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For Tim re NRAS Mutation – help on the way

Forums General Melanoma Community For Tim re NRAS Mutation – help on the way

  • Post
    Bubbles
    Participant
    This new and improved MPIP is sooooooooooooooooooo far from it.  I was not allowed to post this on your thread, Tim.  So – trying again this way:

    Hey Tim,

    Hadn’t heard of this KRAS advance for NSCLC.  So…I read up on that.  Then I found this (granted it is old – circa 2010!!) –

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896549/

    As noted at the start of this report, I fear this is a very important point as in regard to KRAS treatment for melanoma patients – “The small G-protein NRAS is mutated in 22% of human melanomas, whereas the related proteins, KRAS and HRAS are mutated in only 2% and 1% of melanomas respectively.”

    However, there is this pretty cool report from last year:  https://www.frontiersin.org/articles/10.3389/fmolb.2020.00172/full  In the section under KRAS, much like the other report, the authors note:  “In melanoma, KRAS mutations are rare (1.7% of our cases)…”  “In cutaneous melanoma, NRAS is mutated in about 15–30% of cases, while KRAS (∼2%) and HRAS (∼1%) play a minor role…”

    They note: “The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.” 

    And regarding treating NRAS in particular –
    <p class=”mb15″>“To date, therapeutic inhibition of RAS remains an unmet need. Indeed, there are no approved therapies that specifically target NRAS, KRAS or HRAS and RAS-mutated patients are usually treated with immunotherapy. However, several trials are ongoing.</p>
    <p class=”mb15″>Several years ago in vitro studies had already shown that mutated NRAS melanoma cells were sensitive to MEK inhibitors. However, the efficacy of such drugs on mutated NRAS cells was lower than that observed in mutated BRAF cells, and this lower efficacy could be explained, at least in part, if we consider the complexity of the molecular pathways network involving RAS. From these observations, two hypotheses arose: first, that probably a therapy based on a single drug could be insufficient; second, that the best therapeutic possibility was to target RAS directly. Unfortunately, targeting directly RAS did not give the expected results. Indeed, acting on GTP binding pocket in RAS protein is difficult due to the excessive affinity between RAS and GTP . In the same way, the inhibition of farnesylation of a cysteine residue, a post translational modification necessary to RAS insertion to the plasma cell membrane, has proven ineffective. Due to these disappointing results, the therapeutic strategies for mutated NRAS melanoma reverted on MEK inhibitors.</p>
    <p class=”mb15″>Initially, the use of MEK inhibitors led to modest results, with an Overall Response Rate (ORR) of 10% and a high incidence of adverse events. Subsequently, the MEK 1/2 inhibitor selumetinib (AZD-6244) was developed. Phase I trial enrolled 11 melanoma patients and showed promising results; on this wave, phase II trials comparing selumetinib and chemotherapy (temozolomide and docetaxel) in BRAF-WT and NRAS-unselected melanoma patients were initiated. The results were unsatisfactory for both trials, with no difference in efficacy outcomes.</p>
    <p class=”mb15″>Later, other MEK inhibitors were developed. Binimetinib (MEK162) is an allosteric, selective, non-ATP competitive MEK 1/2 inhibitor.</p>
    <p class=”mb15″>In preclinical studies binimetinib inhibited the growth of NRAS and BRAF mutated melanoma tumor cells. In the subsequent phase II trial, MEK162 obtained an ORR of 14.5% and a Disease Control Rate (DCR) of 56%. Median Progression Free Survival (PFS) was 3.6 months, underlying a rapid development of resistance, and the median OS 12.2 months. Phase III trial (NEMO)  compared the efficacy of MEK162 versus dacarbazine in 402 NRAS mutated, melanoma patients. The ORR was 15% in the binimetinib arm versus 7% in dacarbazine arm. Furthermore, binimetib significantly prolonged median PFS, with 2.8 months [3.9 in patients with normal lactate dehydrogenase (LDH)] versus 1.5 months, respectively [hazard ratio (HR), 0.62]. Interestingly, immunotherapy pretreated patients had a longer median PFS (5.5 months). However, no differences in terms of OS were noted, and binimetinib as single agent did not receive regulatory agencies approval for the treatment of NRAS-mutated melanoma.</p>
    <p class=”mb15″>Finally, pimasertib (PIM; AS703026) has been evaluated in a phase I trial with encouraging results. Phase II study enrolled 194 patients to be treated with pimasertib or dacarbazine. Results showed a significant benefit for pimasertib, with a median PFS of 13.0 versus 6.9 weeks and a DCR of 37.7% versus 26.6%. Unfortunately, no difference in OS was showed (8.9 vs. 10.6 months).</p>
    <p class=”mb15″>Combination of MEK inhibition with other targets is currently being evaluated. Among all, the results of a combination trial performed on 14 patients treated with ribociclib (LEE001) and MEK162 are particularly interesting. Indeed, the combination obtained six partial response and six stable disease, with a DCR of 85%.</p>
    <p class=”mb0″>As we mentioned before, NRAS has to undergo some post-translational modifications, like farnesylation. Farnesyl Transferase Inhibitors (FTIs), like lonafarnib, was developed in an attempt to exploit this phenomenon. FTIs inhibit the function of RAS and seem to be able to sensitizing melanoma cells to RTK inhibitors like sorafenib. Unfortunately, FTIs failed in clinical trials showing no efficacy against NRAS and KRAS-driven cancers . The reason of this failure seems to be due to the action of geranylgeranyltransferase I (GGTase I) in the alternative prenylation. FTIs in combination with GGTase I inhibitors have been tested in clinical trials but turned out to be too toxic. Other approaches attempting to inhibit some post-translational modifications are currently being evaluated. However, the great limit remains the toxicity of these drugs and challenges in delivering siRNA using nanoparticles.”</p>
    Still, there is good info here.  The ‘out-of-the-box’ evaluation of tumors in difficult to treat melanoma patients has led to success via atypical drugs.  We have one patient (a male, just so happens) on this forum who has responded well for many years on drugs typically used for HER-2 breast cancer.  In your case the KRAS therapy may be the ticket if your tumor shows that mutation.

    But, the more easily attained option of ipi/nivo (since it seems that you did nivo as a single agent) may provide you with the treatment you need.  There are many studies demonstrating that NRAS patients DO respond to the combo.  And as you note, other NRAS patients have a good response to MEK inhibitors.  Here is a report I put up in 2018 with links to other reports within:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/2018/06/another-possible-option-for-nras-mutant.html 

    I am far from an expert on this.  You are staying on top of things and learned about it before I did!  However, that’s my take and what I would be thinking about and asking my onc about were I in your shoes.  Hope that helps.  Celeste

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  • Replies
      tim brown
      Participant
      Thanks  Celeste/Bubbles, you are a star.
      Tge complexity of the RAS pathway is mind boggling and let’s hope advances in AI can open the door to our particular knave- NRAS

       

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      Bubbles
      Participant
      Yes, this development is certainly a boon for NSCLC patients since a greater percentage of them carry this mutation.  Further, every break through – once thought impossible – is a boon for all cancer patients; teaching researchers more with every advance.  Hopefully, it will bring benefits to melanoma patients and many others.

      Ratties and researchers will take us much further than where we are today!  Hang tough.  Yours, c

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