Posted by Jeff Berk, BOLT International;
Why no blogs for the past few days? Well, I’ll tell ya. I got this new pair of inline skates, and they’ve needed some feet in them to break ‘em in. OMG These things are FAST. Faster than me, that’s for sure. I’m moving up from 84mm wheels to these 110mm wheels. Do the math. These skates were made to go faster. And faster. I’m still working on the slowing them down thing. Thus far only a couple of scrapes with traffic. But as they say, “no blood, no foul”.
Then, distraction #2: Here’s what the garden had to offer this morning. The purple flower is ice plant. If you email me with the species name of the white flower, and live in the States, I’ll fed ex you a clipping (yes, I know the name. It’s a TEST).
So I’ve gotten a lot of email questions on MEK inhibitors for melanoma. There are a lot of them in development, and BOLT’s Melanoma Thought Leader panel (December 2010) thinks that they make a lot of sense by virtue of putting a second hit on the BRAF pathway. For the purpose of teasing you, I’ll be leaking out comments from the panel over time. Today you get their thoughts on GSK1120212. And a mere fleeting glimpse of commentary on PD-1 (MDX-1106, Medarex, Bristol-Myers Squibb):
- GSK is studying GSK1120212 as monotherapy in patients who have failed either their own BRAF inhibitor, GSK-2118436, or RG-7204 (PLX-4032, RO5185426). The Ph-III registration trial is set to start in 2011, with results expected in 2012. GSK is also running the combination of MEK + BRAF (obviously their own and their own). Patients with BRAF or NRAS mutations show dramatic responses within days. In the combination trial there is an arm where the two are started together, and an arm where the MEK is added in patients who have failed the BRAF. There is “scuttlebutt” suggesting that adding the MEK inhibitor to GSK2118436 is producing responses.
“Actually probably we will have the combination of BRAF and MEK inhibitor phase III study already starting next year. I think you have the scenario 2012, I think in 2012 we will already have results of such a trial; a combination trial of BRAF and MEK inhibition. And I am pretty sure that will even add some extra time in progression free survival and overall survival. I am pretty sure”.
“The scuttlebutt data but obviously the phase I trial is not yet complete so it is still very early is that the MEK inhibitor that GSK have added to the BRAF inhibitor has achieved interesting effects. I am not privy to any of that data. So that is the scuttlebutt. But if that were true that would be substantiation of the columnated pathway inhibition approach”.
“With a BRAF inhibitor, and possibly also the MEK inhibitors, you have a dramatic effect on the tumor in days or weeks”.
“GSK is in the lead here because they are already combing a MEK and the BRAF inhibitor with some success. The big phase II trial is approaching soon so I can only say it is a very good idea”.
“The trial we are actually doing is a MEK inhibitor from GSK for failures of either chemotherapy or immunotherapy or BRAF therapy. There are two arms, one is for BRAF failures, one is for the other failures. The BRAF arm will have both failures of the GSK BRAF as well as the Plexxikon BRAF. The data is slow to accrue and so there is no idea yet if that will be one way or the other. So it is a MEK inhibitor for RAF failures. I just want to make sure I understood this. So if patients fail a BRAF inhibitor they are given the MEK inhibitor plus BRAF inhibitor? No, it is a MEK inhibitor by itself. It is a different study. It is a study where MEK inhibitor is a second line trial, second-plus line trial. And you have two arms; one with people who got BRAF and one with people who didn’t get BRAF. And this is just to see any activity with the MEK inhibitor as monotherapy? That is right. It is separate from the combination trial where you actually use RAF and MEK together”.
“So in your real life clinic right now when you have patients who progress on RG 7204, the Plexxikon drug, what do you screen for and how are you driving them towards either a particular clinical trial or how are you choosing to treat these patients? I basically biopsy them of course, but I don’t make my decisions based on any activation. I don’t have the data. We biopsy them and put it in storage because we need more collection to actually make any conclusion. And then I screen them for the MEK inhibitor trial, because that is what I have open because they are BRAF positives, they qualify a MEK inhibitor, second line after RAF failure. We know about the feedback loop, so that to me is like number one trial for these patients”.
“I think they are kind of doing it but both companies are now actually kind of getting smarter. GSK jumped into the combinations quicker. They have the MEK inhibitor. So you know they have the phase I dose escalation open a few centers. And now they will be going to dose expansion. Roche is getting ready to open their Plexxikon plus MEK inhibitor from Genentech as well. So one thing would be that if they get data on combinations sooner they can say well you can start Plexxikon drug, but GSK have the data showing that if you start our GSK drug plus or MEK inhibitor drug you get progression free survival of, I don’t know, 12 months instead of seven months. And that of course would change you from starting people on Plexxikon to start people on GSK because it is hard to extrapolate and say, okay, I am going to start MEK inhibitor from GSK in combination with Plexxikon drug. I think that is what they are doing. They are jumping into combinations boldly”.
“Are the patients who have MEK pathway mutations are those MEK pathway mutations there at the outset or is there something about BRAF inhibition that is upregulating a process to cause the MEK pathway mutations? That is based on limited amount of data that resistance to PLX would be from a secondary downstream mutation in MEK. I don’t know that is true in any way. There is obviously no data for it, or there is only one paper on a cell line. I wouldn’t make a generalization about that. The clinical implication is if the tumor continues to be dependent on the MAPK pathway and you block BRAF you had a response and then he progresses then the idea was you block MEK, which is immediately downstream of A, B and CRAF, then you may have a secondary response. The data is still not out on this and is this true or not. I cannot comment on it. We have worked on the GSK trial and we modeled it in vitro and neither one of them are publicly available. Okay. Anything else I should be asking you about clinical developments in the melanoma world that I didn’t think to ask you? You focused on the important things. We can talk about a whole bunch of things; abraxanes, Vicals, and Vivaxis. All of those are completely obsolete right now. If I was in one of those companies I would either focus on BRAF negative or close the program. All of it is going to work we have seen the night and day differences. So why ipilimumab? Because it has impacted survival for the first time. Then closely following is PD1. So those are the two immunotherapy strategies I would focus on. Then BRAF and more BRAF and more BRAF. And then MEK inhibitors maybe if they treat resistance or they help prevent resistance and what about the targeted therapy where you can make BRAF work better”.
“If I am not mistaken there will be a possibility, and I don’t know from the top of my head, that if you failed the RAF by itself that you can add MEK inhibitor at that time. There will be an arm I think which will be a combination from the beginning and the other one will be like you start RAF in some shape or form and then at the time of failure you add MEK inhibitor and see what strategy might actually be better”.