Replies to post #115357 on Biotech Values

[DewDiligence]

EXEL—As to your point of flare, it gets back to whether bone involvement for prostate cancer is primarily an osteoblastic or osteoclastic affair. I went into it thinking it was primarily an osteoblastic affair because the scintographs target osteoblastic activity. I'm not so certain now.

You may not ever have a definitive answer to this—please see #msg-60128822.

[biomaven0]

Finally, even if there is a flare the FDA is clearly willing to allow for protocols that try and eliminate this for purposes of progression adjudication.

I think there is some confusion here. Drugs like paclitaxel help some with bone mets but often cause an initial flare that then resolves at the next scan. So an initial flare is not considered evidence of progression.

For the EXEL drug, the question has been raided why there isn't a temporary flare if the lesions are in fact healing. I don't think anyone yet has a good answer to this - all we know for sure that there is no significant osteoblastic activity. There could still be osteolytic activity or there could be non-progression or even slow healing of the lesions.

Peter

[iwfal]

EXEL -

Once you have corresponsing pain location and scintograph lesions established at baseline, it isn't too much of a leap to assume cessation of narcotics combined with bone scan resolution equates to clinical benefit.

As I said in a PM I wanted time to think through implementations and what they would mean. Below is one such implementation:

1) Randomize patients with pain that maps to a particular spot that shows hot on the bone scan

2) XL184 patient gets pain relief for that spot and bone scan will almost certainly show 'colding' of the hot spot. Great, no issues.

3) Dox patient gets equivalent (perhaps better) pain relief for that spot - but bone scan does not show 'colding' and in fact shows a hotter hot spot (flare indicating healing?).

Would the FDA really let a poorly understood test like a bone scan turn an equivalent clinical result (pain relief) into a very significant benefit for XL184? I don't think they will - nor do I think they should.

And I think that conceptually almost anything that takes significant advantage of XL184's bone scan clearing phenomenon is likely to run into the same issue (with one exception - see below). OTOH if they pair it with another imaging technique that can detect dead tumor then, maybe..., but of course it is a debatable question as to whether XL184 is doing better in that regard.

The one exception would be to take advantage of the FDA's weakness of allowing existing standards to be used even if they are clearly asinine. In this case taking advantage of the fact that a hot spot is counted as progression in RECIST. In a simple prostate cancer trial isolated to patients with a high ratio of bone mets to soft tissue mets they could just run a pfs trial and I'd bet most progression would be bone scan progression so XL184 would win hands down. The FDA might bite - I don't think they should, but they might. No need to even go after a composite.