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 - 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."
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.
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.
CCR 10/28/14 Katayama, et al
Despite trastuzumab's tenure in breast cancer care, it's MOA and mechanisms of developed resistance are not well understood. A synergy of response with cabozantinib might compel Roche to take note, but better still might be if Cabo disables the cascade of signaling events that lead to HER treatment-induced resistance. Definitive links have been made in past research assays, and both HER2 & HER3 inhibition by trastuzumab have been shown to upregulate cMET expression in BC. There is solid rationale for patient benefit w/ Cabo.
With T quickly moving toward patent expiry, biosimilars are being explored, and Cabo might play right into these BC subset treatment groups...particularly if induced resistance to T is disabled.
JMO - I believe this is (at least in part) Roche's way of putting a viable price tag on Cabo.
This trial is worth watching...
"Enrichment of c-Met+ tumorigenic stromal cells of giant cell tumor of bone and targeting by cabozantinib", Cell Death & Disease October 16,2014... Liu et al. Open access freebie... Standard chemo for GCTB is methotrexate, and this study suggests that pCabo may be a superior future treatment option. Of particular value is the documentation of Cabo effect on CSCs within the stromal environment.
Fast Track Designation of V&C could mean a lot for melanoma patients, especially those most recently diagnosed and faced with the decision as to which therapy is best suited to their need. In the wake of BRAF monotherapy, the combination of V&C is relatively ineffective than if it is administered from start of therapy as a doublet. This is very meaningful. I have posted in the past that BRAF monotherapy in advanced melanoma was about to become a thing of the past, and this is the forebear of that prediction. I expect EXEL to report revenues from cobimetinib by the 2nd quarter of 2015. As to why there has been no PR on the FTD - the development of that compound is up to Roche, not Exelixis. It's all about their gameplan till approval, at which point EXEL gets to share marketing costs and profit/loss structure. Lots of misinformation is being posted on this MB of late. Be careful...
It is correct that the FDA has awarded fast track designation to the combo of V&C...
For those interested in reality, check out slide 35 of the Roche investor presentation from ESMO 2014.
Look at the last line on that slide....that's right....where it says...
"VooDoo melanoma medicine gets fast track designation..." That's the ticket...
I see no importance to the timeline. I figure a collaboration like this one is solely directed toward placing a compatibility value on Cabo in combination with Roche's existing onco-arsenal. Since Herceptin has become an SQ injectable, compatibility with Cabo would be viewed as a marriage of convenience. An additional small Genentech-sponsored trial or two wouldn't surprise me...if there is unexplored commercial value in Cabo, Roche will find it.
"...more than doubles survival in some pancreatic tumor models."
It could be the presentation will give us some direction wrt the recent CDX IP patent filing. Doubling survival is no doubt a great feat, but predicting the patient group that will realize that benefit is potentially a huge play in trial population enrichment.
"What is the new IP worth?
For now...priceless. With competent CDX, everyone benefits. Docs, institutions, patients, payors, shareholders...everyone. Identifying high response patient groups is the stuff of the future, and I am thrilled to see HALO has recognized the importance of targeting specific patient subsets. This cannot be overstated...
Trial designs of the future will reflect the competence of the IP...
I suspect that one of Mr Market's observations that is sitting on the SP is the prospective tenure that V&C may enjoy in the advanced melanoma treatment algorithm. By far the preponderance of superior data is coming from the checkpoint inhibitors, and I think market perception remains focused on the perception that Cobi will enjoy but brief adoption, and eventually be replaced by a CI with a more moderate AE spectrum.
At any rate, I'd be prepared to see PDi displace TT in adv melanoma. Nivolumab isn't the one, but it's out there... Hopefully, Cobi is compatible, synergystic, and economical.
Posted in today's JCO. JMO - but I suspect BRAF monotherapy in advanced melanoma just became a thing of the past, so we might actually see an expedited review for Cobi...
"Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy."
The balance of future use if Cobi still lies in the comparative AE profile. Stay tuned...
Dr Paul Corn has published extensively on Cabo in prostate analysis, and it's good to see he still appears to be on board in the wake of Comet's failed OS signal. A strong showing in a Comet -2 could provide the NCI / IST funding for a VDA/chemo/ Cabo designed study such as these authors have suggested.
Looks like another semanresu/ Offsitehelp alias to me...
2 posts | Last Activity: 5 minutes ago
Member since: Sep 26, 2014"
Two thumbs down within a half hour...it's great to feel welcome.
Another interesting note here, PCF SR14 abstract submissions have been extended to 10/7/14, making this a possible venue for further prostate results, perhaps including additional readout on Comet-1.
Now, y'all can put those thumbs where they truly belong...
Amongst the interesting prostate-related studies being presented, I found this:
"C-Met and the emergence of resistance to potent androgen suppression" Morgan, et al...
Using bortezomib to sensitive cMET accumulation to XL-184 inhibition in AR axis manipulation in PCa...
Another with mention of Cabo:
"Crizotinib and enzalutamide before and after progression on docetaxel" Harshman, et al...