"The other BRAF/MEK combo has shown an OS advantage too: "Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib" and it has a head start."
I see that now. Thx for the correction. The OS advantage hasn't made it onto the label yet and the FDA currently has it under priority review to make that change. I remember the initial ph 1&2 comparisons favored the V/C combination somewhat, but with the two phase 3 trials to look at, I suppose it's time to reevaluate that initial impression.
"Yeah, it was a little short on sense. But I needed a card to play."
Says everything anyone needs to know about how much you value your own credibility.
"$4.70 Getting closer. Waaaaaaaait for it....waaaaaaait for it. LOLZ."
You two clowns are every bit as irrelevant as Salydog, only on the other side of the spectrum. Might be time to dump the ID's and start fresh with a clean slate.
The treatment algorithm for frontline melanoma is a bit of a confused mess right now. The subgroup that is relevant to EXEL is the BRAF V600 mutant group, about half of all patients.
Dacarbazine (also known as DTIC or Temodar) Ineffective chemo and will slip to salvage.
Ipilimumab- Approved for all frontline patients based on OS improvement vs chemo, 10 months vs 6 months
Nivo- To date has not shown a survival advantage and ongoing frontline trial is in BRAF negative
Ipi/Nivo- Frontline approved in BRAF negative only
Tafinlar/Mekinist (Dabrafinib/Trametinib) Approved in frontline BRAF + based on PFS advantage
Vemurafinib Monotherapy - Irrelevant as BRAF/MEK is now available
Vemurafenib/Cobimetinib - Superior to Ipi and other than Ipi, only treatment to show a survival advantage.
As I see it, the BRAF/MEK combinations will be the frontline BRAF + standard of care and the V/C combo will be perceived as the superior choice of the 2 combinations available. I like it.
This is good news, but again, was a predictable result. It should be worth a bump in pps, but perhaps not as mucn as the pre-market is giving it. I have been selling my trading shares this morning.
"So you're saying that they will always test for BRAF+ patients and always put them on a BRAF/MEK combo? I think it could default to Nivo/Ipi first and non-responders might be tested for BRAF+. These then trickle down to V/C or D/T."
Here are the commonly used drugs approved for frontline metastatic melanoma.
Ipi (irrespective of mutational status)
Dabrafenib/Trametinib (BRAF V600 only)
Vemurafenib monotherapy (BRAF V600 only)
Nivo "OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of:
Unresectable or metastatic melanoma:
as a single agent in patients with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
(1.1) in combination with ipilimumab in patients with BRAF V600 wild-type melanoma. (1.1) These indications are approved under accelerated approval based on tumor response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials."
That's the official FDA policy and there are decision tree choices to be made depending on mutation and pretreatment status. These drugs are all approved, clinicians can prescribe them in any order they want, but then you run into reimbursement issues if you deviate from the approved indication. Considering the cost issue, I don't see much frontline Nivo/Ipi use in BRAF + patients. The landscape is continuously shifting and I suspect there are more ph3 trials underway that will affect the present algorithm.
The pps is petty much right back where it was before the ACC meeting in Vienna. That makes sense considering the picture that emerged from the conference simply confirmed the general consensus wrt the RCC treatment algorithm. I'm not surprised that the market initially sold off on the headlines. Even though the news was actually a little better than anticipated, the market was more interested in who won the game rather than who beat the point spread. The stock bounced off the $5.40 secondary offering price from last August and now we are pretty much back where we were a few weeks ago.
Next up is the Nov 11 PDUFA date for Cobi. This is not a well kept secret that is going to rock the market in a positive direction when announced. The premarket will react strongly and the general market will take it in stride or perhaps sell off a bit on the news. I think if we go all the way to Nov 11 with no news (Nov 11 is a Wednesday) the pps will rise somewhat in anticipation.
The FDA could surprise us with an early announcement prior to Nov 11 and I think that would be somewhat constructive. Then there is the anticipated JV. I've seen a number of these and if it is a good deal for EXEL, usually the market reacts more positively to this type announcement than it does to other types of discounted news. Debt and burn are issues that are a drag on EXEL and a JV that addresses these in a positive way would be helpful. The 3rd quarter conference call will be in early November. Last year it was on Nov 5. A comprehensive business update including such things as status of the Cabo NDA, Celestial enrolment progress, anticipated timing of CRADA results, and future clinical trial plans would contribute to momentum and a continued positive outlook.
"Dual BRAF, MEK Inhibition Provided Benefit in BRAF-Mutated mCRC"
The article is about a Deabrafenib/Trameinib trial, but it is another indication that there are other avenues of development for Vemurafinib/Cobi after melanoma.
"Bristol-Myers Squibb Receives Approval From The U.S. Food And Drug Administration For The Opdivo (nivolumab) + Yervoy (ipilimumab) Regimen In BRAF V600 Wild-Type Unresectable Or Metastatic Melanoma BMY"
Doesn't affect V/C as the indication is "wild type" BRAF and does not overlap with that being sought by Roche.
"When do you expect those results?"
Advertised is October 2016. The two interims will occur before that date. I think a positive result at the 2nd interim is even money or better. May to July is a reasonable guess.
"I am thinking by the time they arrive, its Dilution Time again."
Couple thoughts here. We need to see what happens with the JV first. There could be upfront cash, an equity buy, offloading a significant portion of clinical costs or some combination of all the above. From there, projecting capital needs will be a more clear picture. Even if there is another secondary down the line, it they launch it from something north of where we are now, then so what. Last June did you even consider it possible that there would be a summer secondary priced at $5.40?
"- correlate YMB and the market sentiment about a stock? really?"
I actually believe this is likely a tradable indicator of sentiment. I just think it works in a counterintuitive way. My best 'buys" seem to occur when I have to hold my nose and ignore the flow of sentiment and the selloffs almost always start during periods of euphoria.
I just used the Nasdaq website to draw a 30 day chart with EXEL, the BTK, the IBB and bellwether AMGN. Of the 4, EXEL is down about 1% and the others about 8-12%. If I fiddled around with the timeframe or other comparisons I could make it look better or worse, but this was my first stab at it and it illustrates the point I want to make, All of the news over the last 6 months has been at the upper end of reasonable expectations, including the Vienna ECC results. Looking forward, the probability is for that trend to continue peaking with the eventual release of Celestial topline results.
"Ultimately I believe this company will be able to unlock the value in its products and pipeline. But probably not until 2016 and maybe through a JV or buyout. What do you think Ernie?"
I have a biased viewpoint as I own a chunk of EXEL stock. It's a tough read, but if you look at 6 months of my posts, you will get the answers to your questions and much more. I think that the window of for a potential acquisition of EXEL just opened, with the highest probability of that event with Celestial results in hand. I think the stock is undervalued in the $5's. Depending on the details, a JV announcement may be a catalyst for price movement.
The reaction to the weekend news has been overdone. None of what occurred should be a surprise and in fact, the news is better than what was anticipated as little as a few weeks ago. The emerging consensus regarding the treatment algorithm going forward is a bitter pill here on Yahoo, but this is a very partisan crowd. Somewhere between 2/3 and 3/4 of the patients coming off Nivo will get a 3rd line treatment and Cabo is well positioned to grab the lion's share of that market.
"My one concern is that all of the updates have already been baked into the share price."
There is still a steady news flow coming.
Cobi PDUFA date of Nov 11 approaches
Cobi EMA approval after CHMP positive opinion. Likely in December.
Celestial full enrolment
CaboSun in 2016
Cobi and Cabo revenue updates throughout 2016
Other CRADA trial updates
Cabo JV which will trigger another wave of pivotal trials
Early results from the Cabo/Nivo genitourinary trial
Pricing of Cabo for RCC and Cobi for melanoma. Votrient is about $7163 wholesale for 30 day supply and Mekinist is $8700. Cometriq for MTC is nearly $12k for a 30 day supply. Genentech will set the Cobi price and obviously EXEL will set the RCC price. Cometiq for MTC is a capsule and for RCC a tablet.
Question for you. Is a lower post count and lack of enthusiasm more indicative of a temporary low or a temporary high?
"I wouldn't put it past Morrissey and his new Lieutenants to decide they want to do this on their own and they don't need a JV partner."
They could take it all the way through approval in the major markets, but they don't have the wherewithal to build out a worldwide sales structure and they know it. They also have growth ambitions and need the capital to do the clinical trials. They could do another offering, but I really think they would prefer to partner away half or maybe all of the future clinical trial expense. Delay is costing them and they realize it. If hey had had the funding to do the trial, Cabo could have been the frontline standard of care for DTC already. The JV is coming some time in the next few months.
"I mention it only because it is close to home, and I figure it is best to toss such findings out for commentary rather than wait for an expository "oops" scenario."
That was my rationale for posting about the high cost of drugs, especially doublets and triplets. I knew there was a reckoning coming, I just did not expect it so soon. My portfolio has a concentration of companies that will be pricing new drugs in the next 2 years and that seems to be the sweet spot for the current correction.
Regarding the clinical trial population issue, neither FDA nor Congress is going to do anything to make drug approval more difficult or expensive. It's just an issue oncologists will have to deal with. I appreciate the compliment.
"I am trying to think if someone would still consider other drugs in the 2nd/ 3rd line RCC."
There may be exceptions, but the large majority will go with Cabo ahead of sorafenib, axitinib, and pazopanib. Where the indirect comparisons are possible, Cabo looks better and soon it will have the very convincing advantage of having shown a survival advantage. That's a big selling point and it's presence or lack thereof is included in the FDA approved label for the drug.
"Conclusion: Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible."
There's a reason for this. Sponsors have to meet a primary endpoint. Recruit too many patients with brain mets, multiple systemic pretreatments, poor Kharnofsky scores, etc. and the potential treatment benefit is less and it is more likely the trial will fail. The alternative is larger more expensive trials to demonstrate a smaller benefit. This sounds more like a pet peeve of the authors than something that really requires serious consideration. In the long run what they are proposing would actually make drug development even more expensive than it already is. I think all the concerned parties are aware of this except for perhaps the authors.
Besides, EXEL is less guilty of cherry picking from the available clinical trial patient pool than most.
"Contrary to your opinion, they almost hit on OS. We'll see how it plays out..."
This is what I posted on July 25:
"I don't think many appreciate how close Cabo came to achieving the OS endpoint on the interim. Here are the stats, HR=.67 p=.005 with statsig at p=.0019 or less. I ran some numbers and if the HR had just been a little better at .63 or if the trial had been 100 patients larger with the same HR or the analysis occurred just 1-2 months later to capture more events with the same HR, then this trial would be over without the need to continue to the next analysis. It is almost statistically inconceivable that the final analysis for OS will not reach statistical significance as the requisite p value then will be much more permissive, somewhere in the .03 to .04 range."
We now know that the exact HR they needed was .645. Obviously you see me as somehow complicit in you suffering a loss to your portfolio. Salty, I'm merely the messenger. If you disagree with any of the specifics of what I have posted, let's discuss it.
So Ernie, Did you bad mouth EXEL enough to reload your trading shares?
Unfortunately I reloaded on Friday. GLto you too Salty.
"The notion that Opdivo offers a survival advantage over Cometriq is baloney."
This I agree with. In fact, I pointed this out both here and on Seeking Alpha even before the release of the data sets. I am not trying to build a bear case for EXEL as an investment. I pointed out that Cabo had exceeded the market expectation for the weekend. I just don't want anyone making investment decisions with the expectation that Cabo will be the drug of choice over Nivo, I see that as a most unlikely scenario unless the eventual Cabo OS analysis has some real surprises in it.
The pre-market is behaving in what I regard as a fairly rational way given the existing circunstances, trading $6.25 to $6.40 so far.
"Oncologists drawing conclusions about which therapy will be used ahead of another or in preference to another made before all of the relevant clinical data are obtained are irresponsible."
As Joe pointed out, a truly conscientious oncologist might not have the luxury of waiting for the full data set. If that oncologist can arm twist the relevant reimbursement agency into approving either Cabo or Nivo, he may have to make that decision tomorrow instead of next year.