CCR 10/28/14 Katayama, et al
Listed as corresponding author-
"Naoya Fujita, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research"
Probly a byproduct of the Nippon P2 trial. Alice Shaw is a player, that speaks to Mass General involvement. Small study, small subset...but ROS1 rearranged cancer activity opens another door to revenue potential.
I won't bet against PD-1 inhibition, but neither will I deny the future of BRAF/MEK combination. JFYI - there's a great piece of research posted on the BJC this month that proposes a clinical cocktail of BRAF/MEK with an Aurora Kinase A inhibitor that has huge potential. Think Alisertib.
FWIW - The Prostate Cancer Foundation has not given up on Cabo. This project is being mentored by Dr Arul Chinnalayan and may bode well for the future of cabozantinib in AR treatment-induced resistance.
"The androgen receptor (AR) is the engine that drives prostate cancer progression and survival and is the primary therapeutic target for this disease. Resistance to AR medicines is inevitable and new treatments for drug resistant patients are urgently needed.
Dr. Todd Morgan hypothesizes that the HGF/c-MET cell growth pathway is a potential mediator of resistance to AR-targeting therapies. In this project, HGF/c-MET activity will be assessed in prostate cancer cell lines and in patients receiving enzalutamide and other AR-targeting therapies to determine mechanisms of drug-resistance.
c-MET inhibitors are being tested in phase 2 and 3 clinical trials in patients with AR-targeting drug resistant tumors. c-MET activity will be correlated to treatment response in patients with an experimental c-MET drug (Cabozantinib) and mechanisms of resistance will be studied in these patients.
If successful, this study will identify a mechanism of AR-targeting drug resistance and treatment implications for c-MET inhibitors."
While not considered to be stat-sig, EXAM top-line OS definitively translates strong PFS to a pronounced survival signal....particularly if we consider that high EXAM dosing will never be replicated in another patient group - ever. More on NSCLC next week, and yet another IST for XL-888 based upon synergy of response with Vemurafenib in advanced melanoma. A .05 beat on consensus, to boot! Congrats to longs...
FWIW - SNTA's HSP90i, ganetespib, is the subject of some 35 clinical trials. It has displayed efficacy across the board, and is also being studied in synergy w/ Crizotinib, Vemurafenib, and gemcitabine. Several complete remissions have been documented, including a very dramatic radiographic response in TNBC. That said - XL-888 could appreciate considerably. Lots we still don't know here, particularly wrt AEs...
Clinical findings of Cabo compatibility with erlotinib, Crizotinib, gemcitabine, and AR modulation therapy bode very well in a future seemingly inclined toward cocktailed therapeutics. Despite the comedy of errors that has brought us to this share price, things are looking up once again.
"...it is very clear that Cabo prolonged OS...in RET positive MTC."
This is a very valid point that was not at issue when the EXAM trial was designed. The importance of RET rearrangement in MTC was still a wild card back in 2009. A phase IV trial is due as a requirement of MTC approval, and I am hopeful to see that trial well-stratified wrt individual genomics. Cabo's best target population has yet to be defined, and I remain convinced a viable biomarker would quadruple market valuation of EXEL.
Blah, blah, blah zero shareholder equity...
Blah, blah, blah Baghdad Bob...
Blah, blah, blah worthless voodoo therapy...
Me and offsite...we be mates...
From a 10/14/14 update to the UM Healthcare Center website:
"Project 2: Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib in Castrate Resistant Prostate Cancer
Co-Leader: Evan T Keller, M.D.
Co-Leader: David C. Smith, M.D.
Co-Leader: Scott Tomlins, M.D., Ph.D.
In a recent clinical trial led by Co-Leader Dr. Smith, Cabozantinib (CABO; XL-184) showed unprecedented bone scan responses in men with castration-resistant prostate cancer (CRPC). Although marked responses are seen, patients eventually progress and about 30% of patients do not respond. CABO is a multi-tyrosine kinase inhibitor with greatest activity against MET, VEGFR2 and RET, which have been implicated in prostate cancer (PCa) progression and the bone microenvironment. Using preclinical models we have found that some PCas show differential sensitivity to CABO when in bone versus soft tissue. Furthermore, through integrative sequencing, we have found that MET activation compensates for loss of androgen receptor (AR) signaling in CRPC. These clinical and pre-clinical results provide a compelling rationale for studying the role of both the tumor itself and the tumor microenvironment in predicting tumor sensitivity and resistance to CABO. Hence, the overarching goal of this proposal is to leverage an ongoing investigator-initiated clinical trial of CABO and use in vitro and in vivo modeling to "reverse-engineer" sensitivity and resistance mechanisms using a bedside to bench approach."
An interesting read for you, duffer: "Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to dual BRAF and MEK Inhibition in Melanoma Models" Smyth, et al Molecular Cancer Therapeutics 10/27/14. This reporting comes from the same Moffitt CC research team currently working with XL-888, and proposing to sponsor the P1b IST.
Therein find the rationale for a cocktail of V plus C plus XL-888 in BRAF driven melanoma.
Certainly Roche has got to be paying attention here...
Gosh darn it, just as we are broaching cocktail hour...
Best start mixing with the Uncola...
Get a grip, Bozo-breath...
From today's PR:
"Based on available clinical trial data, the primary endpoint assumes a median PFS of 5 months for the everolimus arm and 7.5 months for cabozantinib arm. This provides for a hazard ratio (HR) of 0.67 and 90% power and requires 259 PFS events among the first 375 patients randomized. The secondary endpoint assumes a median OS of 15 months for the everolimus arm and 20 months for the cabozantinib arm. This provides for a HR of 0.75 and 80% power and requires 413 events."
The key to determining trial duration to the primary PFS endpoint lies within the announcement that the first 375 patients were recruited by June 2014. If the trial design assumptions are correct, we could see PE results available much sooner than Q2 2015. Additionally, start-up dosing at 60mg is a first for Cabo in a P3 trial, and less than half the start-up dosage we saw in EXAM. I am very optimistic that we will see a direct translation of PFS to OS at these dose levels in mRCC.
I mention this only due to the potential for early unveiling of the primary analysis, which simple math indicates could occur as early as Feb 2015. As there are no provisions for crossover, it won't make any difference for trial patients, but it could easily impact SP as favorable early results (if released) could revise analysts' handicapping of top-line reporting.
Not for EXEL, Clem. Viva la manipulata.
Deserve it or no, someone wants EXEL at rock bottom market cap, regardless of clinical valuation.
"Who knows what other nuggets of gold are sitting in that group?"
This question begs some visitation. Look at the long list of oncodocs still researching Cabo effect, and look harder still at the growing list of oncodocs that continue to RE-visit ongoing Cabo research. The best and brightest are still carrying the ball here, and non-company funding is still supporting new projects, Cabo effect is that compelling. State-of-the-art biopsy, biomarker, and imaging technologies have been thrown at Cabo for these past four years in an attempt to gain insight into metastatic bone disease.
And that's just Cabo...
Cabo, cobimetinib, foretinib, and most recently XL-888 - remarkably promising pipeline. Four clinical assets under investigation, with many positivities noted. Patent filings are up - perhaps an attempt to ensure IP is adequately protected before they light the fuse? Lowest market cap in years, prime for takeover...highest debt load in its history...highest short interest in its history.
At this market cap, the odds of finding gold are increasing...
"Anyone knows why they are dosing 60mg in RCC ph3..."
The early clinical development of Cabo has been hall-marked by a continued balancing act between optimal efficacy and manageable toxicity. Dose reductions (due to AEs) in early stage trials - including the one you cite - have run as high as 80%. MGH actually sponsored a dose-finding trial a couple years ago that roughly halved dosing perceptions, and determined efficacy values for dosing down to 20mg/day based upon bone scan response and supporting biometrics. Come time to design the Meteor trial, 60mg had come to be considered optimal dosing, though I still expect we"ll see some dose reductions noted in top-line reporting.
Thanks for posting this, Bif. I'd been looking for a good comparator of mixed trials, phases, endpoints, etc to contemplate as a template for future regulatory considerations wrt Cabo in mCRPC, once Comet-2 results become available. I'm not quite prepared to add mCRPC to the Cabo list of missed opportunities, but still don't see a clear pathway to regulatory acceptance.