How to Develop a c-MET Inhibitor for NSCLC

So before I share some thoughts on how to develop a c-MET inhibitor for non-small cell lung cancer, I can’t resist commenting on the executive order, issued today by Darryl (I was in Run-D.M.C. before I was a community organizer) McDaniels, establishing a White House Rural Council.   Seems that Darryl wants to “make sure we’re working across government to strengthen rural communities and promote economic growth”.  How, dude, exactly would you like to do that?  By regulating my God and my guns?!  No thanks.  God knows, I like my God, and I LOVE my guns.  BTW, if you look beyond the SIG-556, on the left side of the photo, you can see a baby Pachycereus pringlei.  Also known as Cordon, this species is the variety of the Sahuaro that is found in northern Mexico.  Anyway, Darryl, why don’t you move to Yemen.  I hear they’re gonna need a new dictator there pretty soon.  And you’ll really like it there.  They have TONS of guns for you to try to take away, and a (false) god for you to expunge.



BOLT ran a Lung Cancer Thought Leader Panel just before ASCO 2011.  We covered a ton of topics, one of them being how companies with cMET inhibitors can catch up with ArQule (ARQ-197) and Roche (MetMAb).  We asked how a Ph-II program should be run for follow-on molecules.  Here’s what one guy had to say:


So where is c-MET inhibitor going to fit into our discussion?

That is a really tough area.  And one of the real problems is that…so both of those drugs have largely been developed in a way that never made sense and makes even less sense now.  So they were developed with the idea with some rationale that acquired resistance to erlotinib can center around c-MET and so we should try to treat people up front with erlotinib and a MET inhibitors.  But these were never done in targeted fashion to give only to patients with EGFR mutations and so we are left with these big trials, both for MetMAb and ArQule in which patients were treated with erlotinib or erlotinib plus the MET inhibitor.  And then we have the result in the ArQule case that it is just better in general to give the ArQule plus erlotinib or in the MetMAb case in patients who have immunohistochemistry positive tumors they are most likely to benefit from the combination of erlotinib and MetMAb versus erlotinib alone.  The key question of course, which nobody seems to want to answer from a corporate perspective is what is the role of erlotinib in these studies.  My guess is the answer is nothing, that erlotinib isn’t doing anything.  But those studies are built on that and so we have all this data that says erlotinib plus MET inhibition makes sense.  So they are developing these drugs with the combination so that the phase III trials are being done with the combinations and that is where it is going to take us.  Hopefully some small scale studies will be done in the interim while these phase III trials are ongoing to help us understand what role erlotinib is playing.



From a corporate standpoint, ArQule and Genentech are locked into the paths they have chosen.




But we have a number of other c-MET inhibitors in earlier development.  So do this thought experiment.  Design for me a phase II proof of concept for a new c-MET inhibitor.  If you are not stuck with all the baggage that all these other companies have how would you run it?

One thing we don’t have a lot of data about and would be nice to see is something to suggest that a MET inhibitor by itself does something.  So single agent, single arm phase II trial and you can take all comers to look at MET inhibition to see how it goes, but of course you want to see if patients have MET amplification because there is some modest degree of increased copy number of MET in a lot of patients and then there is frank amplification even more.  So I think you would want to see if that teases out.  You could even use Genentech’s immunohistochemistry thing and look at the single agent activity in patients who have MET over-expression.  I think just doing that with a relatively small single arm, single agent, phase II makes some sense.  And then one would presume you would see some activity there.  I would say you go straight to a randomized phase II comparing the MET inhibitor to something else.  If you wanted to be cynical or if you wanted to sort of stack the deck and make it work for you I think MET versus erlotinib would be a rational and defensible approach to studying it, you actually have single agent activity for MET which all the data suggests you do you are probably going to see activity for that that is better than erlotinib than in an unselected patient population.


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