Also, from the panel, you also can't help but get the feeling from the doctors that Cabo is another TKI on the long chain of similar therapies whereas Nivolumab is the magic Jesus drug.
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's no direct comparison between Nivolumab and Cabo at this point, and if cost is what drove Cabo approval, I imagine an insurance company could make a strong case for Cabo vs Nivolumab based on the superior PFS and strong trend in OS that Cabo did demonstrate.
Even if Nivolumab dominates in second line, PFS is only around 4 months and the median duration of treatment for the RCC trial was 5.5 months, so most patients will quickly need another option after they progress even given the trial demonstrated survival advantage they will ultimately experience. They won't be left hanging by their doctors or tolerate not being offered a salvage line of therapy after they get worse.
Despite the efficacy of Cabo, both patient and doctor were holding out hope for Nivolumab.
"Dr. Nick Vogelzang:
So, I asked and did not get nivolumab approved. I did get cabozantinib approved, which struck me as being very interesting. So, I was able to get him on cabozantinib and sure enough he’s in the midst of a response again. Very rapid, again within literally days of starting the therapy he began to feel better, his appetite improved. I was very worried that he would get the cabozantinib diarrhea and the other side effects, so far nothing.
Now, I did start him at only 20, worked up to 40. I’m a little reluctant to go higher than that and meanwhile I’m hoping, as is he, that nivolumab will be approved shortly because his insurance said, no, it’s not on the market for renal cell. 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, and he’s an electrician, you know, not a wealthy guy. He can’t go out and by it himself.
So, at this point I guess my question is aside from nivolumab, is there anything else out there that anybody has available, new therapies, any new clinical trials? That’s the questions the guys in practice ask me all the time, and since I’m in practice I get to ask the experts."
Do you think waiting for an OS readout is really necessary thought? Nivolumab looks like a lock for precedence in 2nd line treatment. Cabo will compete w/ other TKIs and everolimus thirdline where it clearly demonstrates better PFS "post sunitinib". A label change can probably wait as there's no immediate need.
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? Waiting for stat-sig OS or CaboSun might mean quite a wait.
Looks like the FDA consistently gives extra love to BMY, but then again the AE profile is better than Cabo and OS efficacy are stat-sig.
The other side of that story is that Shkreli took over as CEO of KBIO. If Shkreli has any involvement w/ EXEL, I'd take a long cold shower after dumping my position.
There were a number of departures from the company including the CFO and CMO. Plus the disclosure of Rociletinib ORR on presentations was quite misleading unless you dug up the September ESMO poster and looked real close. This calls the management into question.
There had been hints for a while that Osimertinib was better than Rociletinib and now that's pretty much confirmed. Their competitor will seize market share for being better and earlier. They made excuses that they had a non-asian population but I think the market size of Rociletinib is vastly diminished. They've also got Rucaparib and Lucitanib but Rucaparib has a direct competitor in Olaparib and I don't know much about Lucitanib.
V/C has high incidences of: severe diarrhea, severe photosensitivity
and low incidences (but worse than D/T): Retinal detachment
D/T has high incidences of: severe rash, severe pyrexia, severe chills, severe fatigue, severe hypertension
Doesn't seem like one is clearly better than the other though, the profiles are quite different.
CoBrim HR: 0.56 (0.45, 0.70) p less than 0.001; 12.3 vs 7.2 mos
Combi-V HR: 0.56, p less than 0.001; 11.4 vs 7.3 mos
CoBrim HR: 0.63 (0.47, 0.85) p less than or equal to 0.0019 by interim allocation; not reached vs 17.0 vem. arm
Combi-v HR: 0.69, p = 0.002; not reached vs 17.2 vem. arm
Makes sense. Positive opinion was given by the CHMP in July for the Novartis combo and September for the Roche combo so it looks like it will be neck and neck in the EU.
Dr. Ribas seems to think the difference is like Coke vs. Pepsi in "Phase 3 data on BRAF and MEK combos for melanoma" on youtube but seemed to indicate that patients in colder climates might benefit from the Roche combo's lower pyrexia AEs whereas those in sunnier climates could benefit from the NVS combo's lower photosensitivity profile. He attributed those specific toxicities to the BRAF inhibitor component.
Dr. Luke in "Dr. Luke Discusses the Phase III COMBI-d Trial Results" mentioned that some patients on the NVS combo will exhaust themselves from having pyrexia all the time.
I seem to recall too that the COMBI-D results had cross-over in the PFS curves, but perhaps that's not as relevant that it has demonstrated an OS benefit.
Roche priced the combo at $11k a month for Vemurafenib and $6.5k a month for Cobimetinib. GSK priced Dabrafenib at $7.6k and Mekinist at $8.7k a month, Novartis presumably raised their prices a little if what Morrissey said about their combo being 5% cheaper is true. Dabrafenib continues to undercut Vemurafenib and a BRAF inhibitor is more useful than a MEK inhibitor as monotherapy. Cobimetinib undercuts Mekinist, but Mekinist is approved as monotherapy; I doubt it'd be insurable or FDA permissible to use Dabrafenib with Cobimetinib as neither is Cobi approved for monotherapy nor has the combo been run through trials.
Vemurafenib sales have dropped by a quarter year over year, but this drop seems seems low given the much better performance of Dabrafenib and Mekinist. Perhaps the lower cost, pharma representative connections, and physician familiarity kept its momentum going.
The $6,590 a month price for Cobimetinib is just enough when summed with the $11k a month for Vemurafenib to undercut Novartis' combo by a little bit. You can bet that if Novartis decides to lower the price of its combo that Cobi will be the one Roche chooses to cut into first as well due to the economics of the deal. At least the label for the combo sounds strong, and Roche's $500 mm estimate (or is it an upper bound maybe?) for combo revenue is actually slightly higher than what I was expecting.
"In a concession likely to be problematic with leading Republicans, the United States agreed that brand-name pharmaceutical companies would have a period shorter than the current 12 years to keep secret their data on producing so-called biologics, which are advanced medicines made from living organisms. Senator Orrin G. Hatch of Utah, chairman of the Senate Finance Committee, which has jurisdiction over trade, has threatened to withdraw his support for the accord if United States negotiators agree to loosening pharmaceutical industry protections against American law."
"But arrayed against the United States, which said the protection was a necessary incentive for drug makers to innovate, were virtually every other country at the table, led by Australia. The generic drug industry and nonprofit health groups also strenuously opposed the United States’ position, pressing for access to the data within five years to speed lower priced “biosimilars” to market. The compromise is a hybrid that protects companies’ data for five years to eight years."
The difference between the pair of combos seems to the AE profile with D/T treated patients experiencing more pyrexia and V/C treated patients having more photosensitivity. I seem to recall an expert saying in an interview that geographical location may affect which treatment a patient will receive (i.e. cold versus warm climates).
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. That said, Vemurafenib is still making plenty of sales and has practitioner familiarity along with Roche's marketing muscle behind it so the transition ought to be rapid.
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.
There's also promise in NSCLC: "Interim results of a phase II study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAF V600E mutated (mut) metastatic non-small cell lung cancer (NSCLC)."
"Conclusions: DT in BRAF V600E mut advanced NSCLC pts shows early antitumor activity with an ORR of 63% and a manageable safety profile. The study met the criteria for progression to the second stage. "