"Cabo was listed for RET driven NSCLC in the 2013 version, only to be deleted in 2014..."
Ernie, the version I'm reading is "NCCN guidelines 3.2014 NSCLC" which still lists cabozantinib for mutation-specific NSCLC treatment. Have I missed something? Where do you see this deletion? TIA
Ernie, you are once again keeping me honest. Of course you are correct in this, but here is the precedent I see for my commentary. The pre-approval status of a drug has not disallowed publication in the JNCCN wrt off-label potential. In Sept 2012 - clearly some 3 months prior to Cabo approval in MTC - Choudhury and Kantoff published "New Agents in metastatic Prostate Cancer" in the JNCCN. We are forced to guess at it's impact, but shortly thereafter - in 2013, cabozantinib was also added to the JNCCN bone health task force report "Bone Health and Cancer Care". In that same timeframe, David Emerson became a PCF poster boy for Cabo in advanced Prosca, and the oncodocs at "The Prostate Snatchers" began their cabozantinib off-label campaign. The NCCN Cobi assessment process is a pre-approval certainty in my mind, and regulatory approval could easily lead to an immediate compendium listing, even if only to enable the groundwork for reimbursement.
As ever, GL...
7/15/14 Ribas, et al with commentary by Infante and Swanton.
Co-published in British Medical Journal...
European campaign has begun.
EMA filing on deck.
"...are you implying that the shares....don't have to be returned?"...
Returned to who?
The new owner of the IP...???
Yes...that is precisely what I am implying...
If Roche is the major short, and they end up buying EXEL...they will ride the short trade into ownership without having to cover. In the meantime, they are making a percentage on the convertible holding. It makes good business sense for Roche to short EXEL, especially if their intention is to eventually own the IP...
My opinion, for many months now, is that Roche is a major short of EXEL. They likely are also holders of the convertible notes offered a couple years ago. They stand to best best benefit from an eventual buyout. Ask yourself this: "What becomes of the short position if that short is also the aquirer of the shorted company?" I mean - wrt EXEL, 50 million shares short can't be wrong, right? If I'm right, those shorted shares are the real winners in a buyout, but if only if they are held by the suitor...
Roche is my best guess...
"How does the Cobi combo compare...to GSK...??"
The Phase I data is clearly superior, tho with a much smaller trial pop.
All else is a guess at this point. Still, I'm very optimistic. The current literature touts cobimetinib success in advanced mM and exploratory theoretical MEK combination trials. A future NCCN compendium listing wouldn't surprise me. We'll have to wait and see, but the JCO has already published compellingly on Cobi, and the NCCN melanoma steering committee won't be far behind in making assessments. Patience. If the stats are Inspirational, chances are good we'll see an uptick in off-label use as a precursor to approval. JMO
"I wouldn't get excessively congratulatory as we don't know the true results..."
Roche designed the CoBrim trial. Roche is huge and very successful.Their Phase 3 trial design met its primary endpoints. Think they'd have designed it with endpoints they couldn't file on? Guidance has been for an FDA-NDA filing by year's end. I expect a regulatory filing with the EMA any day. Roche is a European pharma. As such, they are not restricted to dealing only with the FDA, and are more likely to enjoin an early and successful filing on their own turf. You are dealing with a global enterprise now, expect news to come from anywhere at anytime. Check out the May 2014 Cobi pediatric investigative plan filing - it has already been updated and refiled. The "Dear healthcare provider (DHCP) letter is already in place. The combination of Zelboraf and cobimetinib in advanced melanoma could conceivably be filed upon as an NPU at any time, enabling reimbursable off-label usage as early as Q3. JMO
"Any ideas...on Cobi trial (presentation) ..."
I sent IR a congratulatory note last week wrt CoBrim achieving its primary endpoint of statsig PFS, and also posed this very question - suggesting ESMO as my guesstimate... and Susan agreed that ESMO was a likely presentation venue for a CoBrim data unveiling.
I like Susan, though I don't expect her to divulge much in the way of strategy. It's not in her disposition. I've taken to posing questions to her, and in turn suggesting an optional array of possible answers. She isn't inclined to offer much, but - if you are correct in a supposition - she will not hesitate to agree that you are probably spot on. I have found her to be much more responsive than CB...
Absolutely omniscient, dude...
It's like every time you post, I hear the voices of Rod Serling, Darth Vader, and Mister Ed all rolled into one...with the repetitive three-note crescendo of the Twilight Zone backdropping in metronomic harmony.
Nomad, you are one goofy dooshwaddle...
Given the May PIP filing and the expeditious revision filed in June, I begin to suspect it likely that we could see a Roche regulatory filing for cobimetinib in Europe before we see an NDA filed with the FDA. I can't find guidance to the contrary, but being a Swiss-based company - the European skids of the approval process are probably pretty well lubricated - another potential catalyst in the works. JMO
"...must be expecting something bad to happen..."
Consider this, stinkee...
The largest institutional short is Hoffman-LaRoche...
They won't need to cover their 30+M shorts when they buy EXEL.
The way they see it, something good is going to happen.
They are going to buy EXEL on the relative cheap.
But still not for much less than $10/share. If they wait for trial results from Meteor and Celestial...they'll pay closer to $20/share. JMO
In earlier studies of cabozantinib potential, RANK ligand inhibition has been inconclusively suggested. I like the direction this study suggests. RANK ligand expression has been linked to inflammatory and immune response. Not to say that Cabo could displace an intended, targeted RANKL inhibitor (like denosumab), but it's interesting to consider that cabozantinib may supplement denosumab therapy, perhaps lending anti-inflammatory and improved patient immunoresponse in advanced CRPC...not to mention increased bone density.
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."
Keep bring in' her down...
I'd love to buy some more in the $2's...
Anybody that'd take the advice of a prom-night dumpster baby like you...
Has lost their free-kin mind...
"Large Oncosomes in Human Prostate Cancer Tissues..." De Vizio, et al.
Published 2012 in the American Journal of Pathology
Further to this, it's important to recognize the impact that a successful Comet-1 outcome could have on prostate cancer treatment. It wouldn't be quite as simple as the introduction of just another drug into the algorithm. Cabo stands to supplement the ongoing validation of quite a number of bio-markers thought to be predictive of OS. Bone scan response, CTC reduction, post-treatment LDH levels, bone turnover marker improvement, pain relief, and the as-yet meagerly described improvements to ADC, bone density, and the trabecular bone environment. Cabo stands to change the game in many ways, and the greatest impact of all may be in redirecting the conventional wisdom of treatment overview to incorporate a whole new generation of predictive assays to replace trial structures which now are necessarily defined by OS endpoints. I think the regulatory impact of Cabo is huge. JMO. Hope this helps...
At any rate, for many years now, the gold standard for FDA approval of oncology drugs has been overall survival - a lengthy, enduring, and expensive proposition. More recently, surrogate endpoints have been developed and accepted by the FDA - the most obvious being progression free survival. There are many clinically relevant observations in a variety of studies as theoretically being predictive of overall survival, and these investigative analyses comprise the leading edge of current investigative wisdom.
Several months ago, I joked that the Cedar-Sinai phase 2 Cabo study was probably arranged to calibrate their relatively new (and unapproved) nano-Velcro CTC enumeration platform. In hindsight, maybe I wasn't far off base. To date, there are few oncology drugs to my knowledge that offer the fast-acting reproducibility of Cabo effect. It makes Cabo a wonderful research tool.
There are huge gray areas and gaps in theory, but FWIW, here's my take...
Prostate cancer has known symptoms and a somewhat recognizable clinical rate of progression. Defining stages of cancer progression is currently tied to PSA doubling, tumor response via RECIST, and factoring sequential analysis of Gleason score. Though determined to be clinically relevant -BSR, CTC enumeration, bone marker response, hemoglobin content, LDH therapeutic response levels, etc..carry no regulatory weight. Due to this, studies to further the understanding of disease predictability and progression are important to validate our evolving understanding of disease.
Gotta run...hold that thought...