"However, a very important point people are forgetting is that the trial was not cancelled by the IRB which would have happened if the drug was ineffective against the cancer."
One would think that should be the case, but it isn't true. The stopping rules did not include a futility analysis. Regardless, it is a moot point. I am certain the drug is not ineffective. Perhaps it won't be effective enough to reach statsig (I think it will). but past experience makes it pretty clear the drug is active and patients do derive some benefit. We are just struggling right now to quantify that benefit.
"Say Comet 1 reads out positively for overall survival, but those results are not statistically significant - though trending toward a continued lower p value. Given today's discussion - entirely possible. Next day, Comet 2 reads out as an overwhelming home run...with solid gains in pain relief, narcotic use reduction, bone marker redux, ctc redux - good as it gets - the whole enchilada.
Would this picture paint a sufficient picture to enable a successful SNDA filing?
If not, why not?"
Past precedent and current guidance both suggest that if a drug provides a tangible benefit as compared to the current standard of care, it can and should be approved. ODAC and FDA are not supposed to take cost into account when making their recommendations and decisions. All that said, we all know that accelerating drug costs are becoming more and more of a political hot potato.
Here is the counter argument. Alpharadin and Cabazitaxel are drugs approved post-docetaxel and essentially occupy a space that very much overlaps with the pending Cabo indications. Both of those drugs have demonstrated a survival advantage so another drug should not be allowed into the space based on a less meaningful endpoint. The real reason for saying "no" might be something entirely different, but I can see that as a justification if one is needed.
"Ernie, do you think Comet 1 meeting it's primary endpoint would be as conversely corrective as the spanking we just received?"
There is a certain segment of the market, swing traders, that simply read "success" or failure" and then start hammering away on the buy or sell side. To answer your question directly, Comet 1 successfully attaining the primary endpoint would trigger a big rally. IMO we would take out the previous all time highs.
"Also, is it actually a requirement to announce that a trial has reached full enrollment?"
No, but everyone would figure it out anyways and they did it for Comet 1, so my guess is that they will do it for C2 also. They are looking for any good news right now and it helps out the treatment community to know that a trial is closed to enrolment.
"As I see it, the window for read-outs on Comet 1 & 2 may be fairly close, and if Comet 2 were to actually readout first - with positivity - it might provide the impetus to drive SP prior to a final OS readout."
I'm pretty sure now we will see C1 first and then C2.
"You had mentioned this before, and thought to ask if you still held this opinion."
Before they announced C1 full enrolment I was pretty sure C2 was going to finish first and that did set up a lower risk trade to unload after the C2 results, but Robert Burns said it best:
The best laid schemes o' mice an' men
Gang aft a-gley, [often go awry]
An' lea'e us nought but grief an' pain,
This was a pretty blatant setback, but I've always taken the long view on this stock and I even passed on the opportunity to lighten up for the interim, so we'll see what comes.
There are three more potentially near term news items.
Full enrolment for Comet 2 which is frankly not a big deal as it has a certain inevitability to it.
OS update for EXAM. First my best guess is that the last observed HR will show some improvement from the last reported .825 but that drop will not be as pronounced as the improvement seen from interim 1 to interim 2 (1.00 to .825). Even if the HR does not improve the conf interval will continue to narrow and the p value will drop (improve) from the last reported .24. Expecing it to drop all the way to .04 or less (requisite level for statsig) is probably unrealistic. Cabo already has full approval in MTC and will not lose its approval if statsig is not attained. HOWEVER, as shareholders I do not know how the market will perceive to news that can be spun as another failure on top of Comet 1. Just saying....
Roche can report out CoBrim topline at any time. There is little doubt but that the combination will successfully reach the primary endpoint at the first interim. That would be a nice shot in the arm for EXEL.
I expect the Comet 1 final in 2-3 months.
"Since Cabo is a toxic drug much like Jevtana, I suspect the HR may improve over time simulating both TROPIC and EXAM experience.-------Just thinking out loud---The committee probably was concerned with first 3 month OS placebo benefit in Jevtana TROPIC trial."
Very similar to my thinking, especially the comparison to the EXAM trial and its first two interims. I also think the Jevtana filing is a relevant example and I think you are on the right track that this is a toxicity issue.
The action of the abiraterone DSMB was very attention getting, but I'm pretty sure that what happened was a back channel communication to the FDA by the DBMC before they unblinded the trial. Seen in that context, it really wasn't all that controversial. DSMB's typically look at safety on a set time basis, I've seen quarterly and also semiannual schedules, so this was not the first "safety" look and I think they are aware that some drugs have a delayed benefit and in a terminal population they give a drug some leeway to show a benefit before they pull the plug on a trial. Look at Arqule's HCC trial, it got pretty far along before the DSMB stepped in suggesting a lower dose.
Back to Cabo. Let's dispel a few notions. The HR that will yield a statsig result at the final is higher (considerably less difficult) than that which was required by the interim. It is completely reasonable and plausible that the drug is already displaying sufficient efficacy to meet the requirements of the final analysis. There is a prevalent notion that somehow the interim indicates a subpar performance that needs to improve between now and the final. There is no basis on which to believe that is (or is not) the case.
"...contamination from additional treatments post progression..."
Let's talk about this one a little bit. First the patients have already had docetaxel and either abi or mdv. The only other treatment left is a repeat cycle or alpharadin. Alpha is still in its early adoption phase and not readily available in all locales. Plus any treatment available to control patients who progress is also available to Cabo patients who progress. I view additional treatment as a confounding factor, but if Cabo has a meaningful clinical effect on OS, it will show up at the final analysis. We'll see.
"Would you not agree that Comet 2 has become essentially irrelevant at this point?"
Let's just rephrase. If the Comet 1 final analysis fails, then is Comet 2 irrelevant? You notice in my post I referred to 3 good and one mediocre opportunity, guess which one is mediocre. Irrelevant is a bit extreme, but a filing on Comet 2 alone is possible, but problematic. It partly depends on the Comet 1 data. Let's hope we don't have to contemplate that possibility down the road.
Gotta go. See you guys tomorrow.
'...to see that with significance at the much less interim 387 events it would take an HR of 0.7 (upper 95% conf..."
Ok, you were doing good and had it all correct until you came to the part about conf interval. To be statsig, the upper conf limit of the HR needs to be less than 1.0. In this case though it would not be at a 95% level is would be at 100 minus ten times the requisite p value. Normally we think of requisite p value at .05 or less, but that only applies to a single analysis trial. At the interim the requisite p value was something south of .01 (best guess .007). So the conf interval for the interim was at 99+%. Yes you can trust me on this.
"....would the hazard ratio have a p-vlaue - might it be the HR is 0.7 or lower or whatever but the 387 events aren't enough"
Look, everyone wants solid firm answers and they exist, but only on the laptops of the DSMB members. I'm giving you informed guesswork based on common practice in the industry and past experience with EXEL. Sure, maybe the observed HR was .70 or less and the p value barely fell out of the stopping criteria, It's possible, but I categorize that notion as wishful thinking.
Now is good time to explain power. The trial is powered at 90% to show an HR of .75 at the final analysis. Here is the literal meaning. "IF" the real world efficacy of Cabo is HR=.75. Anotherwords we treat 100% of the worlds eligible patients with Cabo and the result is HR=.75. So to start again, If the real world HR is .75 then there is a 90% chance that the trial as designed will be statsig. This accounts for sampling error. The sample you select from the real world population may do better or worse than HR=.75 and the 90% power implies that 10% of the time, the sample will do so much worse that the p value will fall outside of the statistically significant range.
"When you say "use the EMA announcement to soften the blow" do you mean more bad news to come?"
I think it possible they sat on the interim data for a few weeks waiting for the EMA announcement so that they could present a mixed bag. Its trying to hide the snickers bar in the punch bowl with some ice cubes. The next news item is the EXAM OS analysis. It could also be perceived negatively. If you want details, search EXAM for 6 months and read my posts. This has all been discussed in some detail previously.
"What were the interim points to the HR we were expecting if .70 is considered 'failed'?"
Who is "we?" I know what I expected and it was for the interim to fail and continue to the final analysis. That said, it is a binary event, but we have levels of conviction. My best guess was about a 1 in 3 chance that the interim might succeed. That gave what I viewed as a very positive risk/reward. I also take the long view that we have 3 good and 1 mediocre opportunity to restore the luster to the stock. Comet 1 final, Meteor, Celestial and Comet 2 all will eventually read out and all have a much better probability of success than the Comet 1 interim.
"If we 'failed' why didn't the IDMC recommend the study be stopped?"
The DSMB had a very simple task. If the p value was less than the stopping threshold they would recommend halting the trial for efficacy. We call that success. If the p value was more than the threshold (as it was) recommend the trial continue. We call that failure. Halting the trial would only occur if there were an obvious and prevalent safety signal disadvantaging the Cabo patients.
"How significant a difference between the .70 and what we were expecting?"
I was expecting an HR something north of .70. I'm expecting the result at the final analysis to be somewhere in the .75 to .80 range, but that is just a guess. We have zero randomized comparative data on which to base an educated guess. We look at Cabo's results and try to compare that to a similar historic result in the literature. Guesswork.
"What is the likelihood that we can still meet the .70?" Low.
"If we don't do any better, what happens then?"
There is still lots of room for a clinically and commercially successful result at the final analysis, that is what I am banking on, it just won't be with an HR less than .70.
"Did I understand correctly that the test itself was expecting some 587 people of the 961 to die?"
No, that is the triggering point for the final analysis.
"I don't think there'd be a very differently worded release whether the current HR were 0.75 or 1.05 but correct me if I'm wrong."
No. you're correct. Even if the Cabo arm were slightly disadvantaged the trial would go to completion with this set of stopping rules. Many companies do not even acknowledge that an interim took place and of those that do, yesterday's press release is pretty much standard. My best guess is that EXEL did not receive topline efficacy results from the DSMB, but I can't say that with certainty.
As for why I didn't sell. It's a risk/reward thing. 20% downside vs 250% upside. I mentioned before that there would be one more buying opportunity and I believe that we are nearlng that opportunity. The final analysis will come rather quickly, I said 8-10 weeks yesterday and that still sounds reasonable. It's entirely possible they used the EMA announcement to soften the blow.
"Ernie would you venture to guess the median overall survival for the entire group and the two arms of the study."
It can't be done with enough accuracy from which to draw any conclusions. We don't know the enrolment profile and we don't really know when the triggering event occurred. From what little we do know, I'd say the overall median is between 8 and 12 months, but that doesn't really tell us much of anything useful. My guess is that the treatment benefit will be 2-3 months based on the phase 2 trials. Keeping my fingers crossed and hoping I'm right.
"OK, the waiting time might be shorter than I thought. Are they going to release some data on interim analysis tomorrow?"
I'm pretty certain this is all we are going to hear about the interim. I wish I had been wrong, but this is the outcome I anticipated and now we will see how well the market takes it. Here are the facts. More than 960 patients were enrolled with 960 attained right around 9/26/13. 387 have died and the final analysis will occur at 578 deaths, an additional 191. With the compressed enrolment, best guess is that we will see topline results in 8-10 weeks. Having failed the interim points to the HR running somewhat north of .70, but we will see the real numbers on down the road.
Next up will be the EXAM OS analysis which should be announced shortly.
Melanoma is an interesting disease and yes, it will increase in prevalence. My generation (boomers) didn't see the long term implications to excessive sun exposure as children and young adults and that exposure is a cumulative risk factor. A single sunburn increases the likelihood of melanoma and 5 burns doubles the lifetime risk (parents take note).
Melanoma treatment is a fascinating topic. Like prostate cancer, if caught in its pre-metastatic stage it is quite curable with surgery, but you only get one chance. If it returns in a metastatic manifestation it is virtually (but not totally) incurable. Melanoma is unique in that it is occasionally curable in its metastatic stage with immune therapy. Spontaneous remissions are recorded and some success was seen with interferon and interleukin treatments. Then Ipilimumab entered the treatment picture and perhaps 2% of patients enjoy a durable total remission. Nivolumab will do better and the Ipi/Nivo combination better still. Unknown is whether adding chemo or TKI's to the checkpoint inhibitors will improve outcomes and whether those treatments should be employed in tandem or sequentially. It must be exciting for the researchers to actually see such substantial progress in what was previously such a difficult disease.
Nice to see the EMA come through, but the "conditional" approval implies some sort of ph 4 requirement, probably a trial to determine benefit of the treatment in wild type (normal) RET patients. Cabo already has an FDA mandated high dose/low dose commitment and Caprelsa a RET+/- ph4. From a commercial viewpoint, its almost not worth the effort. With a patient base of 1000/year there are barely enough patients to go around for the requisite post approval studies. Plus other companies are running trials in MTC with their small molecules (Pazopanib, Ponatinib and Nintedanib).
"This question has been bugging my mind for quite a long time. Do any of you believes that Cabo may be used some day for bone therapy like "Degenerative bone loss/diseases"?"
Let's talk about this one a bit. My first observation is that this group has not done much work with Cabo in the past. They are in essence a "fresh set of eyes." The numbers are disappointingly small, only 3 patients treated with Cabo.. Going in Cabo was not the first drug of choice, frontline treatment was done with Nexavar and Caprelsa. Cabo was used as salvage for Caprelsa refractory patients. Despite the pretreatment, Cabo still achieved 2 of 3 responses. This is consistent with prior experience in other venues (but again precious few numbers).
Despite the early relegation to a lower priority on their treatment algorithm, the last paragraph of the abstract makes it clear that of the three drugs tested, the authors were most impressed with Cabo's activity in this indication. This is also an additional data point contributing to the notion that Cabo retains activity in heavily pretreated patients across a wide spectrum of indications. This isn't a market moving report, but I still like the consistency with prior experience and it also indicates a somewhat greater prevalence of this NSCLC subtype than postulated in previous reports.
By November 2013, 529 consecutive tumor samples were analysed by RET-FISH in our diagnostic laboratories. Twelve (2.3%) samples were positive, and none carried a secondary mutation in EGFR, HER2, KRAS, BRAF, ALK, or ROS1. So far, 4 pts with RET fusion and previous chemotherapy received one or more lines of targeted therapy. One pt received sunitinib and had prolonged disease stabilization. Three pts received vandetanib as first targeted therapy and 2 had a response. The same 3 pts received cabozantinib as second targeted therapy after progression on vandetanib. Two pts had a response to cabozantinib and one pt started with ponatinib recently. Three pts had tumor rebiopsy after targeted therapy. Molecular analyses are ongoing and updated results will be presented at the meeting.
The incidence of RET fusion was higher than expected, and preliminary activity of targeted therapy was confirmed. Of note, we observed preliminary activity of cabozantinib in pretreated tumors with primary and secondary resistance to vandetanib. Activation of a global phase II trial with cabozantinib in RET fusion positive lung cancer is planned. Clinicians should be aware of it, and refer eligible patients to participating centers.
"We are about to see if he's a visionary or just another deluded smuck who drives a half billion dollars over a cliff flogging a biotech dream."
I agree. It is too early to judge his performance. That will require some perspective that can only be realized once the Comets, RCC and HCC results are released.