NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

From that link RK posted and the section you mentioned (1:35:07):

The kinetics that you see on survival, and how do the non-survival endpoints - response or progression free survival - ultimately relate to the survival outcome. We know historically from cytotoxic agents, or from targeted therapies that there is often a dichotomy between the PFS and the OS endpoint. Often, the hazard ratios for PFS or the benefit in PFS has been greater than that which you see for survival.

With immunotherapy, we’re making the opposite observation.

And at minute 1:36:53...

Renzo [Canetta] made this case already [earlier in the presentation] for Provenge or Sipuleucel-T… that is a cell-based cancer vaccine, that has shown no benefit on PFS at all, basically no responses but a reasonable sized benefit on survival. And that falls more in the category of cancer vaccines where you historically have not seen responses. We’re still grappling with how to make cancer vaccines work, but there is still a lot of interest in the field. And if you now think of the spectrum of immune therapy agents that are being investigated, they’re not all checkpoint modulators. They’re not all PD1s. So you might find within the check point category, you know we’re going from blocking agents, like PD1 and PDL1, to antagonizing agents like Ox40 and (illegible) and other ones, you see new dynamics. So for us to be able to measure what these agents do is important. And I believe for that, you will need a more flexible tool than conventional response. So for PD1 you may not. But for the spectrum of immunotherapies we’re dealing with, you know, that flexibility may have to increase.

Also earlier and in the same presentation (I'm still watching), there are some interesting points made about how the FDA approaches approval of immunotherapy drugs.

Slide 14
21 CFR 314.015(c)

FDA is required to exercise its scientific judgment to determine the kind and quantity of data and information an applicant is required to provide for a particular drug to meet the statutory standards for safety and effectiveness.

FDA applies flexibility regarding the evidence required to support approval to address particular challenges posed by each disease.

And at minute 10:40, the presenter discusses Ipilimumab (Yervoy) approval and the endpoints that may be what the P3 trial here is waiting on.
K-M curves of OS which showed a delayed separation of the curves and a late plateau with the tail at the end.

In this case, tumor response based endpoints, which can be measured earlier, did not adequately capture the anti-tumor activity of this drug, and would not have led to a demonstration of effectiveness without the results of the overall survival.



And then at minute 12:27, the presenter offers relevant comments on the approvals of Nivolumab and Pembrolizumab which were based on low objective responses:
12:27
The initial approvals of these two agents (Nivolumab and Pembrolizumab) were based on the objective responses of 24 to 32%, which are low. But with response durations of more than 10 months, and even in a phase one study with longer follow ups and response durations of 23 months were observed. And these results were in a very refractory population because all of these patients had been treated with Ipilimumab, and those who were BRAF inhibitor, and with BRAF inhibitor, if they were BRAF 600 mutation positive.

Slide 19 (minute 12:50) entitled: Immuno-oncology Drugs - Considerations
(suggests a recognition of some of the issues that might arise from the endpoints used and the standard measures of efficacy such as medians.

Low ORR with prolonged duration of response which may reflect the dynamics of the immune system

Small differences in median PFS
Delayed separation of PFS and OS K-M curves
The magnitude of median PFS shown previously (Nivolumab and Pembrolizumab) may not present the treatment effect if benefits are delayed.

Median OS may obscure long-term benefits in minority of patients

Late plateau of survival curves likely represent long-term responders who remain progression free for years

Jumping ahead to the section when Renzo Canetta speaks to traditional endpoints, and at minute 47, he states:

Now, just for the fun of it, I would remind you of a paper that ASCO, which is an society I'm a member of, published recently, indicating that every drug that achieves a hazard ratio below .80 for survival should be made available to the public. So keep that in mind.

Thanks for finding and posting this very helpful presentation RK. Thanks Highway for directing me to that later section. :)