RK.
Thankyou for this very well-reasoned and well-argued post.
I think your conclusion, that the company probably initiated the hold in order to submit some protocol changes is most likely correct.
Although they probably initiated the hold, in doing so, they effectively lost control of timetables, and put themselves in the hands of the FDA, who could respond expeditiously, or more likely in a 'leisurely' fashion.
Possible protocol changes?
Well, elevating OS to co-primary endpoint is a possible. I think maybe unlikely though. As we know, OS is somewhat compromised because of crossover, and even if median OS proves to be totally unprecedented, as I'm sure it will, it can only be measured against historical norms, due to absence of control, hence of limited statistical value. Plus the issue of possible use of other post-crossover therapies. And the OS data will take several years to mature...
You could not estimate trial ending Sept 2016, if this was your co-primary endpoint.
Employment of immunotherapy imaging protocols?
More likely I would suggest.
From NWBO's point of view, they cannot allow the trial to fail on its primary endpoint, due to pseudo-progression being mistaken for disease progression. Use of iRano or irRC would ensure that that scenario does not happen. It's a tad unfortunate, that the original trial design goes back to a time when pseudo-progression had not been fully recognised, as a confounding factor. This would fit with the comment from Doc Bosch that the pseudo-progression issue was wreaking havoc with clinical trials.
Though quite how you go about retrospectively re-visiting progression decisions, using immunotherapy imaging criteria is not easy to see.
Subgroup identification?
Can they identify mesenchymal patients prior to commencement of L therapy? If so, how? What is the test? If they want approval for a subgroup, then there must be a routine test to identify a subtype prior to commencement of an approved therapy.
High TIL score? Same thing applies. Must be a simple test that can identify trial patients with this attribute, prior to commencement of therapy.
Heck, if they were submitting protocol changes, perhaps they took the opportunity to include patient-reported quality of life. An often forgotten major advantage of immunotherapy. Especially when compared to Keytruda, with its frequent serious and debilitating side-effects, and Optune, with its deleterious impact on patient life quality, when 'worn' for the recommended eighteen hours a day.
You only need to read a few of the patient forums to see how some of the treatments (excluding L) make life so very difficult. This is where L additionally scores.
If there is justice in this world (which I sometimes doubt..) then approval of L will be expedited some time, somehow, this year.
