We already know the results are good enough to move from post-chemo into prechemo - possibly putting Cabo in it's first frontline setting in PC. The rationale for this trial was endorsed & touted by some of the best & brightest thought leaders in PC investigative therapeutics.
Given the encouraging biologic rationale, I - personally - am very optimistic.
If there remain concerns that have gone unaddressed, I simply wanted to create a forum for response.
We're due a simple "whiff" of results from this early trial in the next couple weeks...
...and I'm curious as to what ya'll are thinking... I - for one - am up on this one...
...and I like the fact that it's gotten but very little publicity.
No one seems to be saying a word. Whassup w/ that?
I'm saying it's all synergystic and all good - just cuz they're moving it forward. They're not simply continuing the trial - they are moving it from a salvage scenario into a frontline scenario. I like this a lot...
Any naysayers? Gimme yer thoughts...
Don't get me wrong, I'm not saying that Cabo/Abi or Cabo/MDV are not promising possibilities. There is every reason to believe that the benefits could be additive and there is the informed hope that Cabo could extend Abi's efficacy by shutting down a means of treatment resistance. I'm just saying that it may be a bit early to have high expectations for the upcoming presentation. A good result would be one in which it is reported that there have been no indications of combined toxicity and enrollment is progressing through the low dose cohorts toward a full therapeutic dose with very few unmanageable SAE's.
Thanks for the feedback, Ernie.
I keep looking for that next piece of news that could arm the launch sequence. The recent flurry of NCI trials has been reassuring...and recruiting of the earlier NCI sponsored studies seems to be going well. Looking at the most recent update to the "younger patients" trial - nearly half the treatment locations are listed as "active, no longer recruiting"... Leads me to believe there must be a lot of sick youngsters w/o viable treatment options. I'm hopeful that trial produces some useful dosing insights - lower BMI... youthful physiologic factors.
Conversely, Comet enrollment seems glacial. Hopefully, the next update for Comet 2 will reflect some numbers to get excited about. EXEL needs to produce some news to make shareholders feel downright giddy with their holdings - something to rival the bone phenom reporting of Nov 2010.
Yeah...that's the ticket..!! Have a good weekend!!
"I'm gonna play devil's advocate and say with a measure of confidence that Cabo and Abi have displayed no pronounced nor additive toxicities that might prohibit an expansive move toward an earlier indication."
Informed consent was mandated and the patients' interests were monitored by an IRB. But don't forget, even with the spate of AE 5's back in 2011, there was no IRB intervention in any of the Cabo trials. As long as an investigational drug even has the theoretical chance of having a positive benefit/risk ratio FDA will allow trials to continue. It is not that uncommon for drugs to make it all the way through phase 3 before statistically proving that they harm more than they help. Yes, there is a sliding scale of acceptable toxicity and disease stage, but with drug combinations, early cohorts usually start at a very low dose and as a safety profile is defined ensuing cohorts are titrated toward a full therapeutic dose. We don't know how far along the trial has progressed and in my conservative opinion, I think it is premature to assume that enough data has been accumulated to make anything but the basest assumptions regarding safety. Remember that in the pre-chemo setting, abi typically results in durable PSA responses. Even if the trial has already progressed to a therapeutic Cabo dose, it is likely that patients have not accumulated enough time on trial to determine if the combination has any additive temporal benefit.
The interim results will be in small numbers at possibly subtherapeutic doses. All of those limitations aside, we will be looking for the combination to improve on Cabo's 65% BSR of 5 months duration and Abi's PFS response rate (30% post-chemo and 60% pre-chemo.)
"It has been EXEL's greatest financial misfortune to sponsor an oncodrug that plays well to a set of biomarkers that have yet to be sanctioned by regulatory concensus, but I expect that when this does change - it will change with a flourish. Should the Cabo bone phenom bear witness to undoubted proof of clinical benefit anytime soon - I expect regulatory acceptance to get fast and furious."
I see the bone effect more of a commercial competitive factor/differentiator than an expedited regulatory approval opportunity. Exelixis will be well into pivotal renal studies, but I hope that Exelixis can somehow incorporate the bone phenomenon into the pivotal trial for commercial competitive reasons. Breast cancer is right after prostate regarding the propensity of distant metastasis traveling to bone, but I still think Exelixis will have to abide by current standards for approval if/when that opportunity arises.
We still don't have large cabo treated bone met data in these other indicatons anywhere near what has been collected thus far in prostate.
P.S. I couldn't respond to your post either, and used alternative methods to get around the issue
This is actually a reply to hbomb, but somehow yahoo won't let that happen...
"...but I can't imagine Exelixis wanting to sponsor these trials with underwhelming data."
I feel this way about much of the current and proposed trial(s) structure. In the addition to the EXEL-sponsored Comet trials, there are currently 8 additional IST/NCI PC trials in process. I view these trials as substantiative, corroborative, and validative. It appears that the overall clinical momentum is one of a positive - yet cautious - nature. The wealth of corroborative data that is being generated is being pursued in the wake of the JCO-published RDT P2 data - some of the most encouraging data in all of Cabo's clinical repertoire.
The EXEL-proposed pivotal trials in RCC & HCC will likely follow suit in this regard, and I expect some confirmatory NHI monies to play these arenas as well.
It has been EXEL's greatest financial misfortune to sponsor an oncodrug that plays well to a set of biomarkers that have yet to be sanctioned by regulatory concensus, but I expect that when this does change - it will change with a flourish. Should the Cabo bone phenom bear witness to undoubted proof of clinical benefit anytime soon - I expect regulatory acceptance to get fast and furious.
Hopefully, that'll add a little spice to the PPS...
"I think it is premature to assume that enough data has been accumulated to make anything but the basest assumptions regarding safety. " Ernie
I agree this is a very real possibility. This is certainly the more pessimistic outcome of probabilities.
"EXEL needs to produce some news to make shareholders feel downright giddy with their holdings - something to rival the bone phenom reporting of Nov 2010." Wilderguide
This certainly has the same feel as early Nov 2010 bone phenomenon. I just hope the results exceed my expectations the same way that bone phenomenon did. (I had fairly high expectations for that bone phenomenon, but the results exceeded them, and certainly surprised wall street)
I'll add my optimistic speculative thoughts here.
I suspect we could see a few complete responses by recist criteria, and larger combo drug partial response numbers by recist criteria than either monotherapy alone. I suspect Exelixis would want to confirm initial results from this early trial regarding response rates, and determine durability of this effect. While they are at it, they probably want to get looks with enzalutamide. At the same time, they would likely get more information on durability with randomized data to determine pfs with a monotherapy AR drug vs the combo to clearly demonstrate the difference. Abiraterone had a median pfs of 16.5 months in prechemo setting, so Exelixis probably wants to gather enough data quickly to prepare for possible pivotal trial in 2015. (Maybe ISP's are too slow to act, or Exelixis too excited with results seen thus far in these early combo trials) I don't know how much the Exelixis funding trials will cost, but I can't imagine Exelixis wanting to sponsor these trials with underwhelming data.
Just my speculative thoughts
"No one seems to be saying a word. Whassup w/ that?"
You voice so many of my thoughts, I don't feel any urgency to respond. Sorry to leave you hanging out there. You also defend yourself with factual posts spiced with wit and humor that make for very pleasurable reading. No need to clog up the mb with my ponderous explanations/musings as long as the message is getting out there. Plus, I been busy. I am greatly appreciative of your efforts and insights. I'll try to post something soon.
"We already know the results are good enough to move from post-chemo into prechemo"
You're presuming that the trial had to show some measure of efficacy in the post chemo setting as a prerequisite to moving to a pre-chemo indication. That's not really how the process works. The FDA doesn't require efficacy to continue clinical testing. The change in the protocol conincided with the approval of Abi in the pre-chemo setting. It was that approval that triggered the move. It makes sense. Now you are adding an investigational drug to an approved drug at its approved dose in its approved indications.
I have no idea what the interim data will show, but hopefully some sort of synergy will be apparent. We'll see.
"You're presuming that the trial had to show some measure of efficacy in the post chemo setting as a prerequisite to moving to a pre-chemo indication. That's not really how the process works"
I'm gonna play devil's advocate and say with a measure of confidence that Cabo and Abi have displayed no pronounced nor additive toxicities that might prohibit an expansive move toward an earlier indication. Why waste the money unless you see the potential? The lower dose efficacy trials play favorably for us here, and I actually expect to see lower dose studies in earlier indications as we move forward. I realize the move into the pre-chemo space was prompted solely by the forward move by Abi, but I also feel that it would be medically irresponsible for the trial clinicians to expose early stage patients to Cabo unless there was a requisite measure of confidence in prior combination trial results. In this regard, I view any expansion into new patient space as a positive.
I am continually reminded of Dr Nicolas Vogelzang's pointed commentary wrt Cabo's being a potential game changer in the prostate space...and Dr Ezra Cohen's commentary regarding a liberal posture toward dose-reduction of Cabo in MTC. It makes for very compelling clinical argument to explore the Cabo dose that works for your patient. I think it's important to acknowledge that Cabo's bad press wrt AE5's might have easily been avoided if liberal dose reduction had been recognized as a best option early in the RDT.
EXEL mighta been in a whole different place if no patients had ever seen a 140+mg dose.
Now that we know better, it's a brand new ballgame, isn't it?