On twitter there was a link to a Jefferies report from Friday that estimated the odds of success for Comet-1 at 35% due to their belief that the study was underpowered and the control arm would exceed Exel's estimation of 7mo OS. They put their OS at 10mo v 8mo. Haven't been able to find the complete article yet. Any thoughts?
Sentiment: Strong Buy
Before I leant an inkling of credibility to an obscure, unconfirmed tweet on Twitter, I encourage you to consider the SEC case against Jesse Litvak, former managing director at Jeffries.
"Criminal Charge Against Jefferies Trader Should Have Wall Street Quaking (Update2)"
If this case validates the charges against Litvak, it would appear that fraudulent trading practices, illicit client communications, and outright FUD dispensing are daily drivers at Jeffries. Who do you suppose has mentored the next generation of analysts? You might actually be better off to listen to ol' Jonesy and dansmiley2000...
FUD is where you find it.
"They put their OS at 10mo v 8mo. Haven't been able to find the complete article yet. Any thoughts?"
Of the current phase 3 trials underway, Comet 1 is the most troubling to me. I've said in the past that Comet 2 is "shooting fish in a barrel." I still have that opinion. Because Cabo does so well in VEGF pretreated patients, I feel confident about HCC and RCC. If we see Comet 1 results in 2014, it will only be good news, otherwise it will simply be noted that the trial did not pass the rigorous standard imposed at the interim analysis. We will have EXAM OS data, Comet 2 results and perhaps RCC results before the Comet 1 final analysis. So whether or not Cabo will attain its endpoint on Comet 1 is not too worrisome simply because that news event is still pretty far down the road and there will be other positive events occurring before we need to worry about it.
I take it you expect them to file for approval based on COMET-2 next year even if the interim report isn't sufficiently positive. Do you think substantial pain palliation, PFS, and bone scan resolution combined with a non-worsening OS trend would be sufficient to secure approval or a compendium listing?
Regarding the 10.8 months median OS from the Phase II PC trial:
- The 60 mg dosing from the start in COMET-1 should allow more patients to keep dosing for longer as evidenced in EXAM; the effect of dosing seems quite important.
- On the other hand, COMET-1 has more Abiraterone and Enzalutamide pretreated patients than the Phase II trial. Some of the patients from that earlier stage trial will have gone on to Abiraterone and Enzalutamide which would boost this figure in Phase II. (Some call it a wash when taking both of these into account.)
Regarding the hypothetical placebo arm's median OS (our control group doses w/ prednisone):
- Some have cited that following progression on Abiraterone which is likely most of the population in COMET-1, the median survival is 7 months. (Ernie posted this earlier, independent source unknown)
- The Abiraterone Phase III PC trial had a control group dosed with prednisone and reported a median survival of 10.9 months. Presumably no one was pre-treated with something like enzalutamide.
- The Ipilimumab Phase III PC trial had a control group dosed with placebo and reported a median survival of 10 months, with patients being less heavily treated than those going into COMET-1, and less likely to have been on the two advanced anti-androgens mentioned above.
- The Xofigo Phase III PC trial had a control group dosed with prednisone and reported a median survival of 11.3 months with patients having only bone metastases and no visceral metastases.
The COMET-1 control arm will have more advanced patients all treated with the advanced anti-androgens and various cytotoxic agents. We could see anything between 7 to 11 months for our control group.
"- Some have cited that following progression on Abiraterone which is likely most of the population in COMET-1, the median survival is 7 months. (Ernie posted this earlier, independent source unknown)"
I'm pleased you are paying attention. This statistic is the assumption EXEL used when developing their parameters for powering Comet 1&2. They got it from the abiraterone post chemo ph 3 trial. After discontinueing abi, treatment patients in that trial experienced a 7 month median survival.
Regarding Cabo's HR and general effectiveness:
- Xofigo has show that targeting bone delays skeletal related events (SREs) and improves OS. Cabo has the added benefit of targeting visceral metastases as well but has a worse adverse effect profile than Xofigo.
- The phase 2 trial associated responses in pain, bone scan, and circulating tumor cells from Cabo with improved survival. There probably won't be much of a response in the prednisone arm.
Jefferies issued a report with concerns back in February of 2012, well before the RDT OS data was published and some of the more recent MTC OS interim data. If there is an updated report available, perhaps it is modifying their concerns, but they have been a Cometriq/Comet trials "bear" for a while.
Sentiment: Strong Buy
They are concerned the trial is underpowered because they are assuming that more than 20% of participants would drop out of the trial, therefore they would need more than 950 events compared to the trial design that requires only 578.
If 20% of the patients were dropping out, the trial would be amended and dosing changed. Do not believe everything you read. I do agree that OS is tough. Some of these patients full of bone mets can live a very long time so selection is key
Sentiment: Strong Buy