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Exelixis, Inc. Message Board

  • hbomb57108 hbomb57108 Feb 15, 2013 10:44 PM Flag

    ASCO 2012 with Dr. Smith

    I took a look into the presentation made by Dr. Smith. It was interesting in that he compared Cabo to Sunitinib. Some observations were

    Sunitinib bone biomarker improvements were weak. Bone responses with Sunitinib were at 30%.(Didn't break down extent of responses) Described Cabozantinib bone responses more dramatic than Sunitinib. Dr. Smith mentioned that bone response in trials is pretty easy to find if it is there. He went on to state that he didn't believe single MET target inhibition likely to have this dramatic bone response as it would have been teased out already in prior failed Prostate trials with one drug in particular.(I think he mentioned METMAB but not sure)
    The other interesting tidbit that I keep wondering about is that bone markers have dramatic changes, even in patients that don't have bone metastasis by bone scan criteria. Even though Sunitinib didn't demonstrate statsig survival, it sure looks like it favored Sunitinib on Kaiplan Meier curve from the beginning of curve down to the bottom. Sunitinib is probably the closest to demonstrating an OS benefit of all TKI's, but just not enough. I still think Cabo clearly showing better early activity in prostate despite many similar targets to Sunitinib. I agree with Ernie, and have more confidence in RCC and HCC regarding successful pivotal trials. At the same time, I don't have too much doubt in Cabo demonstrating statsig OS in prostate.

    I still can't believe how D-mab got such an easy route to market. I thought the lack of OS for D-mab had to do more with patients taking off drug after seeing bone mets, but I'm not quite so sure anymore. D-mab probably would not demonstrate survival benefit even if patients had stayed on drug following intitial bone met finding. Cabo demonstrates very large bone biomarker changes on top on the biophosphonates including D-mab.

    Dr. Smith also pointed out that RDT with Cabozantinib is probably the most refractory prostate patients ever studied up to this point. I think that is probably the difference between the UMASS poster and extension cohort of RDT.

    I know it is kind of lame to talk about purchases, but I bought a pretty decent chunk earlier today for the first time since 2010. Not that Dr Smith presentation swayed me or anything as I bought earlier before viewing. I usually don't add to an already substantial position, but other stocks I have been looking at have made some pretty strong runs of late. Anyway, mostly bought for long term and have no idea what is in store over next 12 months.

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    • "Dr. Smith also pointed out that RDT with Cabozantinib is probably the most refractory prostate patients ever studied up to this point." You may have noticed, but I'll point out for general consumption, the RDT required RECIST criteria measurable disease, so 100% had visceral (soft tissue) disease As such this was a very advanced group. The decision was made to terminate the RDT and enroll an expansion cohort. These patients were a trial run for the Comet trials. Because the RDT was over, there was no requirement for measurable disease, but bony mets were required and more attention was paid to data collection consistent with Comet 2 criteria. Sometime later, it bacame obvious that 100mg was overly toxic and the NRE enrolled a 3rd cohort at a 40mg dose. Which presentation was this??

    • Thanks for the presentation from the researcher's mind.

      - From the Q&A: it sounds like Cabo is the best prostate cancer related bone agent he's seen, with substantial benefits in addition to the osteoclast specific compounds currently in use.

      - For bone scan response: a fully automated system was used to evaluate, although it is not an accepted surrogate and doesn't count in RECIST numbers. Among accepted surrogates, CTCs improved but PSA response wasn't as convincing. (They really ought to standardize bone scan as a surrogate, and if Cabo is accepted, the techniques he described could gain traction. Look up "radiologist dancing gorilla" on google.)

      - Bones: Seems to promote normal bone growth. This is an effect independent of the presence of cancer. It sounds like Cabo wouldn't compete with Enzalutamide and Abiraterone in the prostate space as Feuerstein seems to believe so much as it would complement them with its preservation of bone health.

      - c-Met: Seems to be the key here although c-Met only targeting (as we've seen even in conjunction with other inhibitors) doesn't exhibit much efficacy. Cabo also blocks other signals as well and has a bone response independent of cancer.

      - COMET-2: Should be a slam dunk from the expansion methodology he revealed.

      - COMET-1: He stated that OS is a necessary component in a good drug. I think there's a good chance we'll see OS benefits as SREs are a major cause of morbidity and Alpharadin worked.

      - Toxicity: 60 mg is used because it allows for a 20 mg dose reduction to 40 mg which is still.

      - Rebound: The scans of the patient rebounding after being taken off Cabo but remissing after reintroduction indicate that Cabo is far from a cure but exhibits a consistent response for important symptoms.

      - From the applause near the end, it sounded like kind of a small crowd which is too bad because it was an interesting presentation, and it would be nice if more clinicians were interested in / could know about the compound.

      • 2 Replies to wildbiftek
      • "- Bones: Seems to promote normal bone growth. This is an effect independent of the presence of cancer. It sounds like Cabo wouldn't compete with Enzalutamide and Abiraterone in the prostate space as Feuerstein seems to believe so much as it would complement them with its preservation of bone health."

        I agree there is room for optimism here, but I'm going to keep a "show me the money" attitude on this one. I still remember the animal study in which the treated mice invariably developed a loss of appetite and translucent teeth with prolonged use. I'm not saying this will happen in the human trials, but we don't have much data on prolonged cabo treatment. Having an effect on markers of bone turnover is not the same as promoting bone health. So while I agree that there is room for optimism and recognize that prechemo is where the big money is, I'm still going to wait for some trial results before I factor that into any realistic projections.

      • Rebound: I really should say that the PFS Kaplan Meier diagrams and bone scan indicate this. The single patient is important as an example about determining whether specific phenomenon exist at all but anecdotal for measures on the entire population.

 
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