I've sure considered the possibility, but am hopeful for an improved SP (thus a more productive fund-raising) with a not-too-distant Cobi approval, top-line METEOR results, or some commercialization partnering agreements on any of those fronts. This stock could really take off if management displays a little financial creativity.
I've also considered the possibility that Roche may be interested in renewing the current partnership to include xl-888 as a part of the package. I sort of expect the Moffitt CC melanoma study to have further reporting on the triplet expansion cohort at this year's ESMO. In addition - and I've not yet researched trial design for the possibility of interim reporting - but the Daiichi-Sankyo partnership on CS-3150 entered into P2 in January, and could also produce some surprise news by year's end. Lots of irons in the fire...
Great informative treatise on the current state of MEK inhibition. Titled as above, posted to the ASCO website 5/22/15 by Adjei & Zhao. Listings of all the competitors, clinical trials in progress, comparative reviews of efficacy & toxicity. Solid rundown on MAPK regulation. Really well done review. Of course, Cobi gets it share...
The competition is fierce, and we'll simply have to watch how this all plays out. As Bif has pointed out, Nivolumab threatens market share for Cobi in melanoma. As Ernie has pointed out, rocelitinib threatens to displace erlotinib in NSCLC - possibly rendering Cabo results in E-1512 less relevant than anticipated. JMO - but I think this'll be a very exciting ASCO all around - and, as the dust settles - I expect surprises as the treatment algorithm evolves and new data is assimilated by the clinical community. I really don't expect quick answers here, as there remain many unknowns, and lots of data to review. I expect at least a few treatment paradigm shifts to manifest at this ASCO - and more than a few theoreticals to be displaced by newer data.
Closing SP was in-line with recent option grants. Seems no one's buying - no one's selling.
I'm in a holding pattern, FWIW. GLTA
"...as a rank scientific amateur am I overstating the case for immunotherapy drugs in combination with Cabo or Cobi?" Enabler - you made me laugh with this question, but I knew I'd recently seen answers to some of this, and will do my best to help you out. If you are "overstating the case for combination therapy", you are not alone. I posted earlier this week on further rationale for Cabo integration with immunotherapy, and I expect to see an NCI-sponsored trial (Cabo and Nivolumab +/- Ipi ) announced in the near future. In fact, the cancerdotgov site already shows that funding is enabled - trial activation appears imminent. In addition, I encourage you to check out "Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma" in SCI Tranl Med published May15, 2015. Therein you will find the rationale for a trial putting Vemurafenib and cobimetinib in bed with nivolumab - or perhaps another PD1 modulator. Nivolumab is no doubt a valuable tool, but doesn't supply all the answers as a mono therapeutic. I see positivity ahead for both Cabo and Cobi. Have a good weekend...
"Or perhaps both..."
Both. I think most of us have suspected this would be the case...and for quite awhile now.
But, it's good to see ongoing expert reinforcement. Clinical preferences of D/T over V/C (or vice versa) may take some time to ascertain, and I expect to see a lot of publications comparing AE profiles in the coming months.
Richman J, et al Expert Opinion Pharmacotherapeutics June 2015
"Dual BRAF and MEK inhibition in advanced BRAF-mutated melanoma is superior to single inhibition in terms of efficacy without significant increase in toxicity. Therefore, BRAF plus MEK inhibition is expected to supersede single-agent BRAF inhibition in these patients in the near future."
(Wrt PD-L1) "I am not aware of any planned or ongoing trials..."
The following excerpt is from page 3 of the 2014 Annual Report:
"...expect those data to be presented this year, and top-line results from an ovarian cancer trial are also expected shortly. Other trials expected to be launched in Q2 2015 by the NCI-CTEP team include a combination study of cabozantinib with nivolumab, or with nivolumab and ipilimumab, in genitourinary tumors including bladder cancer and RCC."
I figured this trial would initiate in the wake of ASCO reporting.
Have I missed something?
From Cancer Cell & Microenvironment, May 2015 - authors are NCI Bethesda...
"Immune consequences of tyrosine kinase inhibitors that synergize with cancer immunotherapy"
Kwilas AR1, Donahue RN1, Tsang KY1, Hodge JW
Pay particular regard to the attenuation of cabozantinib in signaling pathways of immune response.
Free at PMC, along with some recent TKI comparison studies in HFRS and cardio-toxicity.
Lots getting published ahead of ASCO...
"There is something to be said about the Rain Man, numbers and Peoples Court, but the option players will not know unless they can count cards from multiple decks..."
"Has cabo ever been combined with everolimus for mRCC?"
I don't believe it's been considered as yet. Put on everlolimus' other hat as an immuno-suppressant to prevent tissue rejection on the wake of organ transplant, and it becomes a rather awkward coupling consideration. If there are hidden rewards, I suspect they've not been considered. Interesting...
Ernie, my apologies... I should have better phrased my intro.
I meant to say I did not expect the PD class inhibitors to present with durability. As an intervention, I see near-term commercial success...but as you have pointed out - the effects are less than durable. Are you invested in HALO? I've been for a while, and am beginning to see PEGph20 as a platform drug in high HA tumor presentations. No telling as yet where the compatibilities lie, but the current IP presentation suggests that mitigating Hyaluranonic acid presence may lead to better chemo therapeutic exposure - favorable responses with lower dosing structures and optimal metabolic delivery. As PEG data matures, I consider a future in which drugs like Cabo are delivered via conjugated delivery into an optimally pre-conditioned tumor environment, ideally lowering toxic exposure times while maximizing cellular interaction - more localized than systemic. Even electro-poration has gotten my attention in this...
"Are there a particular class of medications that you view a threat to Cabo..."
Just conjecture on my part, but I don't see PD immunotherapy as a mono therapeutic success over the long term. Hormone axis manipulation - while an effective intervention - doesn't yet appear to hold all the cards. I'm still self-familiarizing with the rationale for PD/PD-L1 combinations with existing TKIs...looking for fast-acting intervention, high-end response rates, and patient tolerability that also presents with a durability of response not yet reported. I look forward to the ASCO Cabo/Abi update wrt to svAR-7 impact. I'm not a clinician, and perhaps a bit naive on the statistical uptake...but, I'm a relentless reader. My bet on Cabo is mostly based on my belief that it will find a predictive biomarker as the assay technologies mature. We'll see...
"Making Progress on Progression in Metastatic Prostate Cancer"
Armstrong & Halabi, JCO April 2015
Though this editorial doesn't specifically mention Cabo (nor the Comet trials), I felt its importance in understanding the changing perspective on defining progressive disease in CRPC should not go un-noticed. The use of BSR in making treatment determinations appears to be evolving, and JMO - I think research and investigative work with Cabo has played to inform this evolution of perspective. Good read...
"To conclude at this juncture that there are significant safety concerns is simply ludicrous..."
I prefer to look at it this way. As investors, we will always be looking to minimize downside risk vs the prospect of maximizing upside potential. In the clinic, minimizing patient risk vs measurable health benefit is not only a relative goal - relative to type of cancer, oncogenic origins, known drivers, etc - but also relative to the evolution of the treatment landscape and the introduction of newer (and possibly less toxic) treatments.
In a nutshell, treatments deemed to possess an acceptable toxicity today may not maintain that acceptability in the future. I think that is the greatest uncertainty here - that Cabo may prove too toxic to withstand the test of commercial success over time. Cabo's activity profile as a therapeutic intervention is not so much at question as is its prospective tenure as a commercially successful, revenue-generating enterprise in a quickly evolving treatment theater.
No FUD. No BS - just a little recommended reading from the ASCO Post:
"Expert Point of View: Eric J. Small, MD
By Alice Goodman
April 10, 2015, Volume 6, Issue 6"
To a degree, I share Dr Small's opinion. Also my opinion - Cabo needs a biomarker that best defines it's optimal use in a genetically defined target group...that group being best defined not only in terms of response rates and variables of efficacy, but also in terms of overall tolerability. Nothing new here. I've been saying this for quite some time now. My past posts bear this out consistently, while also acknowledging that TKI use - in general - brings with it a host of undesirable...yet clinically manageable...side effects. If you are aware of an orally bio available TKI that has no history of toxic profile, please share that info. Hope this helps.
Surely all those thumbs-downs came from a bunch of whiny, humorless, Democrats.
Be sure to get yer Mommies to powder yer behinds before you go night-night...
And you, danq - best stock up on Dydees...yer gonna need 'em.
Lots of high-comedy drama on this MB...over-exuberant pumpers, anxious longs, over-confident shorts, hyper-critical analysts, a CEO as obviously nervous as a prom queen at homecoming. Some feller even created an ID just to tell Clem he was "full of it" for quoting IR. Add Wrong-Way Willie and you've got the Keystone Cops.
You can't buy this kind of entertainment...
Not to worry. After both Comet's failed to produce, AF quoted Klein in a Street article giving Cabo a dim future:"We believe that RCC represents cabozantinib's last hope and expect that negative results will scuttle any further cabozantinib development, including the Phase 3 CELESTIAL trial in HCC. Recall the METEOR trial in RCC is 90% powered to detect a hazard ratio (HR) of 0.667 with a two-sided alpha of 0.05, employing a PFS assumption of 5.0 months for everolimus versus 7.5 months for cabozantinib. While PFS may be the primary endpoint of the trial and the company expects to file an NDA on positive data, given the myriad of approved therapies for RCC, we anticipate this trial will need to demonstrate at least a trend toward improved survival in order to gain approval and market adoption. In addition, we note that the safety/tolerability profile for cabozantinib will need to be compelling for commercial usage, and we believe cabozantinib's fatigue side effect may make it unappealing to patients"
My response: ya can't suffer fatigue if yer dead. Cabo can save the lives of some patients. We've all seen this. Ask those patients their opinion. My bet is each one prefers tired to the boneyard - hands down.
Your cheerleading, your commentary on strategy, and your very presence lend new meaning to the phrase deep, dark, and danq...