Melanoma, brain mets and BRAF inhibitors

We asked our Thought Leaders to compare BRAF inhibitors from GlaxoSmithKline (GSK-2118436) and Roche ( RO5185426 aka PLX-4032 aka RG-7204) in relation to efficacy on melanoma with brain metastases.  The key claim for an efficacy advantage for GSK2118436 will be that it is active in the brain, whereas RG-7204 is supposedly not active against the brain metastases. At autopsy 60%-70% of melanoma patients have brain metastases.  In a sub-study, 9/10 melanoma patients with brain metastases experienced tumor shrinkage on GSK2118436.  The caveat we offer from a few of our panelists is that the activity of RG-7204 in brain mets hasn’t been fully evaluated, so there may turn out to be less of a difference than initially thought.

 

“So one thing is the suggestion that it has activity in the brain.  That is something that we don’t have with PLX.  So that would make it a big difference because the relapse in the brain is a big problem”.

 

“So right now GSK is rapidly approaching a brain metastasis trial which starts very soon.  I think that is one of the advantages with GSK; they are extremely fast.  They are asking good scientific questions and they are addressing these questions in sound clinical trials.  I like this very much.  They would certainly be in the lead in developing this drug also for brain metastasis patients.  But nobody knows yet.  But in theory I cannot see why PLX 4032 should not induce the same response rate as GSK”.

 

“There was some claim from GSK that they have better activity on brain metastasis. Well, they have treated, and it was in the presentation at ASCO, one or two patients with brain metastasis, small brain metastasis, and they have seen some shrinkage.  So they are going to explore that by actually doing a trial for brain metastasis.  Kind of like the trial we did with ipilimumab with Kim Margolin which was reported where you basically had small brain metastasis and then instead of giving them steroids you just gave them ipilimumab.  We have seen 28 percent response rate and stabilization or something like that, and if you added steroids it was lower.  So this will be a trial again with GSK BRAF, if you are positive and you have small brain metastasis you go on trial.  We will see if we can actually treat brain metastasis with this.  So that could be another opening there.  I know that if anybody failed on the Plexxikon, and again it is all published, the brain metastasis were one of the failure sites.  So it could be a difference.  Maybe the one gets into the CNS and the one doesn’t.  Just because you use 150 mg b.i.d. and the other one 960 b.i.d. I don’t think that makes one drug inherently better than the other, just the numbers, the milligrams.  That doesn’t tell me anything.  The sun sensitivity maybe a real differentiating factor, and the penetration to the brain might.  But, again, that is going to be hard to discriminate between those two drugs.  I think they are very similar in my mind”. 

 

“I guess that is one of the points of differentiation I have heard from some of the guys working specifically with the GSK molecule and that they have shown efficacy in the brain metastasis. Right.  And that is where I am trying to understand from your perspective how common is that as a secondary tumor site. Yeah, brain metastasis are very, very common and I feel like at autopsy series certainly more than 60 or 70 percent of patients will have brain metastasis that weren’t seen on imaging studies.  Right so then that strikes me as a big deal. Yeah, it is a big deal.  It’s a big deal.  If you are looking at patients with metastatic disease I would say at the time of diagnosis 10 percent will probably have clinically radiographically observable brain metastasis, and then the majority will develop them throughout the course at some point.  The presence of brain metastasis is a big, big deal.  I am looking up and seeing that the phase II study excluded patients with brain metastasis and this is for the Plexxikon drug.  The phase I allowed stable brain mets or brain mets were not progressing for at least three months at a time the patients were put on.  The patients that were treated I don’t think we have a good sense of whether this agent is active against progressing brain metastasis or not.  But again, because of the lead that this drug has, I think we are going to have this information.  Maybe we will find that it doesn’t work in brain metastasis.  And if that is the case then the GSK drug may really have a meaningful difference”.

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