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Exelixis, Inc. Message Board

  • enabeler enabeler Feb 25, 2011 1:53 PM Flag

    Excellent synopsis and summary.

    http://www.istockanalyst.com/article/viewarticle/articleid/4921904

    "Summary

    The preliminary data provided to date puts cabozantinib in an excellent position to revolutionize the way bone metastases are treated, going where no drug has gone before. For the first time, there is a drug with clear activity on established bone mets, which represent a highly unmet need. Needless to say, there are still various clinical and regulatory risks associated with this drug which is just entering late stage trials. Nevertheless, the unprecedented activity coupled with a huge untapped market opportunity makes Exelixis a BUY even with a market cap of over $1B."

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    • I gotta agree,but aren't these trials a ways out? By the way, it's nice to see people who actually know something on these message boards and are not just trying to manipulate the stock.

    • <<I go back and forth on this, but if the bone scan is unreliable and the pain data soft doesn't the case for XL184 begin to fall apart?>>

      If we take this as a worst case scenario, then you are still left with a RCC/HCC/Ovarian cancer drug that will not replace any current CRPC therapies, but would be an interesting candidate to contribute its osteoblastic inhibitory effect to a drug combination. It's still undervalued.

    • What do you think of the thesis that PC is continuing to progress but in a "silent form" analagous to multiple myeloma?

      I now think it unlikely since I don't know of any naturally occurring cancers with bone mets that don't increase either osteoblast or osteoclast activity. Or both. And as ernie pointed out the time history plots of ALP and CTX indicate that this isn't happening. It is still possible, of course, that for instance the tumor escapes via some MOA that is rare in natural cancers.

      More comment later... have to go.

    • Thanks for reply, epecially about the hemoglobin response. I wasn't sure if it was significant/real. What do you think of the thesis that PC is continuing to progress but in a "silent form" analagous to multiple myeloma?

    • <<I go back and forth on this, but if the bone scan is unreliable and the pain data soft doesn't the case for XL184 begin to fall apart?>>

      That is a good one sentence summary of the counter-case and is valid IMO. But FWIW there is supportive data as well. In order of strength of more well calibrated or direct clinical benefit items:

      1) Highly likely that the drug does have some efficacy based upon traditional metrics:

      2) The Randomized portion of the trial appears quite strong (although I expect it exaggerates apparent efficacy).

      3) The hemoglobin jump in anemic patients is dramatic - probably indicating bone efficacy of some kind.

      4) The magnitude of the PFS appears good (but not great) compared to historical - but the data out near the median is still very sparse and so this is still pretty weak data.

      As for the bone data - I wouldn't say that the bone scan data is 'unreliable' - just not well calibrated. I think it is very reliable at detecting osteoblast activity, but it is not clear how well that correlates to bone met growth.

    • You guys are a bit over my head to say the least, but there is one question I've been trying to get answered for a while: The way I read the poster there are a lot of dots showing improvement on bone scan but with progression of PSA from baseline. Maybe I've missed something but doesn't this call into question the usefulness of the bone scan to measure disease progression? I go back and forth on this, but if the bone scan is unreliable and the pain data soft doesn't the case for XL184 begin to fall apart?

    • <<What significance, if any, do you attach to the CTx reductions, including those to patients still on Zometa? >>

      Good point - in that that makes the myeloma model less likely (but not impossible - e.g. is osteoclast activity now completely normalized? Can the tumor be growing somewhere without tearing up bone?)

      <<This ignores the fact that there is also the progression data from the original RDT contingent that was RECIST evaluable. >>

      I fully agree, and have said so for quite a while, that cabo has anti-tumor activity outside of the osteoblastic activity. But the context for our discussion was whether bone scan is reliably correlated with that - not whether it cabo has efficacy of any form.

    • <<Why? If the drug is stopping tumor mediated osteoblastic activity without slowing the tumor (PCa conversioin to Myeloma model) what does 8 months of data tell you that 3 months doesn't?>>

      This ignores the fact that there is also the progression data from the original RDT contingent that was RECIST evaluable. The placebo arm had a 40 day median progression and the Cabo arm may or may not reach its median between now and June. It's clear that Cabo has antitumor activity in CRPC, the only question is to what extent. From a theoretical perspective, it is fairly well accepted that bone tumor growth is fueled by the release of growth factors as bone is degraded through osteoclastic activity. The CTx reductions likely mean osteoclastic inhibition leading to slowing of tumor growth. By 8 months the abscense of skeletal related events and pain progression will take on more meaning.

      <<PS To some extent I am being a devil's advocate.>>

      Nah, say it ain't so.

      <<I'd be surprised if there weren't some efficacy linked to interfering with the tumor mediated osteoblastic activity ->>

      That's a start.

      <<but I'd be surprised if the bone scan remission duration were reliably representative of duration of tumor response.>>

      What significance, if any, do you attach to the CTx reductions, including those to patients still on Zometa?

    • Also worth considering is that nearly half of the CRPC patients had had docetaxel previously.

    • <<With that kind of follow up the bone scan significance should become clear. >>

      Why? If the drug is stopping tumor mediated osteoblastic activity without slowing the tumor (PCa conversioin to Myeloma model) what does 8 months of data tell you that 3 months doesn't?

      PS To some extent I am being a devil's advocate. I'd be surprised if there weren't some efficacy linked to interfering with the tumor mediated osteoblastic activity - but I'd be surprised if the bone scan remission duration were reliably representative of duration of tumor response.

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