"259 event is minimum for stopping it with certain criteria with the criteria "AT LEAST" 259 events. It does not mean they stop immediate at 259 events if the data is only getting better but that is the least of the points."
The data set is locked at 259 events. Data analysis for PFS endpoints is a lengthy process involving independent blinded evaluation of the radiological data to determine at which visit the patient is determined to have progressed. The certainty with which EXEL has identified topline results in the current quarter likely indicates that the triggering event has already occurred and the analysis is underway.
In a sense you are correct in that the trial will continue past 259 events as the survival analysis is yet to come.
"..Pass or fail?"
I've made the point in the past that I was more comfortable with the Meteor than the Comets. The high response rate in the 25 patient phase one clearly indicates activity. I think the observed 13 month median PFS in that trial is suspect, especially when the OS is only an additional 2 months at 15 months. Historic Afinitor results are about a 5 month median. I'm hoping for 8 months vs 5 months, but after the Comet debacle, I will take any statsig result. With a trial this size that implies an HR in the .80 or better neighborhood or about a one month improvement over Afinitor. I think the probability of success is better than even but perhaps not as good as the 90% statistic I've seen batted about here. We'll see.
"Seems to me we can expect the data to be very good, why would FDA grant the fast track just before public release of the data ?"
Sponsors can apply for fast track at any point in time in the clinical trial process. Once applied for, FDA either approves or disapproves within a 60 day window. The timing was controlled by the company, not the FDA.
"Would the FDA grant fast track without seeing the data already?!"
Yes they would.
This trial is open label. The clinicians and patients know if they are receiving Cabo or Afinitor. The company is supposed to remain at arms length from any efficacy data. The contract research organization administering the trial does pass along information on recruitment and accumulation of PFS and survival events, but without attribution to patient or treatment. After the data set is locked, PFS endpoint trials require a fairly lengthy period to determine topline results as imaging data is independently reviewed to determine at which observation the progression is determined to have occurred. As the company is promising topline results this quarter, it is reasonable to assume that the triggering event is imminent or has already occurred and the data set is locked.
“close to 80 percent of all filed applications will eventually be approved.”
Just to make sure everyone understands, the meaning here is that 80% of the fast track applications will be approved for fast track, not that 80% of all fast track drugs will be approved for commercial use. One more time, fast track is about the potential to served an unmet need, not about likelihood of eventual approval. And yes, it is pretty much a gimmie for any drug being tested in a ph 3 superiority trial for a serious indication.
"Another good thing about drugs being fast track is that the drug will have an extended patent up to seven years after approval."
I think you are confusing fast track and orphan status. No patent extension with fast track and even the orphan designation is not that generous.
"As such wouldn't it be safe to assume the potential for superior effectiveness "efficacy" is a factor here?"
We are sparsing words here, but the meanings are important. Fast track is all about potentially meeting an unmet need and the efficacy need only be theoretical, not demonstrated. So fast track is not an endorsement nor should it create an expectation.
"Wrong.Of course I know the Fast Track is a 6 month process."
Pay attention Clem. FDA has more than one program to accelerate drug approval of promising drugs in development. The terminology is confusing and the programs overlap. Here is a thumbnail for you on each.
Fast Track. Awarded based on potentially serving an unmet need. Can be awarded at any point in development. Not based on demonstrated efficacy.
Priority review. After NDA is submitted, priority review shortens the goal for disposition from 8 months for standard review to 6 months for priority.
Accelerated approval. Allows for approval based on surrogate endpoints.
Breakthrough status. Fairly new program that does look at both need and demonstrated efficacy. Most meaningful of all FDA programs to facilitate drug approval. The last 3 companies I have invested in all have breakthrough drugs.
"Fast Track is hardly a overnight review. Its still a 6 month process."
What you are talking about is "Priority Review," not "Fast Track." Fast track makes a drug eligible for priority review, but not all fast track drugs get it. Priority review is not a gimmie, fast track is. Priority review takes into account the degree of demonstrated efficacy in the pivotal trial, fast track does not.
"What I find most intriguing, is the penultimate paragraph. What it implies here then is that EXEL asked for the Fast Track status within the last 60 days...hmmmmmm"
Now you understand. Fast track is a pretty much a gimmie and companies use it as a tool to manipulate their share price. It could be that EXEL is trying to build momentum heading into the top line release or they could be planning one last dilution. I had hoped that they were going to wait on the data release and then either use partnering payments or an after the fact secondary, but we won't know until after the fact.
"Would you consider holding EXEL thru Celestial or is that too far off to consider?"
First, if I "hit the nail on the head" wrt to the Comets, I wouldn't have gotten drubbed by the sell off. I expected better results. Granted, I identified some concerns, but I certainly did not act on them.
Now Celetial....yeah, for the time being it is too far off to say I have a plan in place, but lets look at it in general terms. If the Meteor data is good, most likely the Celestial data will be good. Nexavar and Sutent are effective in both indications, so I would expect Cabo to be also. General consensus seems to be that MET plays more predominantly in HCC vs RCC, so that might even give Cabo a theoretical edge. That's the science side, but don't ignore the business side. The EXEL management team hasn't lost its ability to disappoint. Some success with Cobi and the Meteor trial could send set off a spending spree and more dilution.
"What you say makes perfect sense, but what could FDA have seen?"
Again, the criteria for awarding Fast Track has to do with the need rather than demonstrated efficacy. Efficacy can be THEORETICAL (emphasis intentional). FDA has a separate more discriminating program known as "Break Through" which does evaluate demonstrated efficacy to date.
"EXEL now has TWO (2) COMPOUNDS on FAST TRACK STATUS!!! How many other biotech's can say that?"
Fast track is not a big deal. It should not be confused with "break though" or "priority review." The only criteria for awarding fast track is that the drug can theoretically address an unmet need and the sponsor can apply for the designation at any point in time. Sorry to rain on the parade, but sponsors often time the request to coincide with an offering of some kind. Not saying that it is inevitable, but certainly a possibility.
"I consider any reference to results from cRPC during the Comet tests to be completely irrelevant as will the FDA."
From a regulatory perspective you are correct, any efficacy demonstrated or not demonstrated is pretty much irrelevant. However, from an investment perspective, prior results is other indications is very relevant. The available evidence indicates that Cabo is active in the indications for which other comparable TKI's are already approved and it seems to perform well sequentially following either Nexavar or Sutent. I made reference to published material on sequential TKI use in RCC, anyone interested should read "Sequential TKI May Benefit Advanced Renal Cell Carcinoma Patients."
"They have even wheeled out the ernie profile."
Wheeled me out , eh??
"But now that I have hit a nerve, low and behold, guess who's here."
You give yourself too much credit. Likely the analysis is underway, your post was just a vehicle to give some historical context to the events about to unfold.
The CRPC debacle was very disappointing, betting on EXEL at the time was going against the grain. Other VEGF drugs had tried and failed. At least in RCC, the conventional (and published) wisdom is already forming around the notion that a second VEGF TKI is a superior alternative to everolimus. Cabo just happens to be in the sweet spot to exploit that circumstance first. We'll see. Frankly, I don't like holding this stock. I would have preferred to put it behind and move on, but I expected an overreaction to the downside with the Meteor result soon to follow.
"You would have to speak to Social but my understanding is the OS not the PFS is where the risk lies. The acceptable PFS is already baked in. I see test subjects as last resorters."
Let's look at the history. EXAM (in MTC), the RDT trial in CRPC, Comet 1, and now the NCI Cabo/Erlotinib controlled trials all showed statistically significant improvements in PFS vs placebo. EXAM and Comet 1 showed numerically improved OS results with HR's of .85 and .90 respectively. So I see more risk on the PFS endpoint rather than OS. Cabo has to exceed the Affinitor PFS but only equal its OS. Past precedent for approval of drugs in refractory indications like 2nd line RCC is for a statistically significant improvement in PFS without a worsening in survival. This implies HR=1.0 or less. When the EXAM PFS final analysis was submitted an interim OS analysis was done with the result being HR=1.0 (a tie, ie both arms even Steven). FDA asked for an unscheduled update which showed a modest, but less than significant improvement for the Cabo arm. In response to that update FDA cancelled the advisory meeting and continued the priority review with an on time approval.
So, as long as the Cabo patients in Meteor are not disadvantaged in terms of survival, PFS is the really important statistic. Any statistically significant improvement is meaningful and approvable as the comparator is an approved standard of care. The 25 patient ph 1 trial in RCC is the only reference material we have for Cabo efficacy in RCC. It had medians of OS 15 mos and PFS 13 mos. More telling was the 28% ORR. A small sample size can inadvertently have a high number of participants with indolent disease that can skew PFS, but response rates are a more reliable statistic. Affinitor's historic ORR is negligible and its PFS was 5 mos and OS 14 mos.
"Totally agree, all arguments you mentioned point to success of METEOR, my slight concern is a dose (60 mg)"
You're going to have to trust me on this because I don't think its published or archived anywhere. Dr Toni Choueri was the lead investigator for the original RCC trial. I recall him commenting on the dose issue. By the time the RCC trial was initiated, the investigators were aware of the prior dosing and tolerability issues. His comment was that the trial protocol called for 100mg, but also allowed for titration to a lower dose, so those rules were generously interpreted and he left the impression that patients were immediately titrated lower before tolerability became a problem.
The RCC Cabo ph 1 had only 25 patients. The topline result was PFS of 13 months and OS of 15 months. For comparison, in its registrational frontline study, Sutent had PFS of 11 months, but OS was 26 months. The 13 month PFS enjoyed by the Cabo patients looks a bit suspect to me, especially considering the apparently short survival following progression. I just wish we had a larger sample size to consider. All said, while I don't expect the Meteor result to mirror the phase 1 experience, improving on the Afinitor 5 month standard is a relatively low hurdle. We'll see soon enough.
"PFS was a secondary endpoint and visceral data and time to SRE are at most exploratory."
I have to agree. Cabo is a nonstarter in CRPC. The visceral mets data is at best informative for a future trial. If I remember correctly, only about 30% of patients present with visceral mets, so the commercial opportunity is a fraction of that sought with the Comets. The SRE data is also interesting, but if EXEL wants to present Cabo as a bone drug, it is a long road and rather than comparing those results vs an abi control it would be more appropriate to make comparisons to XGeva and Alpharadin. The overall HR=.90 is consistent or marginally better than those seen with other VEGF inhibitors tested in CRPC (Sutent and Avastin). Factor in the failure of Comet 2 and it further degrades the argument for a benefit not captured in the survival data.
Though disappointing, the results are still informative. RCC will sink or swim based on PFS with the proviso that OS is not negatively impacted. Two phase 3 trials (Exam and now Comet 1) have demonstrated highly significant improvements in PFS with numeric (but nonsignificant) improvement in OS. Granted, Meteor has an active comparator (Afinitor), which showed a 5 month PFS in its registrational study. However, recently published evidence shows that sequential VEGF TKI's achieve a superior result to Afinitor. My opinion is that the recent run up is attributable to positive expectations for the Meteor analysis which is either ongoing or soon to start.