Melanoma: BRAF, MEK, NRAS, PD-1, cMET

Posted by Jeff Berk; BOLT International


Here’s some irony for you.  If you live in Arizona and want to buy a nice machine gun, you have to wait about 4 months for ATF (Alcohol, Tobacco & Firearms; the Arizona State Convenience Store) to complete the background check and let you take possession.  But if you’re a Fast and Furious participant, i.e. in the Mexican drug cartels, Eric Holder will give you your weapon TODAY.  And to top it off, the taxpaying guy in Arizona who has to wait and wait AND WAIT, is the one who actually pays for it.  Right, sure, sure.  Eric can’t remember anything about F&F.  Must’ve just slipped his mind.



Okay, let’s get onto the juicier parts of today’s blog…


Melanoma and BRAF V600E?  Sure, the approval of vemurafenib is big news, and GSK2118436 monotherapy, and RAF/MEK combinations GSK2118436 +/- GSK1120212 and RO5185426 (a.k.a. PLX-4032) + GDC-0973 are all on the way.  But if you’re one of those people who are BRAF wt you’re probably asking…  “WHAT ABOUT THE 50% OF MELANOMA THAT’re BRAF WT?  What’s new for us?!”  Here are some snippets for you.  And if you’re Pharma, and still have 4Q2011 budget and want to get a good deal on BOLT’s Melanoma Thought Leader Panel #28, set to publish in a couple of weeks, email me at




“If they have V600E if they have like a BRAF mutation I either put them on a BRAF targeted trial, which in my hands right now is the Glaxo RAF (GSK2118436) plus MEK (GSK1120212) versus RAF randomized phase II, or we also have a phase I RAF plus MEK from Roche (BRIM7: RO5185426 (a.k.a. PLX-4032) + GDC-0973), which is a little bit more behind.  So these two will be.

So the 50 percent that come back as BRAF wild type, what do you do?


So we also screen them for NRAS, c-kit, GNAQ, GNA11 and one other thing.  So if it is a c-KIT mutation, I put them on the nilotinib versus DTIC trial, which I have open or would put them on imatinib off label; because there is no phase II data.  If I can get imatinib I put them on imatinib.  If they are NRAS mutated we actually have an NRAS directed trial, a few slots left, with sorafenib plus ARQ 197 which is a c-MET inhibitor from ArQule (partnered with Daiichi-Sankyo), Brian Schwartz.  Believe it or not, we had some responses in NRAS mutants and so I think actually maybe a combination of c-MET and VEGF might be a good combination for the NRAS.  You know there goes the XL 184 (cabozantinib; MET/VEGFR2) as well because XL 184 also had some patients with NRAS mutated melanoma responding.  So it is like you said in the other question, assumption NRAS is the new unmet need.  It is a true unmet need and we are trying actually to develop something so we try to develop this idea for an NRAS mutated trial, but it’s in development.

I met with (censored) from Merck.  Nice guy.  Really smart.  So we got to talk yesterday and hopefully we will talk some more about maybe doing a PD-1 for Merck in combination with commercially available Zelboraf if nothing else.

You were talking about the PD1 from Medarex (BMS/Ono).  That is the fully humanized IgG4, right?


That is correct.

And Merck’s PD-1 you are saying is an IgG4.


Very similar.  IgG4 as well, humanized.

So what is the difference?


Merck says they (MK-3475/SCH 900475) have higher affinity.

Okay.  And there was one other PD-1 inhibitor you mentioned.  I couldn’t catch that. 


Amplimmune (with GSK, developing AMP-224, a fusion protein that blocks the interaction between PD-1 and B7-H1).  And then there is a Curatech.  It is an Israeli company.  They don’t have PD-1 antibody.  It is like a different mechanism.  They play with the ligand or something.  Honest to goodness, I didn’t get all the details, but I am going to go to investigator meeting for Curatech so I will catch up on the details.  And Amplimmune is just in preclinical.  So that is very early.  It is interesting but by the time they get to the real game maybe it will be a little bit too late.  Who knows?  Although, who knows, maybe not.  The Medarex data, everything they showed, Bristol, it looks great.  They want to go to renal and they struggle how to go to melanoma because they do not want to cannibalize Yervoy.





Oops.  The free-meter just ran out…



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2 Responses to Melanoma: BRAF, MEK, NRAS, PD-1, cMET

  1. MeDoo says:

    I’ve been dealing with mealnoma since 2005 and stage IV since 2008. I’d like to add just a bit of the patient perspective to all of the strategizing so well described above. I’ve participated in peptid vaccines, TIL, Ipi/Yervoy, and braf/Zelboraf trials. Went through four SRS treatments for brain mets, and took temodar, serafonib and chemo to connect the dots between trials. Presently, I am on Day 12 of a 28 day Zelboraf wash and an 8 week post SRS wait. While the Zelboraf has been fantastic below the brain for 11+months, I got brain mets in the 10th month. Hence, I have stopped Zelboraf even though it continues to work amazingly below my body blood barrier, in an effort to qualify for a PD1 trial. Call me crazy but I want to see if PD1 can handle brain mets. If not I’ll go back to Zelboraf, pray it still works and along with my clinicians and advocates watch keenly for my next option. I write this actually as a love letter to all of the researchers in private and public labs looking for mealnoma solutions. After all the business strategies, market indicators and government regs are pushed aside, I feel strongly that it is the patients and researchers left on the battlefield with mealnoma. So everyday that I continue to wake up, I send a blessing and a bit of my strength to you researchers so that you can hopefully put the exhaustion, politics and economics aside to pursue the inspired science you are so very capable of. Together with some determined clinicians and saavy advocates, we’ve kept me alive well beyond any rationale stat. So let’s hope I make it to Dec 26th without brain mets returning and then game on PD1 in 2012.

    • jeff says:

      thanks for sharing your comments. in particular, i completely agree with your patient/researcher comment in terms of who should be making the call on how to use both approved AND UNREGISTERED therapies; particularly those with one or more immunotherapies. email me directly if you want to hear some perspectives on data presented at AACR in Boston.

      good luck, enjoy your christmas, and stay feisty.

      – jb

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