In typical biotech fashion, until the Comet-1 data is published subject to peer review, we won't know too much more than that the trial did not meet the primary endpoint objectives of the trial as designed. JMO, but I expect that the bone scan data and pain management reviews to be superior to all other late stage, treatment-refractory options currently available to this late stage, disease-advanced, heavily-pretreated CRPC patient population. It's unfortunate that MMM's impatience in re-negotiating toward an approved SPA back in 2011 has brought us to this impasse... Fact is, for many advanced CRPC patients, there are no other options other than the clinical trial process. Fact # 2 is, Cabo works when all other options have been explored...
BJC 9/2/14, Fedorenko, et al. Co-authored by Kieran Smalley of Moffitt (PI of XL-888/ Zelboraf P2 trial)
Great comparative commentary on the BRAF/MEK doublets and an update on XL-888 in mitigating BRAF treatment-induced resistance. Good read...
BRIM7 reported mPFS of 13.7 months. Approval of D&T was based on mPFS of 9.3 months. I'm hopeful to see CoBRIM PFS report somewhere north of 12 months. In addition, Cobi seems to be a superior compound in terms of patient tolerability. We'll soon see...
I followed your lead to "The Oncologist" 2008. Pazdur published the following:
"Overall survival remains the gold standard for the demonstration of clinical benefit. An improvement in overall survival is a direct clinical benefit to patients. An analysis of overall survival requires larger patient numbers and longer follow-up than other endpoints. Survival analysis may be confounded by subsequent therapies. Time to progression usually requires smaller clinical trials and may be more rapidly assessed than trials using overall survival as an endpoint. This endpoint is not confounded by subsequent therapies. Time to progression must use the same evaluation techniques and schedules for all therapies being evaluated. Blinding of trials or the use of an external blinded radiographic review committee is recommended in assessing time to progression. Unlike overall survival and time to progression, which must be evaluated in randomized trials, response rates can be accurately assessed using a single-arm trial. Stable disease is not included in a response rate determination and is optimally evaluated by assessing tumor progression in a randomized trial. Improvement in disease-related symptoms is considered clinical benefit and may be an appropriate endpoint for drug approval."
Is this the commentary to which you refer?
Don't stop there, Gaby...
This P3 data has already been accepted for oral presentation at the 9/29/14 Presidential Symposium at ESMO in Madrid. If you are looking to speculate, I think you are speculating on the prospect of game-changing data releases before month's end. Cobimetinib is shaping up to be the play of the month...particularly at today's share price.
Great post, duckduffer. At this point in time it appears that the future and success of BRAF inhibition will be reliant on the success of the MEK inhibition program that supports it. Cobimetinib is in a great opportunistic spot for quick-turn success, and EXEL is fortunate to have partnered with a ginormous enterprise like Roche. I'm considering one last buy-in as a prelude to CoBRIM data releases at ESMO - but must admit - my patience is worn pretty thin. I never expected to see Cabo so heavily discounted by the market. It defies the research imperative we've seen to date.
"What options do they have moving forward with Cabo...?"
For the sake of discussion, let's assume that Comet-2 (as most do) does indeed achieve it's primary endpoint of pain relief response at 6 weeks durable thru 12 weeks. Most clinicians expect this...most analysts expect this...and many posters on this MB have mentioned this as a likely outcome. Past data - while assuring - is no guarantee of future success, but I have high expectation of Comet-2 success. In fact, I've continued to bet heavily on it, based upon increasing hospice influence as a result of improved statistical patient longevity in mCRPC. Patients living longer will require that we revise our outlook on the therapeutic significance of overall survival as a salvage therapy endpoint. Cancer care is forever destined to redefine the concept of clinically meaningful outcome.
This begs the question - can Comet-2 also achieve its secondary end-point of statsig OS as compared to mitoxandrone? I suspect it can...and this would create an additional SNDA filing scenario.
This could conceivably create an interesting regulatory quandary - and, although an SNDA filing might be appropriate, I would think an ADCOM vote would become a necessary ingredient before an FDA approval vote might be considered. This scenario would create an invitation of participation to all those who favor hospice-oriented intervention in late-stage cancer care. JMO, but I expect Dr Ethan Basch might be best enabled to represent this crusade. No doubt about it, the future of cabozantinib in CRPC is questionable - but not completely beyond the realm of clinical reason. There is still a lot of controversy to overcome as Cabo finds it place in the treatment algorithm...although I still this as a viable possibility. I've said it before...but Cabo needs a predictive biomarker of response. That would ice the trial design, regardless of the indication.
"...although I am very surprised the pain data wasn't considered significant."
To anyone that actually DOES read the messages posted on this MB, today's read-out is not over-surprising. A successful clinical trial outcome is predicated on many variables far beyond the control, knowledge, or understanding of investors. With this in mind, your commentary wrt cabozantinib pain data is worthy of comment. Don't be mistaken into believing that the Cabo pain relief data is being perceived as insignificant. It may actually prove to be the most significant play available to the investment community. Once Cabo's mechanism of bone pain relief is defined - and should that mechanism translate into an indisputable causative therapeutic benefit - Cabo could become the forerunner for an entirely new research direction into a methodology of pain management as yet previously unrecognized. I think the key to this point that we might use to infer the logic of may be in the status of the ongoing IST/CRADA/CTEP trials in progress whose design is to definitively examine and attempt to explain the Cabo bone phenom. Ernie commented earlier on the possibility of the effect being illusory in nature. In this case, we are all fooled. But if the Cabo bone effect is not an illusion of uptake... and a genuine, biologically definitive therapeutic improvement with resultant pain relief as the observable response is proven....Cabo may provide the foundation for a road to an entire new class of therapeutics.Good luck to you...
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...
The key to all this is about to become very apparent. The unintended consequences of BRAF inhibition have become quite well-defined, and the putative dangers of paradoxical MAPK activation are becoming better understood. Cobimetinib mitigates many of these concerns, improves PFS, and might actually enable Vemurafenib to optimize its time in the melanoma space despite the introduction of PD-1i's like Nivolumab. This could easily prove to be EXEL's biggest break...
Here's the publication standard which ESMO applies to abstracts chosen for "Presidential" preview. This definitive excerpt is from the ESMO "Call for Abstracts" website:
"Presidential Symposium – Oral presentations by authors of the very best submitted abstracts containing cutting-edge and significant clinical practice-changing studies, followed by expert discussion and perspectives."
"....significant clinical practice-changing studies."---- This particular part of that definition bodes extremely well for the near-term future of this drug combination., particularly if there is significant PFS improvement in the BRAFi-naive patient pool as compared to the D&T combo. BRIM7 showed us 13.7 mPFS vs 9.3 mPFS for D&T. If these numbers hold true for CoBRIM the "Dear Healthcare Provider" letters are gonna fly once again...
Should this prove to be the case, I would expect an accelerated priority FDA review.... If Roche files the NDA concurrent with ESMO data release, this suggests the possibility of FDA approval as early as April 2015.
Very optimistic timeline, but very possible... Melanoma oncodocs will not want patients losing their BRAFi - naive status if a ~ 50% improvement in mPFS could conceivably be lost. The CoBRIM data release stands to raise big questions for the future mono-therapeutic prescription of all BRAF inhibitors, including Vemurafenib.
I'd bet that most LT investors - including institutions - are underwater here. I have traded EXEL for over four years, and have only recently decided to keep my current holdings for the long term. I see inevitable profit, and that profit will most likely come from an array of targeted approvals in several cancer indications (and perhaps some unforeseen bone-health management themes) and will most likely continue to be held captive to some degree by the promise of biomarker-driven therapy. Regulatory acceptance will be the primary delay. Clinical acceptance of the Cabo phenomenon is occurring as I write. Simply put, oncodocs like Cabo... The clinical and hospice communites want drugs like Cabo, and they will legislate toward approval at every turn. Whatever strategically contrived valuation we are currently witness to, it pales in comparison to the reality of Cabo impact on the across-the-board treatment algorithm. Cabo stands to become the go-to therapeutic when all else has failed.
How do you value that...??
Listen up, Spanky...
Give some to get some...
If you expect any value to inquiry, please expect to bring some value to the MB...
You gotta bring something to this party...a little DD would be perfect.
..or you could simply stay at home. Don't be pathetic. Don't be beggarly...
Please don't be a mooch...
Thanks for posting this, Clem...I'm with you, MEKi has great promise.
The technology threatens to change quickly, and it is best to keep abreast of the (r)evolution.
The MEK-exploratory NCI site at cancerdotgov is one I visit for MEK research updates:
"MEK: A Single Drug Target Shows Promise in Multiple Cancers"
The page contains the following hyperlinks that are semi-regularly updated for content:
"Thyroid Cancer: Restoring the Hunger for Iodine"
"Ovarian Cancer: Hopeful Signs"
"Advanced Melanoma: Alone and in Combination"
"More Trials and More Combinations"
Lots of good info here, including optimistic rationale for the PDL-1/Cobi combo...
For which I am becoming quite optimistic...
Keep in mind, Posadas and his research team are participating in Cabo research with a team agenda, and I truly hope this will work favorably for cabozantinib. I posted a few months ago on patent holdings filed by Drs DiVizeo & Freeman wrt IP on oncosome recognition, processing, and enumeration. In addition, CS Ochsner Cancer Center is looking to validate their Nano-Velcro CTC enumeration platform - a "pet" project of the Posadas lab. I had also made a joke about this back when Posadas agreed to head up the P2 visceral mets study, claiming they were wanting to use Cabo to calibrate their CTC device. Competition in the CTC platform space threatens to be fierce in the coming decade, with viable systems in development by Dan Haber at Mass General, Peter Kuhn at Scripps, Posadas at CS, and I also expect see an upgraded Veridex CellSearch in the near future. This technology stands to update very quickly. At this point, I would tend to keep Posadas' enthusiasm in proper perspective...
"Enjoy your Labor Day." You as well...
I suspect it may be too early to tease out a reliably statsig OS signal from CoBrim, but there should be good PFS data to compare to GSK's D&T combo delivery of 9.3 months. JMO, but I think anything over 12 mos PFS will be a solid hit. If memory serves, the smaller population Brim7 reported over 14mos PFS...
"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...
Hard to tell if anyone's paying attention, but I picked up a few shares this week. Not much, but figured it wouldn't get much lower unless Abe had given up the program. It's too early to put much at risk, but if this turns around and keeps enlisting from high academia, it'll keep my attention. The way I see it, a simple P1 announcement in CRPC could create an immediate double...
You'd do well to differentiate between pumping and presenting data. I've never even thought the phrase "shorty's gonna fry", but if yer amongst 'em...we can only hope. Be good to yourself. Pay attention. It's in your best interest to keep informed. The technology of cancer care is going to change quickly in the coming years, and that future bodes well for targeted, personalized therapeutics like Cabo. In turn, that future does not bode well for pathetics of your lackluster ilk.
Sure. Anytime...thanks in turn for your continued worthless MB contributions.
Keep yer thumb up yer patootie where it's doing its best, most deserving work.