For continuity sake, here're the basics of METEOR design from the May '13 PR:
"METEOR is an open-label trial of cabozantinib in patients with mRCC that is being conducted at up to 200 sites in up to 26 countries. The trial is expected to enroll 650 patients with clear cell RCC who have received and progressed on at least one VEGFR-TKI. Patient enrollment will be weighted toward Western Europe, North America, and Australia, and patients will be stratified based on the number of prior VEGFR-TKI therapies received and commonly applied RCC risk criteria developed by Motzer et al. Patients will be randomized 1:1 to receive 60 mg of cabozantinib daily or 10 mg of everolimus daily. No cross-over is allowed between the study arms.
The primary endpoint is progression-free survival (PFS) and the secondary endpoint is overall survival (OS). Exploratory endpoints include patient-reported outcomes, biomarkers, safety, and pharmacokinetics. PFS is an established acceptable endpoint for RCC clinical trials and has been used to support approval of sorafenib, sunitinib, everolimus, axitinib, and pazopanib in this indication.
Based on available clinical trial data, the primary endpoint assumes a median PFS of 5 months for the everolimus arm and 7.5 months for cabozantinib arm. This provides for a hazard ratio (HR) of 0.67 and 90% power and requires 259 PFS events among the first 375 patients randomized. The secondary endpoint assumes a median OS of 15 months for the everolimus arm and 20 months for the cabozantinib arm. This provides for a HR of 0.75 and 80% power and requires 413 events."
"Is there anything in that data that could sway regulators?"
This is the question that will carry us to year's end, and there is no simple answer. There is great potential for Comet-2 to deliver compelling pain response data, which - though an approvable endpoint...may not be an affordable endpoint - given the comparably cheap affordability of palliative opioid meds. I would take it at face value that the decision to close Comet-2 recruiting mirrors the lack of confidence EXEL management has in a successful sNDA regulatory filing at this time. If push comes to shove, and Comet-2 delivers statsig pain data and enough supportive hrQOL benefit data to constitute a filing, I expect it to be a hugely controversial issue - loaded with argument from every quarter of the industry.
On the less conspicuous upside, I expect to see a future filing with the NCCN for off-label salvage Cabo prescription in CRPC, but such a filing necessarily comes with the downside of negated marketing value in that indication.
"...does the pod cast content infer any difficulty for the METEOR...?"
No. Different disease, different patient group, with much different pretreatment regimens. Each cancer indication must be considered based upon its own merits, and cross-referencing trial data -especially between indications- should be avoided. Here's the ASCO 2012 data mostly responsible for METEOR design:
"Tumor Regression. Objective evidence of tumor regression was observed in 19 of 21 patients (90%) with ≥1 post-baseline assessment. Best overall response was determined per RECIST criteria with 7 of 25 patients (28%) showing a confirmed partial response (PR). Importantly, PRs were observed in heavily pretreated patients, including 3 patients with 2-4 prior systemic therapies, and 2 patients with 4 prior systemic therapies. Thirteen additional patients (52%) had stable disease (SD) as their best response, and only a single patient (4%) demonstrated evidence of primary refractoriness to cabozantinib with a best overall response of progressive disease. The rate of disease control (PR + SD) at week 16 for all 25 patients is 72%.
Progression-Free Survival, Overall Survival, and Treatment Duration. Kaplan Meier estimate of median progression-free survival (PFS) is 14.7 months (95% CI, lower limit 7.3 months – upper limit not reached). Median overall survival (OS) has not yet been reached after median follow-up of 14.7 months. The estimated 1-year survival rate is 60%. Seven patients remain on study and progression free with treatment durations ranging up to 21.8+ months."
In CRPC, Cabo displays dramatic efficacy (and perhaps incomparable) in the wake of prior treatment with docetaxel and AR modification in a very difficult to treat population. In mRCC, Cabo displays dramatic efficacy in the wake of prior treatment with up to 3 lines of therapy, including sorafenib, sunitinib, and everolimus - essentially, another salvage group with extremely limited treatment options. Statsig PFS looks doable.
Of course I am paraphrasing here, but the brunt of the Antonarakis commentary is this:
Despite cabozantinib's compelling and apparently beneficial impact on the bone micro-environment in mCRPC, the therapeutic window is likely too narrow to display a measurable impact on survival in this patient population. Follow-up has shown 4 months DOR in both 100mg and 40mg cohorts.
You really need to find a venue to download it and listen to it in it's entirety. It's approx 9 minutes long, and I can't do it justice other than to convey that IMO it is not favorable news, though it's impact on palliative therapy (re:Comet-2) remains to be seen.
"Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study"
Bottom right hyperlink will take you to the podcast.
The brunt of the commentary is that DOR is somewhat less than previously published...
Updated analysis of the Cabo P2 RDT expansion cohort with oral podcast commentary by Dr Emmanual Antonarakis. This commentary takes the conjecture out of today's share price, and I recommend it to all shareholders. Released 9/15/14.
I suspect this research is part of the initiative to explore and define anti-VEGF resistance mechanisms. Cabo's MOA is not completely understood, but it's VEGFR2 inhibitory capacity is well-documented. Fitting together all the puzzle-pieces of cell-signaling crosstalk, feedback, and synergy will create the map that will fuel biomarker-guidance of the future, and perhaps create the sequenced course of therapeutics to mitigate treatment-induced resistance.
In addition, all the mentioned TKI's in this study have shown notable responses of progression free survival in ThyCa. Optimizing that PFS to translate directly into statsig survival benefit might be an additional study goal here. Cabo's notable fast-acting and recognizable early response signature makes it a great research tool. Extending Cabo performance in Thyca to other cancers may prove difficult as a multi-targeted TKI like Cabo plays to a great number of disease drivers, some of which may provide benefit...some of which may induce off-target toxicities, thereby reducing measurable therapeutic benefit. Quite a balancing act...
"Of all the people here, I am the one you should take the most seriously."
Right. You hide behind 4 aliases, so you can always appear to know something. Yer a frickin Etch-A-Sketch...you think vertically and horizontally, with zero capacity whatever for creative, non-linear thought. Yer a frickin robot...
A cubicle tool...
In the Name of All That is Holy, Man...
What is a brainiac Harvard grad like you doing - giving advice on a YMB...??
Behind the guises of at least 4 different aliases..?? One for every occasion that suits you...
Are you some kinda philanthropist..?? or merely a busybody...??
Or perhaps yer one of those nickel per post goomers that needs to be exposed??
Which is it?
This of course begs the question:
Why would you care how anyone else invests?
"...sometimes in Q1 we could potentially be double digits or not.." This one I'm gonna have to give the "two-chance" dance.
As in: two chances - slim and none. But WTH...??
Biotech can rock thataway...
Comet-1 could present as early as EMUC 2014 in Lisbon. Prior EXEL guidance suggests Comet-2 results by year's end, and that seems doable. Final C-2 data lock should occur in or before first week of December. All the urgency of creating an sNDA filing in CRPC has evaporated, and I really don't have an expectation that we'll see a filing anytime soon, unless Comet-2 is loaded with positivity. In which case, I'd expect either an sNDA filing or an application to NCCN compendium listing by late Spring. NCCN annual "Advancing the SOC" meeting is in March, and this would be an optimum venue, IMO. Comet-2's really gotta shine for this scenario...as all the subjectivity of PRO's and HrQOLs must be cleaned up, statistically interpreted and objectively presented. That'll take time to process...
How about if instead of pointing the finger...
I give you the finger... Get lost, you clueless nitwizzle.
Quit wasting air...
Look for what you want in Cancer Discovery, March 2012
Google McDonald Sennino MET VEGF cabozantinib
Yer about a frickin waste of air...just like yer buddy, offhisfrickinrocker...
You guys share the same bedsheet come crackcleaning time?
"I think they could have more than hunches. Those to most likely have the best idea would be those that watched the animal models prior to the clinic."
As a Johnny-come-lately, I'm gonna treat you kindly here. Check out the preclinical work-up conducted by the DM McDonald lab at UCSF. You are talking way off course, and spreading trash much like your buddy, offsite. Look for preclinical work-ups by McDonald and Sennino.
Please don't come back to this message board until you can contribute within limits of reason. This board has become a wasted POS, much like offsite' gray matter...and you are contributing to that morass daily. Do your DD. No one here is going to do it for you.
Come back when have been "edumacated" as to what yer subject is...