Results seem consistent w/ profound responses in a few of the patients, lack of control in most:
Treatment with the PD-1 inhibitor nivolumab (Opdivo) demonstrated an objective response rate (ORR) of 9% as a second-line therapy for patients with hepatocellular carcinoma (HCC), according to updated results from the phase I/II CheckMate-040 study presented at the 2016 ASCO Annual Meeting.
In previous findings from the study, the ORR was 19%; however, for the latest update, the investigators cautioned that data were preliminary and so they may have underestimated the response rate. In the study, responses were frequently delayed, with a complete response occurring after 24 months of treatment. When considering those with stable disease, the disease control rate was 65%.
“The updated nivolumab in HCC data are still very encouraging. The disease control rate was 65%, and there were 3 complete responses,” said Kabir Mody, MD, from the Mayo Clinic.
Both are expensive drugs and a course of treatment in second line RCC with Cabo costs more than a course of Nivolumab. NICE has denied coverage for other highly effective drugs like Kadcyla due to price issues.
While we're speculating, that $5B that Pfizer raised recently is about the right size imo for an EXEL bid. A very low ball bid if it were amde would be $3B but I think the value here could work out to:
Cabo RCC: $1.5B (with less than 1Q past RCC launch $2B fully realized, direct threat to Axitinib and Sunitinib)
Cabo HCC: $1.5B (risk adjusted $2B fully realized, potential threat to Axitinib)
Cobi CRC: $1-2B (risk adjusted $5B+ fully realized even at the discount rate they're granting EXEL)
The Regorafenib second line HCC trial vs placebo RESORCE was first received on clinicaltrials:
January of 2013
It was designed to enroll 560 patients (2 to 1 drug to placebo) and reported topline results May of 2016. By comparison, our Cabo trial in second line HCC vs placebo CELESTIAL was first received
July of 2013
It will enroll about 760 patients (2 to 1 drug to placebo) and is designed around the occurrence of 621 survival events. (It has 2 scheduled interims at 50% and 75% of these events, so ~310 and ~466 events.) The other histology related eligibility requirements are similar so I anticipate a similar rate of accrual as for RESORCE barring other differences in trial design I'm not considering or don't know about. (RESORCE has more locations than CELESTIAL that include many sites in China for instance and CELESTIAL's Asian contigent is from Korea and Taiwan. Whoever is responsible for CELESTIAL's updating of their clinicaltrials info certainly cares less than RESORCE's site manager or METEOR's.)
If you consider the lag of about 6 months for CELESTIAL initiation compared to RESORCE and the larger enrollment target over fewer sites, the Exelixis management's stated topline reporting time of a 2017 time frame makes sense. This is pushed back from their initial target of September of this year, probably due to the excitement over PD-1i related trials. They've reported enrollment and interim results in the past, so just a WAG but full enrollment by fall, 1st interim late 2016, and 2nd interim early 2017.
Today about a tenth of the total float was traded at around $8 now, so it's significant. After the pain from ESPR, GALE, TSRO funds and retail investors might be looking for a safer name in the same space, but today's volume seems like too much to be simple re-balancing or just retail interest.
Today's move might be a much bigger entity taking a stake while attention is still scant and market cap still relatively low. The members of this board might have the impression that EXEL is a major biotech name whose trial results are well known, but existing coverage is pretty thin with just 8 firms that currently cover the stock, and the stock has had a lingering bad reputation following the COMET-1 implosion. A recent article declared it a surprise when a biotech "you've never heard of" doubles and cited EXEL as an example, so it has plenty of room to grab more attention from new analysts and retail investors. Even most oncodocs didn't seem to know much about Cabo's OS results prior to ASCO this year despite it being on the label for about a month prior.
It is however starting to approach what I consider a fair value prior to knowing good RCC sales are taking place and that CELESTIAL is successful and better than Regorafenib results.
Other small biotechs like GALE, TSRO etc. have had a rash of bad news in the past week. Exelixis is looking very safe by comparison.
I agree and I'm starting to build a position; even thought the pipeline is great the finances are now more fragile. I don't think they raised enough money to see 853 through its P3, and they're going to need to raise again sometime next year burning at this rate. Perhaps they should shutter some operations until they see better FCF, but maybe they're anticipating milestones and/or new partnerships.
I think the Regorafenib result gives me a lot of hope for CELSTIAL success, however it's going to need to distinguish itself from Regorafenib in some way lest it be sequence after it or largely ignored. I'm cautiously optimistic for better OS results as Cabo seems much more targeted to the resistance pathways for HCC progression following Sorafenib than Regorafenib. There is also quite a difference between TKIs as seen by Sunitinib's failure in its trial against Sorafenib. There's a chance we may see a better AE profile or superior outcomes for patients with bone metastases as is the case in RCC and mCRPC.
There's also Tivantinib to possibly contend with as well though that requires a biopsy for MET high status. Ramucirumab is taking another swing at a sub-population after failing its P3 and Lenvatinib, Nivolumab are each in first line P3 trials. Axitinib and any number of Vegfr inhibitors may also try to grab some share too.
It's a PARP inhibitor which will directly compete w/ Olaparib. We've yet to see a successful folate targeting agent and 853 looks like the one w/ the most activity as monotherapy.
Cabo and Foretinib both achieved about ~4 months median PFS/TTP, with a median of ~15 months OS. ORR was 3/36 PR for Cabo, 24% for Foretinib. Cabo's trial design was a discontinuation trial so It's not clear exactly how it will read through, but these might give ballpark estimates.
HCC will probably only have 2-3 treatments available (Sorafenib, Regorafenib, possibly Tivantinib) by the time a potential Cabo approval comes around.
That's a nice result:
The ORR with regorafenib was 10.6% versus 4.1% with placebo (P = .005). When considering stable disease, the overall disease control rate was 65.2% with the multikinase inhibitor versus 36.1% with placebo.
Median PFS was 3.1 months in the regorafenib arm compared with 1.5 months in the placebo group, representing a 54% reduction in the risk of progression or death (HR, 0.46; 95% CI, 0.37-0.56; P less than.001). The median time to progression in the regorafenib group was 3.2 versus 1.5 months with placebo (HR, 0.44; 95% CI, 0.036-0.55; P less than.001).
In the open-label study, the median OS was 10.6 months with regorafenib compared with 7.8 months for placebo plus best supportive care, representing a 38% reduction in the risk of death with multikinase inhibitor (HR, 0.62; 95% CI, 0.50-0.78; P less than.001). Findings from the phase III study will be submitted to the FDA and European Medicines Agency (EMA) for potential approval, according to a statement from the developer of regorafenib, Bayer Pharmaceuticals.
The most common grade ≥3 AEs with regorafenib versus placebo, respectively, were hypertension (15.2% vs 4.7%), hand-foot skin reaction (12.6% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0%). There were more deaths in the placebo arm versus regorafenib within 30 days following the last dose of treatment (13.4% with regorafenib vs 19.7% for placebo).
I think a Japan deal will have to wait for CELESTIAL results due to the high importance of HCC treatments for asian markets. It's somewhat unusual that they aren't updating that trial at all; presumably they will announce full enrollment as they have in the past and it also has 2 interims. I would be suspicious if we don't get an enrollment update by this summer.
I'm around, just not much to comment on since it's been a fairly boring stock since late May. We've been pretty much going straight up since April with not much new news since CABOSUN, and a lot more attention post ASCO which was a re-announcement in a big venue of a lot of existing facts.
My target w/ just existing RCC data including CABOSUN is higher still ~$9-10 (it may not get there w/ a straight line), and I'm awaiting any signs of progress with CELESTIAL which I think will succeed. There's also potential debt retirement, European approval, Nivo and Cabo doublet results at ESMO, settlement on Cobi pricing. Longer term, CRC is a big deal as would be a new trial in lung and/or prostate. Baking in a higher valuation based on CRC might be premature and biased by good Cabo results; if it is successful, this may make any Cobi settlement extremely impactful.
Good call, that does seem a bit off. "Colon cancer survival statistics and results" gives a pretty different answer with SEER survival at 6 months of advanced CRC at 63%. It's unclear how mismatch repair proficient patients do relative to mismatch deficient patients though.
I'll have to look into what the standard survival distribution for mismatch proficient CRC patients is on the standard of care. A treatment protocol will likely include earlier withdraw of Cobimetinib and sustainment of Atezolizumab:
"As of data cutoff, 4 patients (17%) were taken off cobimetinib. No patients were withdrawn from atezolizumab. The median follow up for safety was 3.8 months (range 1.1-15.1 months)."
I wonder if Roche asked the PR to do this in order to save them some money in the event it goes big...
The most striking perspective of the benefit that I've read was:
"This combination also improved 6-month overall survival, from 1% in patients treated with the standard of care, to 72%. This represents an incredible breakthrough, and will hopefully pave the way for more effective approaches to treating these CRC patients."
I think NSCLC and maybe another swing at mCRPC are also extremely important to the long term value of the stock.
It simply wasn't the focus when COMET-1 started. Bone was what you wanted to isolate, and if anything, you wanted to exclude patients with especially bad prognostic factors outside of bone involvement. I'm not clear on why specifically liver mets were excluded, but perhaps it was deemed an espcially risky sub-population.