"I have no special insight into the DSMB's instructions, but I'm assuming that there was a delay for data cleaning before the March 24 announcement, so I'm guessing the actual interim trigger occurred in Jan/Feb. I would expect a similar delay period following the final analysis trigger."
Thanks, I had wondered your rationale for some time. That pretty much explains it. I would be shocked if blended median OS was above 10 months. I have yet to see 3rd line active drug result in anything greater than 7.8 months.(mostly low 7's) Unless I am overlooking something such as liver mets exclusion. COMET 2 will be one hellacious population. (greater than 5 pain score 3rd line treatment)
I am really intrigued to compare OS HR's from COMET 1 and 2. I think that would allow us to see how truly difficult it may be to treat these later staged patients. It may be very difficult to get an approved drug in this 3rd line space.-----Still in camp that believes odds are Cabo demonstrates stat sig in COMET 1, but I'm certainly crossing my fingers.
I haven't looked at the presentation yet, keep in mind Zelboraf had 100% metabolic response rate by itself in 24 patient phase 1 study. The early phase 1B Cobi/Zelboraf also had 100% metabolic response rate. Metabolic response rate by PET criteria is much easier to attain than Recist. CT Recist response can be masked by structural scarring. Regardless, I think Cobi/Zelboraf 87% Recist response rate is the most impressive data set in treatment naïve setting compared to 50-60's with GSK combo or monotherapy Zelboraf.
" I am very confident we are overdue. What the tweeter ignores is that we have a hard data point in that the result of the interim analysis was reported in late March, over 4 months ago. The cutoff for that analysis was 387 events. If we assume a blended median OS of 10 months, that would imply an average event rate of 48 per month. The final trigger is based on an additional 191 events."
If we assume 4-8 week data lock that puts us at late August/September for topline results under your 48 per month event rate.
"Additionally, there is a CRADA trial comparing Cabo to frontline sorafinib in HCC."
That was in the original plans, but it got scraped. The frontline RCC comparing to Sutent is ongoing.
"Of course, but a failure of COMET-1 would also be doubly painful since neither revenues nor financing would be as good."
No argument from me here. COMET-1 is awfully important. I really don't want to know how Exelixis would recover financially. Makes me wonder about the covenants. Can Exelixis run near cash depletion past METEOR results? It could be that Exel is banking on positive results in METEOR if COMET-1 doesn't come through. The other alternative could be a sale to Roche upon unsuccessful COMET-1, which isn't a pleasant alternative.
From slide on Exel earnings conference call
"Two randomized phase 2 ISTs have reached full enrollment
•? Eastern Cooperative Oncology Group (ECOG) trial in 2
EGFR wild type NSCLC: cabozantinib vs. erlotinib vs. cabozantinib +
•? Gynecologic Oncology Group (GOG) trial in platinum resistant/
refractory ovarian cancer patients: cabozantinib vs.weekly paclitaxel
•? Both studies expecting data late 2014/early 2015"
It was also stated that existing financial runway will put them past METEOR readout.
With guidance above $200 million for end of year, that puts METEOR readout in 3rd quarter 2015 at the latest. I wouldn't be surprised to see full enrollment from METEOR in next 2 months. 204 of 211 sites are actively recruiting in METEOR according to the site.
With approx. $75 million burn per quarter, we are getting awfully close to another financing. Typically Exel likes to raise cash with 1 year runway. As of now, I take management's not raising cash before COMET 1 readout as a positive. I think it may exude management's confident in successful COMET 1 readout. Not in Exel's nature not to hedge. This group has been fairly conservative with regards to cash on balance sheet to perform daily activities.
"what is NRE?"
The NRE is the non randomized extension of the RDT. The original RDT design was based on RECIST responses upon randomization and didn't incorporate the bone scan phenomenon. The NRE extension was designed to allow continuous dosing to all prostate cancer patients without fear of being randomized off drug.
From below, of 144 NRE patients, 93 of those patients had 100mg dose, while 51 had 40 mg dose.
"Safety data for the NRE were presented at two medical meetings in 2012. At the ASCO Annual Meeting in June 2012, Dr. Matthew Smith of Massachusetts General Hospital presented data from 93 patients receiving a 100 mg daily dose of cabozantinib (Abstract #4513). At the European Society for Medical Oncology Congress in September 2012, Dr. Johann de Bono, of The Institute of Cancer Research, London, presented data from 51 patients receiving a 40 mg daily dose of cabozantinib (Abstract #897O). Across dose levels, the most common adverse events (AEs) of grade 3 or higher were fatigue, hypertension, and venous thrombosis. 25% of patients in the 40 mg dose cohort experienced one dose reduction due to an AE, and 84% of patients in the 100 mg dose cohort experienced at least one dose reduction due to an AE. Overall, the lower starting dose of 40 mg was better tolerated with lower rates of dose reduction and interruption."
"The differences follow: RDT had 46% chemo refractory and 10% Abi/MDV refractory patients. Comet has 100% chemo and 100% Abi/MDV refractory enrolment. RDT had 100% soft tissue mets and Comet will have about 1/3 with soft tissue mets. RDT had about 60% start dosage at 100mg/day and 40% at 40mg/day. Comet has all patients starting at 60mg/day."
The 10.8 month survival benefit only included NRE cohort. Those characteristics were quite different than RDT by itself.
Here are some of the nuggets
-The interim results presented today comprise data from 144 men with mCRPC in the NRE cohort of an ongoing phase 2 randomized discontinuation trial.
- 73% of patients had received two or more prior therapies including docetaxel and abiraterone, enzalutamide, and/or cabazitaxel
-All patients had disease progression in either bone or soft tissue disease within 6 months of completion of docetaxel treatment, and the protocol differed from typical CRPC studies in that it excluded patients who progressed by PSA criteria alone, who generally have a better overall prognosis
-All patients also had bone metastases on bone scan and 31% had measurable soft tissue disease.
-In 36% of patients, disease progression was very rapid, occurring less than one month following the last dose of taxane therapy
I have a feeling Exelixis is going hedge against possible COMET 1 failure. I think they either do a market offering or sell outright to Roche. I have a feeling it is the former.
"72 plus months "
72 plus weeks obviously. I also buy into Ernie's assertion that Cabo will have plenty of patients to treat even if/when Nivolumab were to enter market. Not everyone responded to Nivolumab.
"HCC should be a relatively uncontested indication for Cabo. I don't think the results were nearly so good for Tivantinib"
Right, it will be interesting to see how this market shapes up. Even if Tivantinib were successful, Cabo has a decent financial opportunity on a global scale. I think Cabo early renal data was very strong in heavily pretreated renal cancer population. Maybe underappreciated, and I would like to see eventual OS data. I think Cabo data may be closer to Nivolumab data than you may think. Those bone responses and pain relief going out 72 plus months were pretty compelling. I noticed the recent Cabo patent on bone pain relief and bone involvement.---For lung,melanoma,prostate,thyroid, and renal.cancers.
" The only guidance is that Roche expects to file an NDA in 2014. They need the results in hand soon to make that deadline."
Guidance from Roche hasn't changed since recent phase 1 update demonstrating close to 14 months pfs with Cobi/Zelboraf combination? What is the number of events required to trigger interim analysis?
per clinicaltr ialdotg ov
RCC(METEOR) 198 out of 211 sites actively recruiting
HCC(CELESTIAL) 89 out of 139 actively recruiting
Full recruitment for METEOR is probably right around the corner. CELESTIAL will probably get a much greater focus soon.
No problem. I've been looking in MAPK direction for awhile now.
Here is a good paper
" A Novel SND1-BRAF Fusion Confers Resistance to c-Met Inhibitor PF-04217903 in GTL16 Cells though MAPK Activation"
"I don't think the impact of cabozantinib treatment has been defined as yet in terms of MAPK activation, at least I don't recall seeing it the lit..."
The EXAM trial responses in RAS population is the best we have thus far.
"The results showed that patients with RAS mutations also experienced a significant benefit in PFS with cabozantinib, with patients in the experimental arm achieving a median PFS of 47 weeks compared with 8 weeks in the placebo arm (HR = 0.15; 95% CI, 0.02-1.10; P = .0317)."