BRAF Inhibitors

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3/13/2013 12:42pm
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Replies: 6

I sat through some presentations yesterday on melanoma, and one in particular that discussed resistance to BRAF therapy.  As you know, after 6 months on a BRAF inhibitor about half of patients will see their tumors start to grow again.  A lot of people have tried to understand why this happens, and the MRF funded a researcher who has done good work on this area.

I have also heard that some doctors have started cycling BRAF inhibitors on and off. In other words, give the drug for a while then stop for a while before starting again.

Finally, I heard that a lot of colorectal cancers also have BRAF V600e mutations,  but BRAF inhibitors haven't worked in those cancers 

A researcher yesterday said that colorectal cancers readily activate a compount called EGFR, a receptor on the cell surface that signals pathways that lead to cell growth.  One of those pathways, the MAPK/ERK pathway, includes BRAF.  Another is called the AKT pathway.  

Inhibiting BRAF shuts down the MAPK/EFK pathway.  In colorectal cancer this causes upstream activation of EGFR, which in turn activates the AKT pathway.  Imagine having a favorite road you drive to go to work.  if there is a wreck on that road you find a different path.  You may not like it as well, but it gets you there.  The same is true here.  The cancer prefers growing by an activated MAPK/ERK pathway, but is perfectly happy using the AKT if it needs to do so.

It turns out that melanoma cells really don't like to activiate EGFR.  Unlike colorectal cancer cells, which activate it easily and flourish under that system, melanoma has a hard time with this.  (Imagine that your alternate path to work is a dirt road through the mountains instead of the 4 lane highway you normally use.)  With enough BRAF inhibition the activation can and does occur, but the cells that grow with this mechanism are weak and don't do well.  Removing the BRAF inhibition allows the stronger cells to come back and wipe out the EGFR activated cells.  Then re-inducing BRAF inhibition wipes out the other cells.  

Bottom line is that cycling BRAF inhibitors on and off may provide longer lasting benefit.  Hopefully this will be studied further and, if it is validated, become a new approach to treating BRAF mutant melanomas.

Tim--MRF

 

awillett1991 - (3/13/2013 - 2:03pm)

Tim - thank you VERY much for this update. Did they give any consensus on scheduling? Dr Sosman has me at 2 on/1 off since January, I cannot tolerate it continually at all after IPI. I'm almost 11 mos out from when I started Zelboraf, and it's still working. Also have heard of people 1 on/1 off, 3/1, and 4/2. Seems like a scary guessing game.

Looking forward to seeing you in Nashville again this year.

Amy

POW - (3/13/2013 - 2:56pm)

Tim, thanks for this "hot off the presses" information about intermitted dosing with BRAF inhibitors. Delaying the onset of resistance while at the same time reducing the side-effects caused by continuous administration sounds like a win-win to me!

Disappointing findings about BRAF inhibition in colorectal cancer, though. Such a shame! I sure hope these finding help researchers to find new and better ways to cure CRC.

Mickey n Jo - (3/13/2013 - 2:58pm)

Tim, thank you for the info. When I asked Dr. Pavlick about cycling the dosage of Zel, she wasn't in favor of it, not sure why, it makes sense to me.

                                Thanks again,

                                        Jo

NYKaren - (3/13/2013 - 6:08pm)

Hi Tim,
Thanks for this.
Have you heard any time-frame for GSK MEK/BRAF FDA approval?
Take care,
karen

Don't Stop Believing

Tim--MRF - (3/13/2013 - 7:59pm)

No-one knows for sure when the approval will be, but it is likely to be rather soon.  What I have heard suggests that this should happen by mid-year this year and possibly earlier in the spring.  As we all know, things are very much in flux with the FDA.

GSK did not submit for the combination of BRAF and MEK, though they did submit the combination in Europe.  Not entirely sure why, and data clearly suggests advantages when they are used in combination.  We will need to watch closely to see if insurance will cover the cost of the combination, given that this will not be the labelled use.

Tim--MRF

 

NYKaren - (3/14/2013 - 3:20pm)

Tim,
This absolutely shocks me. I wonder why they weren't submitted for use together. There MUST be a reason.
The cost of drugs in this country, and I guess everywhere, is shocking. I mean, I know a lot goes into clinical trials, but $10,000+ for a month's supply of Zelbarof... $120,000+ for 4 infusions of Yervoy?
My pharmacist told me that a tube of medicine was 19.99 in Dec '12 is now more than $100.00. When I said something about perhaps relegations or some such, he replied that it's pure, unadulterated greed!
But I digress.

So if I stop (G-d willing never) responding to Zel, I guess next step would be Zel plus MEK?? Presumably nobody knows, but hopefully it shall be figured out. That's my Plan B, having basically exhausted everything else. And Pd-1 will be plan c...
Take care, Tim,
Karen

Don't Stop Believing