MEK in use for NRAS … Sam, Tracey, and Mark

Dear Niki and Celeste,

thanks for thinking of us and for posting. I was not too happy with the results of the studies but thanks for remembering us!

that said, i am not sure about these studies. In Niki’s paper the response rates seem pretty low, both for NRAS and non NRAS, lower than in other studies, so am not sure these are correct. Also the lower survival rates for NRAS are disappointing so i hope they are not true

from the abstract I dont see where the conclusion to take MEK inhibitors comes from – how this is this justified. also the authors of this paper are the same as the authors of celestes second paper – where the response rates were higher, presumably for a similar cohort.

Celestes first paper shows a little more promise, in that it seems to show that some NRAS patients who had not done well on immunotherapy did OK with MEK inhibitors with either partial response or stable disease.

when my team was brainstorming (without me!) what to do next given my lack of response to pembro (Stable disease / slight worsening) i think one of them (the most senior) was thinking of giving MEK a try. I guess this was based on the findings of Celeste’s first paper (although only phase 1/2) – which i guess shows they were looking out for me and being imaginative.

in the end, since my disease burden (thankfully and so far so good, dont want to jinx it) we were going to do surgery, but then after a second opinion (and begging insurance) we decided to add tvec to pembro first then surgery if this fails. This tvec pembro combo seems to be working, at least its a partial response (and thus I am a fan of intralesionals plus pembro) 

before re-reading these posts i was under the impression that Immunotherapy tended to work better for NRAS, but the German authored posts suggest this is not correct, that NRAS does not lead to a higher probability of success, that its the same as for everyone else.

if fellow board members find any articles on NRAS if will be great if you can post – and thank you niki and celeste very much for doing this – i wish researchers would look at our mutation as well as BRAF

Thank you and best wishes

Mark

Hi Mark, glad things with t-vec + pembro are working, as far as the study from Niki, it is retrospective( looking back at old patients and data) and when doc do this they are usually looking for trends or ideas that they can then do a prospective trial where they control for that specific drug or condition that they came across in the retrospective data. So, I wouldn't put a lot of stock in data from retrospective papers. I did come across a company out of Philadelphia called "The Wistar Institute" who seem to have some paper out of NRAS research. Here are two links with the condition that I don't know a lot about their research or reputation, they look good, maybe others are more familiar with the Institute. https://medicalxpress.com/news/2018-04-combination-therapy-effective-nras-mutant.html           https://wistar.org/about-wistar

https://medicalxpress.com/news/2018-04-combination-therapy-effective-nras-mutant.html

One last idea from Wistar, https://wistar.org/news/press-releases/targeting-telomerase-therapeutic-strategy-difficult-treat-melanoma

Agree on the need for a like button! Thanks for your postings and for finding these links. I had read them earlier but on my ipad and my typing on that is terrible! Now am on the computer.

I guess I have mixed feelings:

– its good the Wistar people are looking into NRAS, as it seems that few are looking into this mutatation. However, the intros to their research sound all gloom and doom, not exactly uplifting.

– on the MEK – I dont really understand this, but it seems that maybe MEK works for non BRAF people as well – maybe for NRAS and maybe too for Niki who has neither BRAF nor NRAS. So perhaps thats why one of my doctors on the tumour board (the senior one – I never met him) was suggesting MEK I think together with my keytruda

– in the end we went for tvec + pembro instead of surgery. since i only have one tumour (I hope!) plus pembro worked to dissolve a second tumour this seemed to make sense – try to get the thing inflamed and get the pembro to work again

its a weird idea being injected with (dead) herpes virus but it seemed to make sense

it does seem to be working, certainly not getting worse, but its taking time – seems that if I am a responder I am a slowish one. its also scary because every two weeks my tumour is measured by ultrasound so they know where and how much to inject. the ultrasound does not quite match the mri readings but it means i get mini scanxiety every two weeks. at first it was actually growing but i hoped this was inflammation and pseduo progression. now it is shrinking but who knows if it will actually disappear – i have to pray for such a miracle.

thanks to all of you, niki, ed (I saw your photo finally, I am too shy!) and celeste for digging up NRAS stuff

my take on having NRAS is that this solves the decision of whether to do BRAF inhibitors first or go to immunotherapy – we have to do the latter. it would be nice to know whether our response rates are better or worse (why no study on this?) – i was hoping we had slightly better response rates but maybe thats wrong and we may be lucky to have the same response rate

thanks very much for your help and for looking into this

I can at least remember wistar if i need new options

best wishes Mark