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Exelixis, Inc. Message Board

  • wilderguide wilderguide May 3, 2014 1:56 PM Flag

    The Elephant in the Room at EXEL

    The Cabo bone phenom...
    How's it do that? Whys it do that? Do those rumors really go away? Does the patient benefit? Why? How?
    Cabo's bone response in CRPC is a hallmark consideration. It is the singular aspect of of Cabo treatment that clearly differentiates it from other "tumor shrinkers". In addition, patient reported pain relief is directly commensurate and proportionate to BSR. This reduced need for pain management results in a reduction in narcotic use in roughly half the treated population. Further to this, markers of bone turnover (Ntx, Ctx) are improved...serum hemoglobin is improved...LDH levels are improved...CTC's are reduced...bone alkaline phosphate is reduced..PFS is extended...and visceral tumors are also managed agreeably.
    Interestingly, many of these responses are currently under ongoing clinical investigation for their predictive value as a surrogate endpoint for overall survival. Some have been adopted in the clinic as invaluable prognostic indicators of initial response to therapy, predictive indicators of diminishing response to therapy, and forecasters of the pending need for replacement therapy.
    Whether these patient-reported benefits and clinically evaluable responses to cabozantinib actually translate to a statistically significant survival benefit that can be predictably and affordably applied in oncological practice...
    ...with a margin of profit that pays the light bill and satisfies the shareholders...
    That's the elephant on the room at EXEL.

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      Along similar lines of thought, it's also important to understand the regulatory (FDA) posture wrt the Cabo bone phenomenon. Cabo is a unique, novel agent with no known therapeutic equivalents. Prior to the Cabo bone phenomenon being reported, it was generally considered that cancer metastasized to bone was an incurable, untreatable(except for pain management) condition that the patient would carry to the deathbed. RANKL inhibition and treatment with Zoledronic acid has proven of measurable patient benefit resulting in improved bone turnover markers, but confer no known OS benefit.
      As such, the Cabo BSR is currently inadmissible for purposes of FDA approval. The improved biomarker surveys are also considered clinically experimental within the regulatory approval guidelines, and may not be considered of substantive validity to enable FDA approval. Clinically valuable...but again - unacceptable for regulatory approval. Where does that leave us? Here's my take...
      The current literature is full of current research endeavors that are attempting to validate all these biomarker assays (and others) toward a reasonable prediction of survival benefit. Why? Simple...Reproducible, reliable biomarker response - as opposed to realizing an actual survival benefit - would cut trial costs substantially, and shorten trial lengths...perhaps in turn, shortening the timeframe of bringing a drug to market. This could conceivably cut drug costs by more than half.
      I encourage you to at the research endeavors of Drs Howard Scher, J DeBono, Paul Korn, C Logothetis, Dan George, and Ethan Basch wrt biomarker assay (including patient reported pain relief) as a surrogate endpoint for OS. This has become a huge, heavily funded, multi-institutional research project that has produced many encouraging results...many of which bode well for cabozantinib.

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