NorthWest Biotherapeutics Inc (NWBO)

[longfellow95]

This is a pretty good example of how censoring earlier in time can affect the KM survival later. (and, quite frankly, if you understand this, you will understand the ludicrousness of continueing the trial to capture this data - they already have a damn good estimate of the number. Yes, the estimate would improve in accuracy, but unlikely to change much at all.

Not ludicrous at all.

LP is determined to capture the approx 25% who achieve long term remission.
Bear in mind that 50% of the L trial subjects have been in the trial for 4 years or less, and 25% have been in the trial for 3 years or less.

Optune is not curative. No claims have been made that it is.
Though its milestone survival right up to 5 years is undoubtedly good in terms of historical survival.
Their KM curves presumably apply proportional hazards, which, while always an inaccurate estimate, are probably less inaccurate in the case of Optune, because it is not an immunotherapy and does not exhibit typical immunotherapy survival kinetics.



As Tsai-Tsang Chen puts it:-

Overall survival remains the gold standard for demonstrating efficacy in oncology clinical trials. It is defined as the time between the date of random assignment and the date of death. For patients without documentation of death, OS is censored on the last date the patients were known to be alive. The most commonly used statistical methods for time-to-event analyses have been the log-rank test and Cox regression analysis (10,11). These standard analyses have maximal statistical power under the proportional hazards assumption. One appealing characteristic of the log-rank statistic is that it does not require any assumption of the shape of the survival curve or the distribution of survival times. While it may serve as an advantage in assessing the efficacy of traditional chemotherapies or targeted therapies, it does not necessarily capture the key attributes of immunotherapies such as long-term survival. Based on the kinetics of the survival effect, the time to final OS analysis may continue to lengthen. The long-term survival and delayed clinical effects could result in substantial prolongation of study duration and loss of statistical power if the trial was designed based on the conventional exponential distribution assumption (12). This poses a challenge to accelerating the drug development process when the strength of this class of agents is derived from long-term follow-up.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836810/


There is, for me, considerable logic in taking this out to 75% OS events, which could occur any time from now, though 80%, which could occur between 6-24 months from now, is, admittedly, a bridge too far. The alternative metric is actual OS36, which will be available by approximately Nov.


They only get one shot at this, so they must maximize statistical power.



Chen again:-

The statistical power is determined based on the number of events when a randomized comparative clinical trial is designed using a time-to-event endpoint such as OS as the primary endpoint. In general, the target cumulative event rate of approximately 80%, ie, four-fifths of the randomized patients becoming events by the end of the study, usually yields a good balance between the size and length of the trial. When a subset of patients is expected to be event free, a sufficient number of patients needs to be randomly assigned to ensure the total number of events is reachable, because the number of patients at risk is smaller and the events can only be expected from the susceptible population. In addition, the delayed clinical effect observed in most randomized immunotherapy trials leads to the loss of statistical power because the delay at the beginning of the trial will offset any treatment benefit that follows. Therefore, the number of events will also need to be increased to compensate for this loss of statistical power.

And on milestone analysis:-

Once the time point of interest has been determined, although not an absolute requirement, it is preferable to ensure that sufficient follow-up duration among patients be included in the milestone survival analysis. In other words, the milestone survival analysis should not be conducted until at least the milestone duration has elapsed from the time the last patients entered the study in this cohort. The rationale behind this recommended restriction is to ensure the robustness of the milestone survival analysis. If all patients meet the minimal follow-up requirement, ie, milestone duration, the result will not change, because subsequent follow-up in this cohort will only have an impact on the survival curves beyond the milestone. If the milestone survival analysis is to be implemented, that implies the chosen milestone is an important endpoint that can be considered clinical benefit in clinical practice. Any measure that would ensure the robustness of the analysis is recommended.

(My highlighting)



It is in the current period, when the majority of OS events are occurring in the control arm (I believe), that the survival benefit of L treatment becomes more and more apparent.