"Which gets to comments you made today in the "Foretinib in TNBC" thread in response to ville_9..."
The simplest, most direct of answers I could muster. Issues of tumor escape, crosstalk, feedback loops, and induced resistance completely ignored. In its entirety, the signaling cascade is far too complex an issue for lay analysis, though the dangers of denying these concepts must be acknowledged by any informed investor inclined to drug development risk.
The de risking of Exelixis is a pleasure to watch, and I'm looking forward to the next few quarters of revenue reporting with anticipation like never before. Good luck to you, Joe...
If you get the chance, take a look at the P2 NDC CRLX101 combination with Avastin RCC trial that reached recruitment goals last month - expecting some results later this year. Check out reporting from Vogelzang in the Kidney Cancer Journal. With last weeks pullback, I took a small bite. Might buy more... They have another NDC utilizing docetaxel that has potential. Any thoughts on the Cerulean platform?
"The specific pairing of targets has already failed..."
It doesn't diminish my enthusiasm for the potential. I admire the tenacity of the research, if only due to the reality that RCC may not be the appropriate indication to exhibit successful mono-therapeutic manipulation of the PI3k/ mTOR axis. I think the message is becoming increasingly clear that multiple targets need be managed to gain meaningful disease control. I belong to the school that believes the Silver Bullet is a myth. Every lesson learned carries with it a contribution to the scientific overview.
Oncotarget. 2016 Apr 18. doi: 10.18632/oncotarget.8807. [Epub ahead of print]
"Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging"
Inaba K, et al
Sure seems like a lot of increasing clinical interest in Exelixis' pipeline, ay-what Seymour?
"Makes you wonder when they will stop playing roulette and get to the business of making money."
Including partnering and licensing agreements to date, Exelixis will see more than $400M+ in upfront cash, milestones, royalties, and revenues in 2016. 2017 should see quarterly revs upwards of $100M, with the additional promise of a Japan partner infusing another $150M plus royalties. A Japanese partnering agreement announced at next week's ER would grind the collective short pedro into the dust.
Unless your vision is as short as your peter, you'd see this...
BTW - your time is as short as your attention span...
VooDoo medicine rules!
In oncology, designer molecules capable of inhibiting the cell-signaling process are an evolutionary process of innovative theory coupled with observation and analysis. IC50 (binding) values are variable, and that variability has downstream potentials that often cannot be forecast without trial. The complexities and ambiguities of selecting appropriate targets, balancing IC50 values, and managing systemic toxicities makes for many more failures than successes. In side-by-side comparison, XL-880 & XL-184 are very similar in appearance, targeting, and biologic response. As it has turned out - despite its toxic profile - Cabo delivers more reliable benefit than Foretinib with better physiologic compatibility. Every design feature is a compromise; every seemingly desirable change in molecular structure fraught with the potential of induced toxicity; every failure a "return to the drawing board".
It's what makes betting on a particular drug a bit like playing roulette - it's a gamble.
Sort of answered my own inquiry here. Earlier studies of metastatic PHEO have shown some durable responses when treatment with sunitinib was continued beyond disease progression. Evidence published in Endocrine Journal, 2011. The same small study also describes some successes with main thence dosing, intermittent dosing, and the occasional need for dosing holidays. Most evidence I've found to date suggests that holiday dosing w Cabo may be unwise, as disease rebound can prove overwhelming. Good weekend to all. Next weeks ER guidance should be a hoot...
This thread reminds me of the following quote, sometimes attributed to Marcus Aurelius: "Everything we hear is opinion, not fact. Everything we see is perspective, not truth."
To my knowledge, most Cabo trials to date have been designed predicated upon the patient being taken off of therapy in disease progression or worsening toxicity. The 4/25/16 protocol update suggests the potential for benefit despite progression. This seems an important change - in fact, downright bold. Just figured to share...
"If the disease appears to get worse, but the study doctor and those who monitor the safety of this study think you are still receiving benefit from the study drug, you may be able to continue to receive the drug. This will be discussed with you." Any thoughts?
BCRT April 26,2016...Rayson, et al. Still more news regarding Cabo's kid brother. Results of an NCIC/ Canadian collaboration. Might pay to be mindful of these results while digesting ASCO abstract 1093 regarding Cabo effect on circulating immune cells in TNBC. Despite failure to meet PEP, pretty fair CBR...
"There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non-cytotoxic agent in TNBC."
Neoplasia Jan 2016 Qiao, et al.... Check out the list of co-authors. I found this looking for current info on enzalutamide due to the compelling trade gaining momentum over at MDVN. I haven't found the post yet, but I think WildBif had this hypothesis pegged before these study results were published. My hat is off to you, Bif...
"...MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer."
"Their rules are a number of days after acceptance..."
I think we're both in the ballpark. The ruling on an accelerated assessment is a little more aggressive than the standard schedule, and Cabo in RCC has already appeared on a past CHMP agenda. With the USFDA approval, I figure the skids are greased and we should get the initial positive opinion from CHMP sometime soon - possibly before ASCO. The timeline beyond a positive opinion is normally 55-60 days. As the FDA approval came in nearly 2 months early, I'm thinking the EC decision just might be sooner than the published timeline as well - especially if Ipsen weighs in with strength of lobby.
From the 4/28/16 Q1 conference...
"Marc de Garidel added: “We are fully committed, upon regulatory approval, to preparing the upcoming commercial launches of cabozantinib in advanced renal cell carcinoma in Europe..."
Any guesstimates on Euro approval? My hat's in ring for 7/1/16...
"Magical Mystery Tour"...
Amazing to consider the transitions that we witnessed as the Beatles grew through early Rock/ Baroque/ Pop...found LSD and became yet another band...
Found the Maharishi and became yet another band...
I cried when John's life was taken. I cried when George died...
Probly gonna cry when MMM sells out EXEL for a song...
Such is life in America. You sing a happy tune. Your heroes die.
You drop a little acid. You change. Wall Street takes all your money.
You go to the grave wondering #$%$ it was really all about.
Now that's the real Magical Mystery Tour...
"Finally starting to come around or seeing all sorts of other money making companies and now looking for your deserves?"
Not at all. Times change. Progress has been made. Debt retirement strategies are on the near horizon. The success of METEOR and the pending adoption of Cabo into mainstream clinician use are game-changing components of a strategy many on this MB have considered for quite some time. Glad to see it all. Don't want these opportunities lost to lack of attention, and certainly don't want to overstay my welcome...as you appear to be so prone. It's all about timing, and - right now - EXEL is entering prime time. No other way to look at it...
"I think you should..."
And I think you should hire asianshorts as your own personal crankclanker. You dudes could share a bunk, bob for knobs, & spend some quality time; the rest of us could share some sanity. Peace...out.