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Exelixis, Inc. Message Board

  • xwavve xwavve Dec 11, 2012 10:27 AM Flag

    COMET-2: Fortuna's Light

    COMET-2 will likely read out earlier than anticipated. The primary endpoint is pain at wk 12, and secondaries, BSR and OS. Bone mets and pain are a major cause of morbidity and mortality in CRPC. And, this is the original trial they hoped the FDA would accept for approval (now COMET-1).

    Why will this trial likely read-out early? Because cabo is far more effective than mitoxantrone and prednisone, the active comparator. If a significant deviation between experimental and comparator agents occurs, it will be flagged by the DSMB, and they will be faced with a decision. Should we continue this study? Patients evaluation for pain is at wk 6 and 12, and BSR at week 12. Patients are harvested rapidly on the primary endpoints. The study began in January 2012 (posted to clintrialsgov).

    With significant optics on efficacy and recent publications in the public arena, COMET-2 enrollment has accelerated. EXEL hosted a "dinner meeting" in Vienna to further share data and create interest for rapidly enrolling patients the COMETS. The link is still up, if you search cabo and dinner meeting and Vienna. DeBono, Scher and the usual suspects pontificating.

    Once results are in for COMET-2 (and if positive) a compendium listing will almost certainly occur. And, this will be a tough position for the FDA to be in... a sillly one - as there stated claim is make drugs available to patients rapidly who face high odds for mortality. Similar to Zytig and MDV3100 being reserved for post-chemo use - early compendium listings, and yesterday, finally rapid approval for Zytiga.

    It would appear that the investment community hasn't processed the potential for accelerated CRPC cabo news. Fortuna is likely to shine on early and positive news, and Gisela has seen the light.

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    • With pain as primary endpoint, what indication will FDA approve XL184 for before COMET-1 results? Bone mets with pain?

      • 1 Reply to stocklooking
      • Duck,
        With the FDA nothing is absolute. I was just presenting my opinion/guess about how the FDA might handle one scenario. But the FDA is very much driven by precendent (they like to follow what has gone before and they don't like to create new paradigms).

        As far as your other point, it is certainly possible that within prostate cancer, there are subsets of patients that will benefit thus obscuring an endpoint like overall survival. If that is the case, the likely scenario is that such a population (say for example that patients in the COMET-2 trial with hematocrits of

    • There is currently a presumption that filing of the basis of Comet 2 alone is not an option. At the time of the most discussion on this topic, following the SPA disapproval, most of the analysts questions presumed that a standalone filing based on pain was not an option, but when asked directly, Dr. Schwab made it clear that a standalone filing could occur, but that the company expected both trial results to occur in temporal proximity (50 cents) so that it was more likely that the company would ask for approval based on Comet 1 with a pain label based on Comet 2. My thinking is that if Comet 2 shows an overwhelming pain advantage and a positive survival trend, EXEL will look at its Comet 1 completion projection and may well decide to file on the basis of Comet 2 and then do a supplemental for Comet 1.

    • There is currently a presumption that filing of the basis of Comet 2 alone is not an option. At the time of the most discussion on this topic, following the SPA disapproval, most of the analysts questions presumed that a standalone filing based on pain was not an option, but when asked directly, Dr. Schwab made it clear that a standalone filing could occur, but that the company expected both trial results to occur in temporal proximity (50 cents) so that it was more likely that the company would ask for approval based on Comet 1 with a pain label based on Comet 2. My thinking is that if Comet 2 shows an overwhelming pain advantage and a positive survival trend, EXEL will look at its Comet 1 completion projection and may well decide to file on the basis of Comet 2 and then do a supplemental for Comet 1.

    • Y is blocking me every step of the way. Comet 1. Survival endpoint that is event driven with one interim. EXEL's projects 2014 readout but did not say if this is interim or final. 960 patients with 73 of 225 locations recruiting, many foreign. Both trials assume a median survival on the control arm of 7 months.

      Comet 2. Pain endpoint that is a patient reported outcome reported at 12 weeks after treatment initiation. Entry requirements are very similar, Comet 2 additionally requiring moderate pain. Comet 2 has 34 of 55 locations recruiting, all in English speaking countries. This is important because both trials require pretreatment with Abiraterone or MDV and most of that patient pool is stateside.

      • 1 Reply to erniewerner
      • I think Comet 2 will enroll quickly as it is mostly stateside with the largest pool of eligible patients. Successful attainment of the primary endpoint is a virtual given because the requisite level of efficacy is fairly low. This is a highly powered trial. I do not think the DSMB will stop the trial early because of a superior pain management demonstration on the Comet arm because at this point is unknown what level of efficacy the FDA will require for the drug to be approved. An early stoppage could jeopardize that approval. A remote possiblity would be an early stoppage for a statistically significant survival advantage on the Comet arm, but the size of the trial makes this highly unlikely and even if it were to happen, it would occur after the data collection for patient reported outcomes is complete. This trial is going to move along pretty fast anyways, so I think the DSMB will let it go to completion. EXEL may or may not announce full enrollment but it will be no secret when the centers stop recruiting new patients.

    • I really like your post because it brings up a number of great points. "And, this is the original trial they hoped the FDA would accept for approval (now COMET-1)." EXEL has not ruled out filing on the basis of Comet 2 while waiting for Comet 1. At the time this was being discussed, the SPA had just been turned down and the analysts questions mostly presumed that the SPA refusal was tantamount to rejection of a pain endpoint, which it was not. Comet 2 is a much smaller trial and as you noted, got off to an earlier start. Comet 1 is enrolling 960 patients with an OS primary endpoint and Comet 2, 246 patients with a pain endpoint determined by a patient reported outcome at the 12 week point. Data accumulation for the primary endpoint of Comet 2 will be complete 12 weeks after the last patient begins therapy.

    • I really like your post because it brings up a number of great points. "And, this is the original trial they hoped the FDA would accept for approval (now COMET-1)." EXEL has not ruled out filing on the basis of Comet 2 while waiting for Comet 1. At the time this was being discussed, the SPA had just been turned down and the analysts questions mostly presumed that the SPA refusal was tantamount to rejection of a pain endpoint, which it was not. Comet 2 is a much smaller trial and as you noted, got off to an earlier start. Comet 1 is enrolling 960 patients with an OS primary endpoint and Comet 2, 246 patients with a pain endpoint determined by a patient reported outcome at the 12 week point. Data accumulation for the primary endpoint of Comet 2 will be complete 12 weeks after the last patient begins therapy. Comet 1 will have 2 event driven analyses triggered by mortality events on the trial. If the interim is successful, the trial will end much sooner than if it has to go to final analysis. EXEL has projected both trials will read out in 2014. My guess is that the Comet 1 interim will be in 2014, the final perhaps in 2015. Both trials assume a median survival on the control arm of 7 months. Entry requirements are very similar, Comet 2 additionally requiring moderate pain. Comet 2 has 34 of 55 locations recruiting, all in English speaking countries. This is important because both trials require pretreatment with Abiraterone or MDV and most of that patient pool is stateside. Comet 1 has 73 of 225 locations recruiting, but many of the 225 are in countries where I believe the available patient pool to be smaller.

    • ....Top Buys by Top Brass: EVP Schwab's $109.8K Bet on EXEL

      A company’s own top management tend to have the best inside view into the business, so when company officers make major buys, investors are wise to take notice. Presumably the only reason an insider would take their hard-earned cash and use it to buy stock of their company in the open market, is that they expect to make money — maybe they find the stock very undervalued, or maybe they see exciting progress within the company, or maybe both. So in this series we look at the largest insider buys by the ”top brass” over the trailing six month period, one of which was a total of $109.8K by Gisela Schwab, EVP and Chief Medical Officer at Exelixis Inc....

    • Nice post xwavve and thanks, it's only a matter of time. I hate to quote Cramer but the "best of breed" will eventually rise to the top.

      Sentiment: Strong Buy

 
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