"In light of this, I feel like they should just try to garner approval based on PFS and hope for a label modification later."
There may be a bit of a catch 22 to pursuing that strategy. With the present data set that anticipates a statsig survival result, Cabo was given breakthrough status and will likely get a priority review. If you want an approval based on PFS and push the OS result into the future, then cabo truly is just another TKI showing a PFS improvement and as such perhaps not worthy of even a priority review. FDA probably only wants to go through this process once. The Vem/Cobi approval demonstrates that preference. They gave Roche a 90 day PDUFA delay to get to the scheduled interim analysis that resulted in the statsig OS result.
"It’s funny though, they gave me cabo when it’s thyroid cancer approved, but they wouldn’t give me nivolumab even though it’s lung approved. So I suspect this sort of shuffling behind the scenes is being done by insurance companies related to the cost..."
This situation is already overtaken by events as Nivo now has a full approval in the US. As much as they don't want to pay $29K for a 12 week course of treatment, the reimbursement agencies are going to have to pony up. It is nice to see the awareness taking hold that among the various TKI's, cabo is the best alternative. For it's off label uses, Cabo is prescribed as the capsule form approved for MTC at the 140 mg/day dose. Most patients will settle in at 40-60mg. It kind of means that if managed with some common sense, patients can get a substantial discount. EXEL understandably wants to sell a 28 day supply of the drug at the dose prescribed for a set price ($12K/28 days), but if patients can pay the same amount and get the highest dose, one would think most would try to take advantage of that circumstance. If Dr Vogelzang's patient is willing to roll the dice, he can put himself on a Nivo/Cabo combination with whatever Cabo capsules he has leftover once he goes on Nivo.
"Do you think waiting for an OS readout is really necessary though?"
Necessary, no. Desirable, yes. I think the timing works out anyways. The PDUFA date is going to be Aug/Sep and the OS analysis should be triggered April/May/June. They want "improved survival" on the label. Heck, maybe they can figure out a rationale to get the CaboSun PFS analysis on the label if it is positive. I think you're looking at the treatment Nivo got and think the FDA will give Cabo the same consideration. I don't think that's realistic. I think we can expect a priority review, but waiting for the OS analysis is not going to cause a delay. They could file for an accelerated approval based on PFS, but it would have the same PDUFA date anyways.
EXEL will complete the RCC submission and FDA will have 60 days to assign a std or priority review. Some phase 2 results will start reading out, CaboSun will be important enough to move the share price, the Meteor OS analysis will happen this spring and who knows when there will be a JV. That said, I think we are now past the major clinical trial announcements and regulatory events. I'm frankly getting a bit antsy and did reduce my exposure this week. It's as if the stock needs a constant flow of good news to bounce between $5.40 and $6.30 and I am concerned about what will happen in the nest few months without a news fix every 2-3 weeks. Sorry to be less than cheery heading into the holiday. I do hope everyone has a good Thanksgiving.
"Perhaps Ernie, but I would expect their contract to protect them from clear abuse such as that don't you think."
I think the current pricing scheme is already pretty abusive and EXEL didn't say squat. Novartis prices Tafinlar at $8700 and Mekinist at $10,000. Roche prices Zelboraf at 11,000 and Cotellic at 6590. I was not expecting a 50/50 split, but I think EXEL definitely got the short end. If there are any protections against further discounting Cotellic in favor of current or future Roche drugs, I would certainly like to know what they are.
"BTW, in case you were unaware - the CHMP agenda shows a request for an accelerated review of Lenvatinib in RCC. I'm assuming in combo with Everolimus... "
Eisai is working hard with both the EMA and FDA to accept a filing based on their 3 arm 153 patient phase 2. I'm pretty sure the FDA will say "no." The L/E arm is pretty small at only 51 patients, that doesn't give much of a data set for a safety profile. More importantly though, the final analysis for their trial failed on OS. An updated follow up showed what they call a statsig result. Nivo is already in the space now with statsig survival and Cabo is soon to follow. The unmet need is less acute than it was when Eisai got B/T. Generally, once an indication is occupied by a drug with an OS endpoint, that becomes the de facto standard for that indication. Eisai will argue the excellent HR and mPFS results, but the counterargument is the wide confidence interval that comes with those results because of the small trial size. Their HR of .40 (.24 to .68) overlaps the Cabo result of HR=.58 (.45 to .75). Nivo getting early approval in US may actually help keep Lenvima from leapfrogging Cabo with their ph2 trial.
"Are you saying that they will wait for a stat-sig readout on METEOR's OS data or that they're in the process of reviewing METEOR's interim readout and will approve once that is done?"
The interim failed on OS. The only way Cabo gets a survival advantage on the label is with the final analysis.
I just don't see CaboSun as a factor in the NDA for the reasons I outlined earlier. The only way I see it as n eventlual factor is if one of the PD1 combinations moves to frontline and Cabo then competes with Sunitinib for second line patients. Good CaboSun data might get it used off label ahead of Sunitinib in the 2nd line setting.
"Makes me wonder if MMM's commentary regarding a commercial ramp-up goal of April 2016 might be considered a "tell" of some predictive magnitude."
If they want a survival advantage on the label, they need to wait for the OS analysis. Some time back, I think I looked at the timing of that and came up with the March 2016 timeframe. If the CaboSun data is really good, they may see if they can include that on the label also. That;s iffy though, that trial is not powered to show survival, just PFS and showing a PFS advantage may not be considered relevant. The labelled indication they are seeking is RCC after a prior VEGF, and CaboSun doesn't fit the indication. It is totally plausible that FDA has communicated the intent to get an approval out as soon as they have reviewed the OS analysis.
"So does it look really good and possible for Cobi as front line?How soon before we know?"
The trial is underway with no published data, although Roche seemed enthusiastic at the prospect of moving this particular drug combination forward. If everything goes perfectly, they could get an accelerated approval in 2-3 years. We'll see what happens.
"I think Ernie's point was, they (EXEL and its partner) can't wait that long.."
You accurately recapitulated what I said. I can only shrug and say I've had to update my opinion based on MMM's last investor presentation. I still think they want a deal sooner rather than later and I still think awaiting trial end or RCC formal approval are not the stumbling blocks preventing a deal. I can only guess that nobody has ponied up the kind of offer MMM and BoD are willing to accept.
"I don't expect to see a JV announced this year."
I agree. He was talking overly conceptually and mentioned finishing the EMA submission on their own. My guess is a few more months down the road. We are still looking at a June/July/Aug approval window in the US and they plan to cover the US market themselves. EU approval is a bit further into the year, perhaps November, so think of Au/Sep 2016 as a deadline for a marketing partner. Obviously we would like to see something sooner so that they can get some more ph 3's underway.
""we know which of the 3 drugs will be discounted the most. " Which one?So it looks really good and possible for Cobi as front line?How soon before we know?"
Clem, Roche owns 100% of Atezo and Vemurafenib. Roche owns about 2/3 of Cobi. Roche sets the price for all 3. If they were to want to maximize profitability, they would discount Cobi the most.
"What are you referring to when you say Label?When I look at a label on a prescription bottle it doesn't tell me anything regarding what you mentioned."
Clem what is commonly referred to as the "label" is actually the package insert. If you want to see the label for Cobi (Cotellic), go to the FDA website, and type "Cotellic label" in the search box. The first pdf file displayed should be the one you want. It should say something like Ref 3845167. Open it and go to the table of contents. It has several sections, but for our purposes the most important are:
1 INDICATIONS AND USAGE
5 WARNINGS AND PRECAUTIONS
6 ADVERSE REACTIONS
14 CLINICAL STUDIES
The clinical trial results are always in section 14. Notice section 1 is "indications." The describes the specific patient population for whom the drug is approved. That is why use outside of this description is referred to as "off label" use.
Okay, the dabrafenib/trametinib FDA label is out. FDA did not use the updated combi-v data. Novartis was stuck with their interim analysis data. Even though they continued the trial blinded, per protocol the trial was considered complete at the interim. There were 2 phase 3's for the D/T combination. Combi-d tested D/T s dabrafenib monotherapy and combi-v used a vemurafenib monotherapy control. Roche did a single V/C phase 3 testing vemurafenib/cob vs vemur monotherapy. Here are the efficacy comparisons.
PFS Combi-d D/T 9.3 mos vs 8.8 months HR=.75 Combi-v D/T 11.4 mos vs 7.3 mos HR=.56
CoBrim V/C 12.3mos vs 7.2mos HR=.56
OS Combi-d D/T 25.1 mos vs 18.7mos HR=.71 Comb-v NR vs 17.2 mos HR=.69
CoBrim V/C NR vs 17.0 mos HR=.63
The EMA let Novartis use their updated analysis for D/T, but the European version of the FDA label is a bit less accessible and perhaps less user friendly so the information is buried pretty deep, but still available.
So V/C came out okay wrt the efficacy comparison for the US market. I haven't looked at the tolerability and safety side of the equation yet. Perhaps that's why we are up today.
Not mentioned in the Reuters article is the next step in the referenced trial is a triplet of Atezo/Sel/Cobi. It has the potential to move a Cobi combination into frontline and break the BRAF+ split with D/T. Of course there is a fly in the ointment. In order to keep the triplet cost manageable, we know which of the 3 drugs will be discounted the most.
"Ernie - please chime in if you are paying attention... .I think the market will not like the result for reasons I've already addressed - including the "me too" perception. As a result, I feel Cotellic paired with Vemurafenib may not be a comm success in melanoma."
Your asking more than one question, so I'll break it down. First, the market does seem to react more strongly to perceived bad news than good news. I think the analysts actually pay more attention to every detail and nuance in these presentations than the oncologists. So yes, I do think the market will have a negative reaction to the conference, how much anyone's guess. I don't think it warrants a sell off into the 4's and we are already at the bottom of our trading range, but we'll see what happens on Monday.
I've felt all along that D/T and V/C are likely to split the market. The 2-3 month mOS advantage for D/T is well within the confidence intervals for outcome. I very much doubt that you will see any KOL making the cross trial comparison and claiming superiority for D/T. We will be able to compare the FDA labels next week. I don't think the Z/C label will ever be revised with the updated statistics. The current label shows mOS as "NE" and HR=.63, actually a better HR than D/T's.
You're worried about the commercial success of Cotellic. I think it depends on your expectations going in. I think long term, $50-$100 million in Cotellic annual revenue for EXEL is where it will stabilize unless more indications are opened up. That is consistent with Roche's guidance, but it is on the lower end of most analysts' initial estimates.
"Guys what time today is this today looking to following presentation if possible.."
Sorry, but it is a closed meeting. The C/V CoBrim update was a late breaker abstract and those abstracts will not be made public until after the close of the meeting (later tonight). If you want an appetizer, there are two abstracts available now that mention cobi;
"Gene expression profiling reveals distinct subpopulations of BRAF-mutant melanoma patients each with different outcomes when treated with vemurafenib or combined vemurafenib and cobimetinib"
"Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PDL1) combined with vemurafenib in
BRAFV600 metastatic melanoma"
I have a number of points to make about the median survival data for V/C to be released today. First. I don't know if it will change the label. My opinion is that it will not. The current approval is a full approval and not subject to further review and the current approval includes the statsig survival result based on a scheduled interim analysis. The result was statsig, but insufficiently mature to yield a median survival for the V/C arm.
D/T received an accelerated approval in 2014 without a survival advantage. D/T's label will be revised to reflect its survival results because FDA needs to review it to convert the conditional accelerated approval to a full approval. So in the U.S., until D/T's label is revised, V/C can claim a survival advantage and D/T cannot. In Europe, D/T was only recently approved in September, so V/C will be close behind with approval expected in December.
When D/T's FDA label is revised, it will presumably be with data from their combi-d and combi-v phase 3 trials which showed mOS of 25.1 and 25.6 months for the D/T arms. Those are the benchmarks for comparison. The labelled EMA PFS results for D/T are 11.0 and 11.4 months and for V/C the FDA labelled PFS is 12.3 months. Novartis updated their Combi-v PFS result to 12.6 months but it was not a per protocol analysis and as such did not make it onto the EMA label. For ORR's D/T had 69%, 64% and V/C had 70%.
So currently, from an efficacy perspective, I think V/C has a tiny edge, but all these comparisons are so close that they fall well within statistical margin of error, so unless the updated result today is really good or really bad, I think it will have little effect on commercial competitiveness.
"It's a dose-escalation trial to determine best R2PD. The primary endpoint is safety."
Let me put a name on it for you. It is probably the conventional 3+3 dose escalation design first described by Storer in 1989. Here are the basic rules
3 patients treated per dose level
If no DLT, dose is escalated for the next cohort of 3 patients
If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs
If ≥ 2 DLTs, prior dose level is defined as MTD
MTD decided when 6 patients are treated at a dose level
"Guidance was for 2015 at this analyst event.."
MMM made note of the fact that the guidance for an update had slipped from 2015 to 2016. He wasn't sure if that was good or bad. During Roche's Pharma Day presentation they didn't have much to say about the Cobi/Atezo combination. They seemed pretty enamored with Atezo/Avastin. We'll see. They had a number of Cobi trials underway including some midsized ph2's with control arms for proof of concept.