BRAF Negative

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3/9/2013 1:37pm
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Replies: 20

Hi my wife found out she is BRAF negative. Can someone point me in a direction of new drugs targeted for negative types besides Yervoy, IL-2, PD-1...just trying to stay ahead of the curve if the Yervoy that she is to likley start in a few weeks does not work...first choice if it does not would be PD-1 likely...but just trying to figure out other options for negative types. Thanks

kylez - (3/9/2013 - 2:20pm)

Hi Eric,

One such drug in trials is RAF265. Per http://news.vanderbilt.edu/2012/04/melanoma-drug/, it works best in wild-type melanomas. I know someone with wild type who was in this trial and had disease control for a long time but had to leave on a complicated technicality.

If I think of any others I'll post later.

eric w - (3/9/2013 - 2:21pm)

Thanks so much...

kylez - (3/9/2013 - 2:35pm)

Maybe the human trials haven't caught up with the mouse research yet.

Another mutation notso commonly tested for is NRAS (about 20% of melanomas). Mine tested positive foe NRAS G12A. UCSF sequenced mine, maybe because they're an academic institution. There's at least 5 trials for NRAS patients, including one of the RAF265 trials. For the NRAS trials, go to http://www.mycancergenome.org/content/disease/melanoma/nras/85 and then click on the clinical trials tab. The common theme seems to be MEK inhibitors.

POW - (3/9/2013 - 2:51pm)

Eric, I thought you and your wife were getting expert opnions from both UCLA and MD Anderson. What did they recommend?

Also, many oncologists think that some of the most promising treatments are still in clinical trials or are about to start clinical trials. Whatever your wife takes now may possibly disqualify her from an otherwise attractive clinical trial in the future. So be sure to discuss with your oncologists who are famliar with current or soon-to-be recruiting clinical trials a multi-step treatment plan. In other words, if Yervoy fails or your wife subsequently progresses after Yervoy, what would they recommend next?

For example, I have heard on this forum that in order to qualify for an anti-PD1 trial you have to have already had Yervoy and then progressed. Is that true? And if your wife takes Yervoy would she qualify for an anti-PD-1 trial? Will any such trials still be open? 

These are difficult and complex questions to which there is probably no "correct" answer. However, it's always good to have a Plan B and a Plan C before  you start Plan A. I hope and expect that is what you gained from your consults at UCLA and MD Anderson. 

eric w - (3/9/2013 - 3:14pm)

Hi yes we meet with them yesterday at UCLA...she is BRAF negative so zel is out...but she does not have a high tumor load.....so it likely would not have been suggeted yet anyhow...our onc basically recommended yervoy to start....after doing research and talking to folks i found a trial that combines pd-1 and yervoy...i brough this info to my onc and he said if we could do that...it would be his first choice....

so this week we go to MD to meet with them....assuming they suggest the yervoy then we have two options.....yervoy or the trial...the proble if u call it that is my wife has 5 subcentimeter nodules...they do not meet the measurable diease defition so she can not do the trial...so regardless we get scans done in 2 weeks at ucla....if the size has increased just so slightly and we can get into the trial and it is still open that is what we are doing..if not then we start yervoy in 3 weeks...and this is assuming md does not offer something else...

 

the reason i was asking all this is assuming she does just the yervoy i want to look for trial with pd-1 and maybe another drug that is for braf negative people for her to get into after the yervoy....make sense??

POW - (3/9/2013 - 3:34pm)

Yes, everything you are saying makes perfect sense. As usual, you seem to be a quick learner and a clear thinker. I will poke around and see if I can find anything else that might be good for a BRAF negative patient.

My only suggestion is that in the future you push your oncologists a little harder. Your UCLA oncologist seems to have presented you with 2 options for Plan A (yervoy or yervoy + anti-PD1), which is fine. But I think before your wife starts any treatment, you should discuss with your oncologist(s) Plan A AND Plan B AND Plan C. I, personally, would not accept an "let's see where things stand when we get there" answer because any treatment you get today MIGHT eliminate you from some other important treatment tomorrow. Better to think it through ahead of time and hope you never need a Plan B.  

eric w - (3/9/2013 - 3:41pm)

He also brought up IL-2 and chemo..they had a couple trials at ucla but nothing that sounded right...and we did ask him about exclusions but he still thought yervoy would be the best approach..so im just looking ahaed because if yervoy, pd-1 done work..then what...IL-2....which is not a bad idea becuase i saw something that il-2 after yervoy may help response..but not sure...anyhow just trying to stay ahead of this as much as i can..thanks

dian in spokane - (3/9/2013 - 5:21pm)

there is a dose escalation trial out there that uses IL 21 and anti pd1, and another that is similar that combines IL 21 with yervoy.

I was pretty interested in the first one, but it is FULL in seattle with a long waiting list.

 

the number on this trial is NCT01629758, ..but I'm not sure where it's being offered outside of Seattle.

WendyPam - (3/9/2013 - 3:56pm)

Hi Erin,

You might want to take a look at the other great melanoma board  http://www.melanomainternational.org they have a new interesting post put up by Catherine that runs the board regarding Braf Negative patients.

Once your on that board glick on "FORUMS" then scroll down to STAGE lV and glick on that and scoll down to "TOPIC INTERESTING FOR BRAF NEGATIVE PATIENTS"  I hope the information helps.

Regards,

Wendy

eric w - (3/9/2013 - 4:01pm)

Thanks

kylez - (3/9/2013 - 5:21pm)

Wendy, Eric,

(good job remembering that article Wendy! I should have remembered too)

One thing about NRAS mutated melanoma is that NRAS and BRAF mutations are mutually exclusive if I remember correctly. So if 60% of patients have BRAF, and 20% of patients have NRAS, then if your wife doesn't have BRAF (not in that 60%) then she has a 50% chance of being in the 20% of the remaining 40% with an NRAS mutation. 

So maybe a question fo UCLA would be, can they test your wife for the NRAS mutation? UCSF did for me, before I even had heard of NRAS. They're both UCs, so...? 

So if your wife falls in that 20%, the article is saying that NRAS patients seem to respond well to immunotherapies -- specifically IL-2 but perhaps more generally to other immune therapies as well: “Recent data for mutated NRAS as a predictive factor for response to high-dose interleukin 2 reinforces the notion of immunotherapies as front-line treatment for NRAS-mutated metastatic melanoma,” ... With the caveat that Catherine Poole mentions there is not a wide enough set of data yet to fully confirm these findings. 

And while MEK inhibitors are mentioned for NRAS as well, they're saying at the current time they wouln't recommend it as the first therapy, but rather, immune as first therapy.

So if your wife has NRAS  mutation, is that a plan A (immune therapy) and plan B (another immune therapy or MEK inhibitor) and maybe plan C? (maybe there'll be combined trials of immune and MEK for NRAS patients sometime in the future?)

 

eric w - (3/9/2013 - 6:23pm)

i all,

 

Thanks again...well im pretty good with stuff by im confused with this...I do know that our onc sent off for a sequencing genomic profile..it takes 4 weeks for the results and is done in Europe..it is done by Foundationone....so im not sure where she falls in all this..all he knew was she was BRAF negative and the report states no V600E mutation in BRAF gene...so i guess i need  alittle more help what this means in regards to what you stated....

 

so since she is negative..she falls in the 40%...but i lost you from there..

kylez - (3/9/2013 - 9:29pm)

The head of the UCSF dermatology clinic has told me (before these articles recently came out) that they're looking for targeted therapies for their NRAS patients (of which I'm one), but as of a few months ago nothing has really been panning out -- other than immune therapies which are not targeted to particluar mutations. 

So for your wife, they're doing more sequencing besides BRAF V600E? Maybe that meas they're looking for some other possible mutations -- which could be NRAS (about 20% patients) and/or C-KIT (about 10% cutaneous/skin melanoma patients, and 10-40% of acral and mucosal melanoma patients). Your wife may or may not have the NRAS mutation, and may or may not have the C-KIT mutation.  

What I was trying to say before is that with the caveat of a big MAYBE so far, a couple of recently published articles are saying that for NRAS mutated patients (1/2 of the remaining 40% or so BRAF negative patients), the immune therapy IL-2, as well as possibly other immune therapies (Yervoy, anti-PD1, IL-21 and so forth) there may be a stronger response. And therefore immune therapies should be considered as the first-line therapy for NRAS patients -- but larger studies are needed to confirm.

Also with the caveat of a big MAYBE, there are some indications that targeted thereapies for inhibiting MEK may work in NRAS patients, but on average not yet as well as immune therapies.

Hope that helps. Very interesting that they're doing more mutation testing.

- Kyle

Hstevens0072 - (3/9/2013 - 9:32pm)

I'm following this topic with interest as I am also BRAF negative. I've started Ipilimumab second infusion is Tuesday. My Onc said she tried to get me into a pd1trial but none were opening . That is my planB..... But after reading all these responses I am more confused than ever. Did I shoot myself in the foot by going with Ipilimumab ???? Everyone posts " make a choice and then don't look back", after all this I can't see my way forward. I hope you and your wife have more luck figuring this out.

"The key is don't go to the funeral until the day of the funeral" ~ Valerie Harper

kylez - (3/9/2013 - 9:38pm)

In the summer of 2011 I didn't qualify for the anti-PD1 trial (which was my first choice) and my only option was Yervoy. But I've had stable or shrinking disease since that summer, after Yervoy (and SRS and craniotomy). So even though it's not anti-PD1, it seems like Yervoy probably did something for me, and it's done something for quite a few other folks too. At the time I kind of dismissed Yervoy because it wasn't anti-PD1, but it seems to have helped me stay stable/shrinking for all this time. So... I don't think I shot myself in the foot with Yervoy. My only other previous treatment was IL-2. 

Gene_S - (3/11/2013 - 12:28pm)

Did I shoot myself in the foot by going with Ipilimumab ????

I would say no as my husband has been on Ipi (Yervoy) for 2 years now and if this would start to fail then his oncologist is saying Anti PD1 would be the next avenue.

Hope this helps ease your mind.

Judy (loving wife of Gene)

Live 4 today. Thank God for all he has done for us. Looking forward to enjoying tomorrow.

Anonymous - (3/12/2013 - 4:49pm)

It does indeed! Many thanks.

eric w - (3/10/2013 - 10:40am)

Hi Kyle,

 

Thanks...that makes more sense...and i realize about the maybes and such...i'm just trying to look ahead if the yervoy does not work..then what..and if that does not work...so thanks...i will do some more research on the different mutations and such...i really appreciated the responses...

eric w - (3/25/2013 - 2:03pm)

Hey Kyle,

 

Here is where they sent my wifes sample. Should get results on it this week.

 

http://www.foundationone.com/index.php

kylez - (3/26/2013 - 12:37am)

I'd be interested to hear what they get back to you with. It sounds like FoundationOne's testing will be pretty expansive/thoroug, does it seem that way to you?

The ones my samples tested positive for are NRAS G12A and BRAF G466E.