Home Forums Melanoma Diagnosis: Stage IV NRAS, ERK, and other pathways: what’s new?

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    Mikers asked about the promise of new research on the pathways besides the more common braf. Here is a summary

    There are multiple novel agents and combination of agents that target specific pathways being tested in patients with metastatic melanoma.

    The downstream target of BRAF and NRAS is ERK and many new ERK inhibitors are in early phase clinical trials. As a target, ERK is very attractive since activated ERK is very common in melanoma. However, because ERK is so necessary even in normal cells and rarely mutated, inhibiting ERK in the tumor and not in normal cells has proven to be challenging.

    In terms of NRAS mutant melanomas, multiple combination of MEK inhibitors with other agents are being tested. At present, the combination of a MEK inhibitor with a CDK4 inhibitor has shown some promise in a phase 2 study of patients with NRAS mutations however the toxicity of the combination can be challenging.

    In terms of BRAF mutant melanomas, multiple different strategies are being tested to improve upon the current BRAF and MEK inhibitors. Some of these agents include novel BRAF inhibitors that are capable of inhibiting mutant BRAF at lower concentrations than current agents as well as other agents that bind different areas of mutant BRAF. Hopefully these agents will translate into improved efficacy for patients with BRAF mutant melanoma

    Richard Joseph, MD

    Mayo Clinic

    Assistant Professor of Oncology


    Thanks keeping us updated, Dr. Joseph.

    The early tumors I had 5 years ago tested positive for NRAS G12A mutation. Not sure a test has been done since. It sounds like CDK4 inhibitors should be something I pay attention to.

    I read somewhere that using or combining a strategy other than checkpoint blockade (CTLA4, PD1) could be complementary, like CDK4 you mention. If someone’s fails PD1 would something like CDK4 e.g. LEE011 be worth considering as something using a wholly different mechanism (is that the case?) I’ve seen a number of people here/elsewhere say they’ve progressed on PD1, IPI and BRAF targeted therapy if they had that mutation, and they wonder if there’s anything else left to try.

    I’m about 3/4 through a combo trial with PD1 / Lirilumab now. The target lesion has been stable since about 4 months in. That wouldn’t show up as either a RECIST response or progression as far as I know. I wonder how many are in that status, i.e. getting benefit even if not in the “response” stats.

    I’ve also wondered if anything is happening with pan-RAF inhibitors that don’t require the v600 BRAF mutation. Don’t hear much of anything about those.

    – Kyle


    We can address these further questions in a future column. Glad this was helpful.

    Dr. Richard Joseph

    Asst. Professor of Oncology

    Mayo Clinic


    Definitely many want to know what the “next thing” might be. At one point IPI and PD1 were that.

    FWIW found these (I think) ERK trials for tumors including melanoma —

    Millenium MLN2480 https://clinicaltrials.gov/ct2/show/NCT01425008” class=”bbcode_url”>https://clinicaltrials.gov/ct2/show/NCT01425008

    Celgene C-90003 https://clinicaltrials.gov/ct2/show/NCT02313012” class=”bbcode_url”>https://clinicaltrials.gov/ct2/show/NCT02313012

    Found these (I think) CDD4 inhibitor trials (LEE011 and Palbociclib?):

    Novartis LEE011 https://clinicaltrials.gov/ct2/show/NCT02187783

    Novartis LEE011: https://clinicaltrials.gov/ct2/show/NCT01237236” class=”bbcode_url”>https://clinicaltrials.gov/ct2/show/NCT01237236

    Pfizer Palbociclib: https://clinicaltrials.gov/ct2/show/NCT02065063” class=”bbcode_url”>https://clinicaltrials.gov/ct2/show/NCT02065063

    Thanks again.


    Kyle, I just followed this thread from last month. I see you are in the PD1/Lirilumab trial, I believe I did the same trial (Anti-PD1/Anti-KIR) last year. It’s done with BMS – so the Anti-PD1 part is Opdivo. I had mixed results on this trial and stayed on from April 1, 2014 to end of August, 2014. Some tumors shrunk, others grew.

    However, I ended up getting pretty bad and then went for TIL at the NIH , but I was in too bad of shape to tolerate the treatment. Fortunately I had a good response to chemotherapy and then switched to the other PD1, called Keytruda. I was stable and felt good on Keytruda but after the 4 initial infusions showed some growth.

    I’m curious now, as you asked, what are people doing once you have failed PD1 (both brands), IPI, and BRAF inhibitors? Are any patients still eligible with any of these combinations? Seems to me, at least in trial setting, once patients have been exposed to a drug you can’t revisit it.

    Currently I am out of options, and I’ve been pressing my docs to give me a second chance on Dabrafenib/Tremetenib combo – which is FDA approved. I was on BRAF drugs 3-2 years ago successfully on Zelboraf. I’m hopeful I can shrink some of the tumors at least, but my oncologists seem to think a second round of BRAF inhibitors are unlikely beneficial.

    Let me know how things play out for you. I’d like to see more info about the CDK4 and also about the pan-RAF drugs as well. But I don’t see much.





    Not sure your looking for suggestions and i know this doesn’t sound very promising but on another forum i go on there is a patient of Dr Adi Diab at MD Anderson that was sent home with no options left to try at the hospital he was at. Dr Diab Started him on yervoy after he had failed it and also failed pd-1. The man has over 30 tumors liver, lungs, subcutaneous etc, Also 4 brain mets. He recieved stereotactic for brain and the 4 infusions of ipi. He has responded very well with all tumors shrinking significantly. Dr Diab told him ipi has shown to work a second time around. Just a thought. I’m also being treated at university of Chicago by Dr Luke. Just wanted to wish you well. I’ll be there next Tuesday to see Luke.

    Good luck,



    Shane, I read your message about what you’ve been having to deal with, post-TIL. I guess it’s crazy what need and desperation can drive someone to endure. But even so you weren’t planning on dealing with that. I can’t believe what you’ve been put through.

    I’ve been continuing in that BMS trial with stable disease, not growing or shrinking. The final cycle would end in January.

    I hope you’ll beat back that infection soon. Damn the torpedoes — there must be a trial somewhere that you’ll meet the criteria for and be accepted in.


    Shane, I am not personally recommending this by any means, I guess it is a bit risky as it is still in phase I, never tested on humans before, but I wanted to share, maybe it is worth considering as they have sites in USA.


    I heard for CEACAM1 through my university professor, who had melanoma 5-6 years ago. Dr. Schachter from Israel was treating him, he did many sessions of Ipilimumab, had several operations and did TIL treatment in Tel Aviv. At that time, dr. Schachter was talking to him that he has brilliant young doctor in his team, who is on the verge of discovery of new medicine. His name is Gal Markel, and CEACAM1 medicine was developed under cCAM Biotherapeutics company, which was recently acquired by Merck:


    Once again, I am not propagating this and I do not know about efficacy and safety of the medicine, my professor told me this story as he was cured by Dr. Schachter and naturally he trusts him and his team a lot, but it does not mean anything, this may be either a shot in the dark or revolutionary discovery.


    I think Gal Markel is brilliant – here is his TED talk : https://www.youtube.com/watch?v=tzaUfM0MfaQ


    Thanks for the info and links to new trials. I will keep an eye on these. Kyle, I didn’t realize you were 3/4 done through your whole trial – I thought you had 3 out of 4 infusions done in your first cycle. It’s interesting to see what to do comes in January.

    As for me, fortunately, I seem to continue to improve of late, and the doctors are giving me the ok to start on the BRAF combo Dabrafenib/Tremetenib. Will start Saturday or Monday. Because I’m on antibiotics, hospitalized, and still not fully ambulatory, I’m not a candidate for a trial. Best and quickest option for me is to hope I get a response to the BRAF combo and get better. Then hopefully we can reassess at later date. I’m nervous about this because it’s my second go-around – I did Zelboraf for the whole year of 2013 before failing.



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