OS

2) When you bake crossover into the study, OS becomes almost meaningless, with great difficulty in teasing out the effect of crossover. DCVax ran into this issue, and I'm not saying they SHOULD have done this or that. I agree it's unethical to subject placebo patients to leukapheresis only to be a guinea pig.

But we do not know what the overall survival of the placebo group is in that study. And taking OS from contemporary studies' control arms only gives you a signal, not a definitive answer. The different inclusion criteria of DCVax patients were more restrictive than were the studies chosen for the control arm. If you compare your study against a group of studies where patients with worse prognosis were allowed to enter, then it's not very surprising when your study beats those controls.

So overall survival ends up being a problematic, difficult-to-interpret endpoint in a study of a novel agent that includes crossover. It is elaborated very well in an editorial by Timothee Olivier (https://pubmed.ncbi.nlm.nih.gov/37012085/).

The long story short: when you have crossover and lose the randomized element of your study, overall survival is a less-interpretable endpoint. And the fact that NWBO has not pursued FDA approval and the fact that it's taking so long in review with the MHRA are both illustrative of this issue.

If PFS had been improved, or response rate, or if they had been able to maintain the integrity of the placebo arm, then this would be easier.