BRAF Positive

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1/9/2014 5:04pm
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Replies: 11

Small met located on my right posterior iliac about 6 weeks ago brought me up to Stage 4 after participating in the ipilimumab trial earlier this year.  Will be determining next steps in a week or so after PET scan results are available.  My onc at Seidman indicates that if it is smaller or same as originally spotted, remove with radiotactical surgery.  If gone, wait and watch.  If larger or additional mets noted, systemic treatment is needed.  I just learned that I am BRAF positive and am wondering what systemic treatments this might open the door to.

POW - (1/9/2014 - 5:44pm)

Hi, Mark-

According to your profile,  you had a left axillary CLND a year ago with some positive nodes. In March you were NED and started ipi via a clinical trial. The trial treatments ended in May and now you have a met on your right hip. The met is BRAF positive. You are wondering what systemic treatments are available to Stage IV patients, especially when the tumor is BRAF positive. Does that about sum it up?

Since you are BRAF positive you can get one of the FDA approved BRAF inhibitors (Zelboraf or Tafinlar). You can also take a MEK inhibitor (Mekinist) and as of yesterday (!!!) the FDA approved the combination of Tafinlar + Mekinist, which works in more people with fewer side effects than either drug alone. 

BRAF inhibitors work in about 50% of the people who take them. When they work, they work quickly and well but most people become resistant to them in 5-7 months. Yes, there are those who have not become resistant after several years, but most people do become resistant. So the current thinking is to hold off on taking the BRAF inhibitors unless and until you really  need them. Not all doctors agree with this-- they think that taking a BRAF inhibitor-- especially the combo-- early in disease progression might completely kill the melanoma but there is no evidence about that yet. 

The other really promising treatments we are hearing about are the "check point" treatments-- ipi, anti-PD1 and anti-PDL1. It doesn't sound like the ipi worked too well for you. However, sometimes taking IL-2 after ipi can enhance the effect of the ipi and result in long-term NED. That is something you might discuss with your oncologist.

The other check point inhibitors are anti-PD1 or anti-PDL1. The clinical trials of anti-PD1 are about completed and rumor has it that anti-PD1 might be FDA approved some time this year. If your tumor is not growing quickly or you have it zapped with SRS, anti-PD1 might be an option for you later on. Anti-PDL1 is just starting clinical trials and that might be an option for you, too.

Other than that, you might ask to have your tumor tissue tested for the c-kit mutation-- there are some new data indicating that treatments that work through c-kit in other cancers will work for melanoma, too. This, too, is very new and unproved. Check the clinicaltrials.gov web site if you are interested in that.  

Bubbles - (1/9/2014 - 9:25pm)

So sorry for that turn of events.  I know that wasn't what you were hoping for.  However, ipi and other immunologic agents can somtimes result in an increase in the size of tumors on scans (even allowing new ones to appear) only to have them disappear with a little more time.  Hopetully, that will be the case with yours!!!

From all the current data, and the info I've acquired from the folks at Moffitt, the most recommended treatment for someone with a recurrence after ipi, is to treat with anti-PD1.  Of course, that is easier said than done since it is not currently on the market...but there are some trials still addressing that very particular sequence.

Since you were BRAF positive, that presents another option.  Actually, roughly 40-50% of all melanoma tumors are BRAF positive.  IN THAT GROUP, the response rate is about 80%.  (Not the numbers quoted in the prior post.)  Unfortunately, it is true that many melanoma patients develop resistance after an intial response in about 6-8 months.  (Though we still have Dick K out there showing us all how to hang!!!)

When MEK inhibitors are combined with BRAF, especially when intermittent dosing is added to the mix, patients have much greater odds of having their tumors remain responsive for much longer (as well as diminished side effects!!).

While IL2 provides roughly a 10-15% response rate in general and 5% of patients have a durable response, I have seen no articles or data indicating that those numbers are enhanced when it is administered after ipi in a randomized trial.  One article described increased complete responses when receiving IL2 after ipi, but at rates of only 17% with only 36 NON-randomized patients.  Wish it were better...but I haven't seen it.

While your BRAF positive status is neither here nor there....trials with ADC and PV-10 as well as PDL1 are out there as well should you need to look into them later. 

BUT....I'm holding out for either clear scans or the benefitsof the abscopal effect which can occur when radiation and immunologic agents are combined or used in rapid succession!!

Wishing you my best, Celeste

 

 

 

 

 

chaoticallypreciselifeloveandmelanoma.blogspot.com

POW - (1/9/2014 - 11:32pm)

Celest, I'm not trying to quibble; I just want to make sure that everyone gets the correct information. 

My assertion that 50% of patients with the BRAF mutation respond to BRAF inhibitors (vemurafenib) comes from two published reports:

Phase II trial: Sosman et al NEJM Feb 2012

“the confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months”

Phase III trial: Chapman et al NEJM Jun 2011

“Response rates were 48% for vemurafenib and 5% for dacarbazine.”

Where did you get your figure of 80% response rate?

 

 

Mat - (1/10/2014 - 5:16am)

The GSK press release cites an overall response rate of 76 percent for the combo and 54 percent for Tafinlar  alone.

POW - (1/10/2014 - 8:09am)

Thanks, Mat. Indeed, the press release does say the the investigators determined that there was a 76% ORR for the combo with a median duration of 9 months. The press release also says that a blinded independent radiologic review committee found a 57% ORR for the combo, which I find confusing.

Regardless, clearly Taflinar + Mekinist is a very powerful new treatment for melanoma that works in more than 50% of patients. That's great-- I'll take it.

PS-- I also read a study that says it works in about 20% of brain mets. Too bad it's lower than for non-brain mets, but at least it's something.

Bubbles - (1/10/2014 - 12:33pm)

POW,

You are correct in asserting that we should all be very careful in regard to the data and comments we make on this site lest we lead people astray.  Too many folks speak with “great authority” here despite never having had melanoma nor being medically trained.  Additionally, just like a recent kerfuffle, even when doctors attempt to give advice, while perhaps accurate, it may not address the particulars of an individual patient.

While it is true, as I believe Mark Twain said, “There are lies, damn lies, and…statistics!”  Here are just a few examples of data indicating a greater response rate to BRAF inhibitors than 50%:

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.  By:  Bollay, Hirth, et al.  Nature, Sept 2010.

“Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma.  By: Flaherty, Puzanov, Kim, Ribas, Sosman, Chapman, et al.  The New England Journal of Medicine, August 2010

“Our trial shows that therapy targeting tumors containing activating V600E BRAF mutations can induce complete or partial tumor regression in patients. PLX4032 induced complete or partial tumor regression in 81% of patients who had melanoma with the V600E BRAFmutation.”

Response and Resistance to BRAF inhibitors in Melanoma.  By:  Keith Flaherty at Mass General, ESMO-TAT-2011 Presentation                     Tried but unable to get PDF File to copy…but quote =

“GSK2118436:  Phase II Expansion at 150mg BID, Overall response rate 77%”

Regarding BRAF MEK COMBO’s:

From my Blog post November 6, 2013           Ipilimumab Goes the Distance in Melanoma
Antoni Ribas, MD and Caroline Robert MD Discussion.  Medscape.com.  October 8, 2013

Ribas:   “...the data from dabrafenib and trametinib (BRAF and MEK inhibitors) published in the New England Journal of  Medicine, suggesting a higher response rate, a more durable response with fewer skin side effects from blocking a paradoxical MAPK pathway activation.  [In another study], a dose escalating phase 1 trial using vemurafenib, a BRAF inhibitor, with cobimetinib, ..another MEK inhibitor.  By putting them together...the response rate was extremely high.  They reported a 95% objective response rate.  It is close to a near guarantee of having a response at these levels, and we haven't reached the median progression-free survival, telling us that the curve is staying up quite a bit.”

In regard to BRAF/ MEK combo for brain mets (from Blog post “Latest from ASCO:  Brain Mets” June 2, 2013) {Bear in mind that the data discussed is related to brain met patients only}

Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Dzienis, et al.  Princess Alexandra Hospital Brisbane, Australia

“Responses to dabrafenib have already been reported in over 50% of patients.  We aimed at assessing response rate to vemurafenib.  Patients with BRAF positive melanoma and asymptomatic brain mets were included.  Conclusion:  Vemurafenib resulted in 50% CNS response rate.  Prospective comparison to dabrafenib may be warranted.”

So…that’s a much better prospect than the “works in about 20% of brain mets” comment given.

Data is a very tricky fluid business, and none of these results are what folks dealing with melanoma deserve.  Hope that helps.  Celeste

chaoticallypreciselifeloveandmelanoma.blogspot.com

Bubbles - (1/10/2014 - 12:49pm)

Got the slide mentioned above to copy after all!!!

chaoticallypreciselifeloveandmelanoma.blogspot.com

Bubbles - (1/10/2014 - 12:51pm)

Oh well, guess not.  Sorry.

chaoticallypreciselifeloveandmelanoma.blogspot.com

Bubbles - (1/16/2014 - 12:06am)

Was doing some work for another topic and found a synopsis of this discussion by Ribas and Weber:

"Melanoma:  From Impossitble to Treat to Poster Child for Targeted Therapy" (published October 2013)  that I posted on my blog November 18, 2013....

'Ribas:  Having seen this remarkable change in a short period of time...is a remarkable benefit to patients...but we are still faced...with many patients who are either not responding, responding for a short time and progressing, or having side effects.

Patients who were treated 2-5 years ago [with immunotherapies]...continue to respond and patients with T24 blocking antibodies, the longest...for 12 years...but we need to make it more efficient for everyone... The B-RAF inhibitors, vemurafenib...then the B-RAF that is called dabrafenib, which is a very recent approval. ....when we select patients with the B-RAF mutation, which is around 50% of melanomas, we are close to guaranteed to have some...patient benefit.

Over 80% of patients have some shrinkage of disease....but the majority - not all of them, but the majority - will progress...and the median duration of response is around 6-7 months, although there are some patients from the Phase 1 trial of vemurafenib who are now going beyond 4 years and are continuing to respond, but that is the minority.'

Hope that helps clarify.  C

 

 

chaoticallypreciselifeloveandmelanoma.blogspot.com

mark1101 - (1/16/2014 - 9:56am)

Thanks to all who responded.  The data for these studies certainly can be confusing and even seem to contradict in some cases.  In the end, however, this information serves as a terrific conversation starter with my onc.  I have the utmost confidence in him and trust that his views on these data are valid.  It will be good to use this information when I see him on Monday.

Thank you all for caring.

Bubbles - (1/16/2014 - 6:34pm)

Hey Mark, 

You're right, it is all about as clear as mud, isn't it?  Hope it helps you get some answers and a sound plan from your doc . Even more, I hope that it is a plan you don't even need to try to put in place anytime soon.

Good luck.  Will be keeping my fingers crossed and wishing you my best.  Celeste

chaoticallypreciselifeloveandmelanoma.blogspot.com