When you point out that this was at a 140mg dose, keep in mind that that is the labelled starting dose. I frankly doubt that many MTC patients actually start at that dose any more. In the EXAM trial 86% of the patients did take at least one dose reduction. and most took the allowed 2 reductions. Also MTC patients tend to be younger and in better shape than other indications.
There were some rather gruesome SAE's at the 100mg and higher doses, but better monitoring and lower doses has resolved most of those issues. Again, as long as Cabo is competing against other VEGF TKI's it's safety/side effect profile is similar and it is demonstrated efficacy that will determine approvability and commercial success.
One thing to keep in mind, the safety profile does play a role in the suitability of the drug for potential combination therapy and moving up the treatment algorithm into earlier lines of therapy. What's suitable in a savage setting might be unsuitable for a newly diagnosed patient.
"As so much work has been conducted comparing, combining, and sequencing Cabo w/ erlotinib - how do you see rociletinib introduction impacting Cabo potential in NSCLC?"
Tarceva is still approved for use in EGFR negative 2nd and 3rd line patients. I don't think (haven't really looked hard) that Rocel has been tested in an EGFR negative setting yet so that may still leave a window of opportunity.
"Are you invested in HALO?"
No, I looked at it and I have to say it looks pretty good, lots of irons in the fire and you have to like a company that wants to cure cellulite. I've introduced a new metric into my due diligence process. All three of my most recent investments are in drug companies that have breakthrough status for one or more drugs. Before granting the designation, FDA gets a look under the hood that we as retail investors do not get to see. It gives me confidence that there is less likelihood of an ugly surprise down the road. It also means that FDA is somewhat invested (figuratively) in the success or failure of a particular candidate.
"Just conjecture on my part, but I don't see PD immunotherapy as a mono therapeutic success over the long term."
I disagree. The PD1 and PDL1 drugs will do very well. I can even see them being used in an adjuvant setting, which is where Dendreon should have taken Provenge. Here is the thing, I question whether they will work any better in combination with the various targeted therapies. The only other drug Ipi seems to work with with any synergy is Nivo. And we may not be done discovering other immune suppressing pathways. Here's the thing though, while I believe the checkpoint inhibitors will be huge commercial successes, they still don't do much for half the patients treated and of those who do benefit, the vast majority will progress and move on to more conventional treatments.
Someone asked what will preempt or replace Cabo. First it assumes a successful outcome to Meteor and Celestial. So hypothetically, I think the answer to where Cabo's replacement lies, depends on discovering the primary means of resistance to Cabo. In the non-RET indications median time on drug ranges from 3-6 months. Discovering the biology behind that acquired resistance may lead to the drug that one ups Cabo, much like Roceletinib is about to render Tarceva irrelevant.
"I know you all don't like talking in certainties, but perhaps after you comment, you can put a % on the 'toxicity' realities...Thanks"
This is not new information. Cabo is a toxic drug. 86% of the Cabo patients on the EXAM trial took at least 1 dose reduction. That trial started with QID 140mg. 60% of Comet 1 patients took a dose reduction and that trial used an initial 60mg dose.
Those statistics sound bad, but in reality, they are consistent with similar data from both Nexavar and Sutent, the two most commonly used dirty TKI's for RCC and HCC. The philosophical approach to prescribing TKI's is to start at a high dose and individually titrate each patient down to a tolerable level. I looked at the grade 3/4 SAE data from Comet 1 and it also looked in line with that seen from the other TKI's.
Here's the bottom line. From a toxicity viewpoint Cabo is similar to other competing TKI's and as long as those are the competing drugs in the sought indications, success/failure will hinge on efficacy and not relative toxicity.
"Ernie, Would you care to hypothesize when we might expect results to be made public?"
MMM has created the expectation that it will happen in early July and I have no reason to expect otherwise.
"Projected to reach the event goal the end of june."
That's not exactly what was said. Originally they projected topline results in the 2nd quarter, then late 2nd quarter, then 2nd/3rd quarter and most recently early 3rd quarter. At the end of April it was said they were very close to reaching the requisite event total to trigger the primary endpoint analysis.
If you want to reflect on the EXAM experience, the actual cutoff date for the analysis was 6/15/2011. The topline was announced 10/24/2011. I think it highly likely the event total has been reached already and the data confirmation and analysis is very much underway.
"I saw that abstract. The result was that the 3 patients on Crizotinib had PRs whereas the 1 on Cabo had stable disease."
Stable disease by RECIST, but the PET scan showed a complete response. PERCIST criteria is pretty new and only time will tell how widely used it becomes. Cost is a significant factor. That the RECIST criteria shows a suspicious 0% leads me to wonder if they even did a RECIST measurement on this patient. There are more ambiguities regarding this patient besides the reported efficacy result. She was apparently treated in the RET fusion trial, so one wonders if she had both a MET and RET mutation or was listed in that trial for some administrative reason.
"I'd rather MMM simply applied for NCCN compendium.."
It is certainly worth the attempt and this is the type situation for which the program is designed, yet I still think an NCCN endorsement is unlikely. I see two reasons why they would say no. They do not want to create an incentive to not pursue a phase 3 program and despite lip service that cost is not a factor I still think it really is. Tarceva is relatively cheap and Cabo is very expensive.
"getting it done right"
Unfortunately sitting back and waiting for the treatment algorithm to sort itself out is not a very good option. At some point they need to take the plunge and try to carve out a viable niche and sooner is better than later. One thing needs to be remembered, except in incredibly rare circumstances, none of the new checkpoint inhibitors are curative. Patients almost inevitably progress and most need follow on treatment. 1512 makes it apparent that cabo is superior to erlotinib in a large subgroup of patients. I do agree that it is unlikely (but still possible) that repeating 1512 in an upscaled pivotal trial would lead to an approval. I think there are viable alternatives. Go head to head against Docetaxel. Both drugs have been compared to erlotinib and frankly the Cabo comparison looked a bit stronger, but this is not a sure thing. An alternative might be head to head against erlotinib in a docetaxel or a docetaxel and PD1 refractory population.
Right now there are oncologists prescribing Tarceva to EGFR negative patients and it is still listed in the NIH treatment guidelines. With this in mind it is frustrating to realize that designing an approvable ph 3 trial is so complicated.
"Will CLVS have the marketing muscle to overcome the Astrazenica juggernaut?"
My guess is that it won't be standalone Clovis doing the marketing. It will either be partnered or more likely the company will be bought.
"Docetaxel demonstrating 8.2 month median OS and 15.5% response rate in 2nd line setting.(TAILOR-no EGFR detected) If median OS in this 2nd/3rd line for Cabo is around 8 months are you still excited? OS for erlotinib in TAILOR was 5.4 months."
Interesting situation. Docetaxel was already approved in the indication, so the Tailor trial was not pivotal and is not referenced on the drug label. EXEL could pursue 3rd line treatment in a post platinum and taxane population. Or, if FDA concurs, they could ignore Docetaxel and use a Tarceva control in a 2nd line trial. Or they could go head to head against D. The Tailor trial appeared to have a less advanced population, so comparisons are difficult. D had lengthy PFS and OS intervals, but Cabo had better HR's compared to Tarceva. But, yes I am less excited after seeing the Docetaxel result.
"So are you saying down the road if these kind o trialf numbers hold up in a phase III trial the potential market is 1.5B."
You went off the tracks a bit on this one. Tarceva's $1.5 B includes 2 other indications. It is also a moving target as other companies are moving into the space with their drugs. All the PD1 and PDL1 entrants are going to shake things up a bit. Eventually it will settle out. The checkpoint inhibitors will not "cure" many patients and eventually the majority will progress into the latter stages of disease despite better treatments in earlier stages. Cabo will likely be a 2nd or 3rd line treatment in most of its eventual indications.
"Yeah but how is Cabozantinib going to compete with Rociletinib in this space."
Different space. 1512 was in wild type non-mutant EGFR NSCLC. BTW I like Clovis and pulled the trigger on it a few months ago.
"So if I am following you guys correctly the wtEGFR population is larger with a better OS, HR and PFS for Cabo over Erlotinib?"
That is correct.
The 1512 trial is in the refractory indication. The Erlotinib arm result was pretty consistent with what one would expect in this population. The beauty of this is that while it is a subgroup it comprises about 85% of the approved indication. In 2013 Erlotinib was a $1.5B drug in 3 indications, frontline EGFR pos NSCLC, 2nd line NSCL and Pancreatic cancer. I'm not sure of the split, but my guess is that 2nd line NSCLC makes up at least a third of that total. This is real partnership bait. It is the obvious next step in the clinical development program and the heavy lifting for trial design is already done.
"And did I mention this is in wtEGFR pts. Not exactly a small piece of the pie!!!"
Not everyone follows the significance of this so let me explain. Erlotinib (Tarceva) is a once a day pill that targets the epidermal growth factor receptor (EGFR). NSCLC patients are typically tested for EGFR mutations. Only a small minority of patients test positive for this mutation, somewhere in the 10-15% range. Those lacking the mutation are said to have wild type EGFR or wtEGFR. Tarceva is most effective in patients with the mutation. In the frontline setting patients are required to be EGFR positive. In the refractory setting Tarceva is approved for use in patients with both wt and mutated EGFR. It confers a benefit to the wt patients, but is not as great as that for the EGFR positive population.
I recall when the FDA finally approved Cabo for MTC. The pps actually dropped, and did so significantly. The pps was run up by uninformed speculators anticipating the approval without an appreciation for how small the indication is. The MTC approval serves multiple purposes, but profits from this indications may never cover the clinical and administrative costs of approval and marketing.
So what's RCC worth? Afinitor is the most widely used 2nd line treatment and it is in its peak years in this indication. It pulls in about $100 million per quarter. It is priced at $6k per month and likely treatment duration is about 5 months. Other 2nd line treatments account for about $150 million per quarter making 2nd line RCC and worldwide billion dollar market. If Meteor succeeds, It is not unreasonable to expect Cabo to assume Afinitors current market penetration. It should also be considered that Cabo is a higher priced drug and if superior to Afinitor, per patient treatment duration will be more lengthy. So, if Cabo were to be used over the same patient population, revenue would higher based on pricing and longer use.
So depending on how convincing the actual results are, approval based on Meteor could result in a revenue range of $400-$700 million annually. IMO this certainly would justify a boost from the present pps. Add in Cobi and renewed speculation about other indications and we could see some decent appreciation from present levels. That's the rosy scenario. A failure on Meteor would see us below $1 per share and Cobi asset would just about cover the cumulative corporate debt. We'll see.
Abstracts at 5pm.
'I am finally approaching my average price and am quite tempted to sell, but something keeps telling me this latest climb coupled with all the near term potential will pay off.'
Reminds me off Yogi Berra's "de ja vu all over again.." witticism. There's a difference this time, history and conventional wisdom are on our side. With the Comets, EXEL was bucking a trend. VEGF inhibitors had been tried and failed previously in CRPC. We wanted to believe that Cabo was special and had almost mystical effects on bone mets. The before and after scans were very impressive and the Comets did show a respectable 40% bone scan response rate, not quite equal to the 60-70% seen in the ph 2 program, but still decent. Problematic was effect was very temporary. I suspected Cabo would give about a 2-3 month average benefit and the PFS data seems to confirm this, but the full effect did not flow through to a sufficient OS benefit to give a give a statsig result. The pain data from Comet 2 was an important lesson, never underestimate the placebo effect. I will never again give any credence to unblended self reported outcomes.
Why do I say this is different? In RCC, VEGF inhibitors are the treatment of choice and have shown good results in pivotal trials. There was some doubt about using sequential TKI's, but the Cabo ph1B data and a recently published article "Metastatic RCC patients may benefit from sequential TKI strategy" suggest otherwise. Also important is the PFS vs OS primary endpoint. Cabo has not been compared head to head against other dirty VEGF TKI's (sunitinib, sorafenib, pazopanib, axitinib, et al) but its results in similar trials compare favorably and Cabo has shown very good data when used in sequence after prior TKI use. A statsig result in a head to head comparison with everolimus by any of the effective TKI's would be the anticipated result. So, that's why I feel as if history is on our side on this one as opposed to trying to establish a new paradigm.