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Exelixis, Inc. Message Board

wilderguide 355 posts  |  Last Activity: 1 hour 44 minutes ago Member since: Jan 13, 2011
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  • $$$$
    The Prostate Cancer Foundation has posted dates for the next outing, but I liked the introduction so much I decided to post a pertinent excerpt here, though I encourage you to visit the site yourself.
    "In its twenty-one years of existence, PCF has continually scouted for and funded the most groundbreaking research for immediate impact for prostate cancer patients with advanced disease. PCF stimulated the research community and the biopharma sector, accelerating the development of six new FDA-approved drugs for prostate cancer patients in the past four years.
    • Jevtana (Cabazitaxel, Sanofi Oncology)
    • Provenge (Dendreon Corporation)
    • Xgeva (Denosumab, Amgen)
    • Xofigo (Alpharadin, Bayer Healthcare and Algeta)
    • Xtandi (Enzalutamide, Medivation-Astellas)
    • Zytiga (Abiraterone Acetate, J&J)
    We are also actively involved in a seventh drug expected to receive FDA approval shortly:
    • XL 184 (Cabozantinib, Exelixis)"...........!!!!!!!!!!
    I like this a lot....
    GLTA

  • wilderguide by wilderguide Aug 8, 2014 5:16 PM Flag

    $$$$
    EXEL's largest presentation booth ever, to my knowledge... Booth # 112
    Located right next door to Amgen and Pfizer Oncology...
    And right across the hallway from the Angiogenesis Foundation - very appropriate...
    LBA deadline is 11:59pm 8/20/14...effectively, one week from Monday.
    I think shareholders will see a lot of answers the last week of September.
    ...and I also wouldn't think to be short this stock for ESMO.
    GLTA

  • $$$$
    Posted at cancercommonsdotorg 27 June 2014 by Emma Shtivelman, PhD...
    "A small clinical trial conducted at Dana-Farber Cancer Institute, tested whether adding a new drug called cabozantinib to abiraterone might improve patient responses. Cabozantinib may inhibit metastasis, particularly metastasis to the bone. Patients in the study received three different doses of cabozantinib, along with a standard dose of abiraterone, and across all doses tested there was a marked improvement seen as a deeper drop of PSA levels and reduction in tumor size."
    Between now and ASCO 2015, I expect to find this trial gets a lot of attention, as duration of response to this combination has displayed wonderful potential. Cabo dosing at 20mg/day w/ Abi might just eliminate DLTs and paint a prettier AE profile than we have seen. Solid synergy with pronounced BSR might just make JNJ take notice. In addition, I expect a combo DFT with Enzalutamide to begin by ESMO.
    GLTA

  • $$$$
    PMC July 2014, Suzman & Antonarakis..."clinical efficacy of Cabo may be secondary to effects on the bone microenvironment" -- I really like the wording of this...
    "In a phase II randomized discontinuation trial, patients with mCRPC received cabozantinib for 12 weeks and those without evidence of progression of disease were then randomized to cabozantinib or placebo. The randomization was halted due to early evidence of activity of cabozantinib with respect to improved bone scans and pain. Progression-free survival was significantly increased compared with the placebo arm (HR = 0.12) with improvement in bone pain, suggesting that the clinical efficacy of cabozantinib may be secondary to effects on the bone microenvironment."
    Efficacy secondary to biologically therapeutic bone-targeted benefit is suggestive of healing, isn't it? JMO.

  • wilderguide by wilderguide Sep 2, 2014 12:24 PM Flag

    $$$$
    Condolences to all those losing money down here. I am also sorry for those losing jobs at EXEL. What a waste...I'm hopeful we see more reflection on the future of the cabozantinib program as the Comet-1 data review continues. I feel there are a lot of unanswered questions to address, and hopefully the information gleaned from Comet-1 can provide guidance for future considerations.
    Is EXEL making a wise decision in discontinuing the CRPC program? From a financial standpoint-probably, but it'll be interesting to see which IST/NCI programs follow suit. The activity of Cabo is undeniable as evidenced by a huge research effort. The survival signal delivered via Comet-1 is really the only survival data we have to date. Was an appropriate patient group targeted for a survival signal? Would a less advanced, less pretreated patient group have been more appropriate? A lot of talented folks will be looking for answers, and a lot of interested players will be paying attention as those questions are answered.
    Now is not a time to gloat. Patients have given their lives for the data delivered today. Doctors have lent time, energy, and talent. Investors have lost serious money. EXEL's recent ramp-up is decimated in a glut of lost jobs. Get real...

  • $$$$
    MDACC has put together an interesting PCT web page, specifically addressing known MET mutations, MET inhibitors, etc. with levels of evidence included for Cabo and Foretinib. Interesting that recently handed back Foretinib has the highest (category 2a) LOE listed in papillary RCC. All the up and coming MET inhibitors are addressed, including a lot of pre-clinical newbies.
    Find it at pctdotmdandersondotorg...

  • Reply to

    EXEL presence at ESMO

    by wilderguide Aug 8, 2014 5:16 PM
    wilderguide wilderguide Aug 8, 2014 10:03 PM Flag

    $$$$
    "Sure sounds like they are gearing up for something big..."
    I believe there may be far-ranging clinical implications to a successful Comet-1 trial that go way beyond the vindication we - as shareholders - might enjoy if financial reward becomes reality. Successful Comet-1 reporting would also be a major step in correlating post-treatment BSR to an expectation of survival benefit... and possibly a major step in correlating post-treatment CTC response to improved survival...and a major step in correlating post treatment pain response to survival benefit. The past decade has seen a research imperative that suggests these three correlates are real, and Cabozantinib has the great good fortune to display all three to a striking degree.
    The prospective impact of a successful Comet-1 on current clinical treatment, future clinical trial design, and conventionally accepted approaches to understanding prostate cancer biology is hugely under-considered IMO...and Exelixis - quite literally - stands to upend conventional wisdom to entertain a brave new world of bolder approach to bio marker driven therapy utilizing these hallmark responses. In that sense, they really are gearing up for something very, very big...JMO

  • Reply to

    Comet1 question for Wilder

    by oncodoc02138 Jun 23, 2014 9:32 AM
    wilderguide wilderguide Jun 23, 2014 11:58 AM Flag

    $$$$
    "...the issue isn't so much if Cabo didn't work..."
    The clinical investigation Cabo is loaded with intrigue, isn't it? In prostate cancer, the response rate is very appreciable, with non-respondents clearly being the minority. I would like to see studies of non-respondents as well as for those that do respond and present with obvious benefit. Enriching the patient pool with a "responder-only" patient group would've tempered any doubt in Comet-1, and establishing a biomarker-driven target group for Cabo treatment should be an EXEL management imperative. Further to this, the most-benefitted outliers in the "response" group should also be investigated to determine what creates these overwhelming sensitivities to treatment. Cabo is apparently a very effective and durable treatment for some, and targeting that Cabo-sensitive patient group should be an executive mandate to ensure commercial success.

  • Reply to

    Comet1 question for Wilder

    by oncodoc02138 Jun 23, 2014 9:32 AM
    wilderguide wilderguide Jun 23, 2014 10:06 AM Flag

    $$$$
    "Do you think it possible that enough patients were offered Xtandi that the OS data can be "muddied into non-significance?"
    Going forward - I think this is one of the greatest concerns in those indications which have had the good fortune of recent approvals. Increasing numbers of effective treatment options may be good for patients, but the integrity of trial structure is threatened, no doubt. In the case of Comet - 1, however, we know that every patient will have received prior docetaxel and at least one line of therapy constituting either Abi or Xtandi...and some may actually have received both. It's always interested me that life expectancy is not addressed in either the inclusion or exclusion criteria for Comet - 1, but I think we can also infer that most - if not all - of these patients have also been treated with surgery & radiation. In other words, a very sick, heavily pretreated, and most likely elderly patient group. My opinion is that these poor men may not have enough time remaining in their productive natural lives to fully enjoin the benefit of another therapeutic, should Cabo prove ineffective or non responsive. This is a very unique patient population. I am aware of no other trial that has been so boldly designed to "pull a rabbit out of the hat"...hope this helps. JMO

  • Reply to

    Comet1 question for Wilder

    by oncodoc02138 Jun 23, 2014 9:32 AM
    wilderguide wilderguide Jun 23, 2014 3:20 PM Flag

    $$$$
    "...these patients are late in the treatment cycle with rapidly progressing disease....their options are limited and more focused on palliative care as opposed to slowing disease progression..."
    Hi Ernie,
    Exactly my thoughts...these patients may not survive much beyond what benefit is conferred by Cabo, and perhaps for a variety of reasons - including the naturally occurring comorbidities of the aging process. In which case, any measurable OS benefit would be a direct thwarting of what might otherwise be clinically construed as an "end of life" consideration. I look at Comet-1 as a trial strategically designed to literally free these patients from the grasp of the Grim Reaper. One of the boldest trial designs of which I am aware...Effective? We'll know shortly...
    Good to hear from you, Ernie. Hope you are well.

  • Reply to

    When is the next big calalyst on this one?

    by smithts777 Jul 5, 2014 12:36 PM
    wilderguide wilderguide Jul 5, 2014 12:55 PM Flag

    $$$$
    Any day. We are overdue for EXAM overall survival data.
    If the assumptions utilized to design Comet 1 were appropriate, that trial could report a data-locking event at anytime. Roche's CoBrim could also deliver top line data at any time, and it expect those data releases to be quickly followed by an NDA filing. Lots about to happen.Take your pick...
    I expect we'll hear something substantial this month, maybe next...

  • Reply to

    what is offsitehelp's agenda

    by dawginlife Sep 9, 2014 2:46 AM
    wilderguide wilderguide Sep 9, 2014 6:34 AM Flag

    $$$$
    4) Short hedge fund cubicle lackey
    5) ". ". ". ". ". : Employed by Roche to provide pre-take out control of market cap
    6) Barry Manilow impersonator working to keep himself in sequins and fishnet attire

  • $$$$
    "LBA5_PR - Phase 3, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib + Cobimetinib in Previously Untreated BRAFV600 Mutation–Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma (NCT01689519)"
    FYI - Abstracts chosen for the Presidential Symposium are so chosen for highest quality of presentation and notably successful application of cutting-edge technology. This should be a good show...
    GLTA

  • $$$$
    Published July 15, 2014 in the Journal of Cellular Biochemistry Drs Stern & Alvares
    "....cabozantinib inhibited cell proliferation and decreased MTT activity. Effects on alkaline phosphatase activity were biphasic, with small stimulatory effects at concentrations below 3 μM. When RAW 264.7 osteoclast precursor cells differentiated with 20 ng/ml RANKL were co-treated for 24 hr with 3 μM cabozantinib, expression of RANK, TRAP, cathepsin K, alpha v or beta 3 integrin, or NFATc1 were unaffected. 5 day treatment of RANKL-treated RAW 264.7 cells with 3 μM cabozantinib decreased TRAP and MTT activity. The results suggest that the osteoblast could be the initial target, with subsequent direct and indirect effects on osteoclastogenesis leading to decreased resorption. The multiple effects of cabozantinib on the cell microenvironment of bone are consistent with its effectiveness in reducing lesions from prostate cancer metastases."
    GLTA

  • Reply to

    ASCO 2014 - Takeaways for PCa Cancer Patients

    by wilderguide Jul 1, 2014 9:27 PM
    wilderguide wilderguide Jul 2, 2014 2:15 AM Flag

    $$$$
    "Not one piece of quantifiable data other than one person's opinion..."
    You've just described every post you've ever placed on this MB. Inconsistent, insubstantial, unsubstantiated, and totally discombobulated. Go back to the comforts of your Mama's teat, where you belong. Some folks are clearly a waste of good air, and you lead that crowd, nummnutz...

  • Reply to

    Comet1 question for Wilder

    by oncodoc02138 Jun 23, 2014 9:32 AM
    wilderguide wilderguide Jun 23, 2014 10:36 AM Flag

    $$$$
    In the past, Ernie and I have shared thoughts on the Cabo duration of response, and in the wake of those discussions I had concluded that the Comet -1 had targeted an optimum advanced patient group in which a nominal 6 month DOR would suffice to provide interpretable data. See also the SPORE grant study being undertaken by the Logothetis lab. The concept of bone-secreted "osteocrines" in response to therapy as a method conferring treatment resistance seems "spot on" to me. They are investigating resistance to Cabo, and hoping to implement an improved DOR, perhaps through the development of an "osteocrines inhibitor". Interesting work up...GL

  • $$$$
    Dr Kurt Miller, Chief Urologist Ben Franklin Medical Center, Berlin Germany
    Available at ecancerdotorg. Published 5/12/14. I think this lecture actually took place at the Asia-Pacific Prostate Cancer Conference last March. Good presentation. Dr Miller has published and co-authored extensively on Cabozantinib. My suspicion is that he expects approval. JMO

  • wilderguide by wilderguide Aug 27, 2014 2:47 PM Flag

    $$$$
    Some very interesting insights into the immuno-suppressive side effects of BRAFi, and the curative potential of Cobi. Eruptive Melanocytic Nevi are a relatively common patient reaction to BRAF inhibition, and I don't believe anything like this has been observed with the dabrafenib/trametinib combo. Published in JAMA Dermatology 8/20/14...FW Chen, et al...
    "We describe the first reported case, to our knowledge, of involution of BRAF inhibitor-induced EMN following the concomitant addition of a MEK inhibitor, cobimetinib.
    OBSERVATIONS:
    A woman in her 20s with a history of metastatic melanoma developed EMN while receiving therapy with vemurafenib, a selective BRAF inhibitor. After disease progression, the patient was placed on a clinical trial that combined vemurafenib with a MEK inhibitor, cobimetinib. Within months, we noted clinical involution of many of her EMN. In addition, numerous preexisting nevi were noted to fade in color on the dual regimen. Over a year after initiating this combination therapy, most of the patient's EMN were no longer clinically evident.
    CONCLUSIONS AND RELEVANCE:
    Our case report describing the involution of EMN supports data from previous clinical trials indicating that combination BRAF and MEK inhibition may reduce cutaneous proliferative effects that arise on BRAF inhibitor monotherapy. Further studies are necessary to characterize the biological mechanisms underlying this phenomenon.'

  • $$$$
    "Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors"
    Elizabeth C Smyth, Francesco Sclafani, and David Cunningham
    This piece published in OncoTargets and Therapy 6/12/14-one day after the Rahul Parikh, et al commentary on HGF-MET inhibitor potential. It would appear that the clinical community has been doing its homework. These authors are research docs with The Royal Marsden UK Cancer Research Facility, and all share lab affiliation with Dr JS DeBono...an old hand with cabozantinib, and a likely co-author when Comet-1 publishes.
    I've got those warm fuzzies goin' on...

  • Reply to

    Cabo effective in GBM subset

    by wilderguide Aug 29, 2014 2:18 PM
    wilderguide wilderguide Aug 29, 2014 2:40 PM Flag

    $$$$
    The past few years have run a preponderance of favorable data for cabozantinib - both clinical and pre-clinical. Trial after trial has reported positive, and in some instances - unprecedented - results. All research directed at proof of overall survival is suggestive of future approval. Further to that, any research that suggests evidence that synergystic manipulation of the MET/VEGF axis restages disease favorably is worthy of note. Combination therapy is the stuff of the future, and Cabo is slowly but certainly finding its path into a biomarker-defined regimen. No boastful opinion, just presenting the facts as provided by the clinical and research communities...whose opinion I happen to hold substantially above your own. Milker, you'd best pay attention to something other than yer own voice or yer gonna get hosed...

EXEL
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