Home Forums Melanoma Diagnosis: Stage IV BRAF inhibitor working – stick with it or add MEK inhibitor?

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  • #21395
    Johnfdc7
    Participant

    Hi

    Just wondering with the recent approval of the GSK BRAF inhibitor (Dabrafenib/Tafinlar) and the GSK MEK inhibitor (Trametinib/Mekinist), has any of the long term BRAFi users here proactively sought to add the MEKi to their Zelboraf/Tafinlar treatment regime.

    I realise that the drugs were approved by the FDA individually but studies show that used in combination their effective period is almost twice as long as the BRAFi alone. The combo also showed reductions in some of the more serious skin-based side effects.

    http://www.nejm.org/doi/full/10.1056/NEJMoa1210093?query=featured_home#t=article” class=”bbcode_url”>http://www.nejm.org/doi/full/10.1056/NEJMoa1210093?query=featured_home#t=article

    I think I saw an ASCO abstract (sorry no link) that suggested disappointing results when the MEKi was added once BRAFi failed. A bit of dilemma – stick with a regime that is currently working or be proactive based on some of the clinical data that is out there?

    #61456
    Catherine Poole
    Keymaster

    Great post and question I will pass along to our scientific board, many of whom wrote/conducted that study. I however, did not see where using the combo of braf/mek doubled response time, nor have I seen that in the literature. I agree, that once you have responded to braf and then progressed, adding Mek probably won’t help the response. But let me ask the experts for you.

    #61457
    Johnfdc7
    Participant

    Thanks Catherine – it will be interesting to see the expert’s viewpoint on this.

    In the link to the study above conducted by Flaherty et al , the K-M curves in Figure 1 show the median PFS for the monotherapy with BRAFi therapy alone is 5.4 months while the median PFS for combined BRAFi/MEKi (150mg/2mg) is 9.4 months. I may have been a bit loose with the term “double” but the PFS is significantly longer.

    #61458
    Catherine Poole
    Keymaster

    You are correct. From Keith Flaherty, chair of our scientific board: “Yes, the data supports the statement that combined BRAF/MEK inhibition creates responses that last twice as long as single agent BRAF inhibitor therapy. The idea of adding Mekinist (the now approved MEK inhibitor) to BRAF inhibitor therapy is supported by this evidence, but not yet confirmed by the larger phase 3 trials, one of which is now completed but for which the data is still awaited. For that reason, insurance companies are under no obligation to cover too drugs at once and may well take issue with the idea of doctors prescribing both a BRAF inhibitor and a MEK inhibitor at the same time.”

    It may be they only allow these two agents to be combined, but not zelboraf and trametinib because of lack of data on those two.

    #61459
    Johnfdc7
    Participant

    Thanks Catherine – that’s a very interesting response and may prompt some thinking for those of us currently on BRAFi therapy. It will be interesting to see the Phase 3 results and whether they confirm the increased PFS rate.

    So many questions;

    Should we always be proactive about our therapy or stick with what is working?

    If insurance cover is an issue, should somebody on Zel consider switching to the other BRAFi drug to be eligible for the combo?

    If somebody is responding to Zel does that mean they will continue to respond as well to the new BRAFi drug if they were to switch? (unknown, I suspect).

    I guess these are the sort of questions that always arise when new drugs are approved and really only get answered as Oncs gain experience of using them over time

    Thanks again

    #61460
    Catherine Poole
    Keymaster

    John,

    Great insightful questions again, but I don’t have answers yet. I hope to soon. Yes, the process of approval and prescription will tell us more shortly. I would hold steady until it is being prescribed, I’m told next week it should begin.

    #61461
    bettin
    Participant

    Hi John,

    the data suggests that the combination therapy delays the development of resistance, so makes it harder for the tumor to find an escape route around the pathway blockage you impose with the BRAF inhibitor.

    As you’ve seen, once the resistance is in place, the addition of a MEK doesn’t seem to bring much benefit- so preventing/ delaying resistance build-up seems to be a much smarter strategy.

    In the US, GSK BRAF and MEK inhibitors are now approved as mono-therapies. If you look at the trial data and considering the fact that GSK has filed the COMBINATION THERAPY for approval in Europe, I think that the question whether the combo is superior to mono-therapy has been answered.

    Melanoma therapies have been evolving so quickly so that unfortunately, we don’t have the perfect way through it. So in a situation when you are confronted with a terrible diagnosis you paradoxically get to make treatment choices with major impact on your life. And as you don’t have a control group for yourself, you’ll never know whether you’ve made the best choice. When Peter was diagnosed with Melanoma, we decided that we’d do all the research we could, make a decision and never look back.

    Strictly speaking, there is no hard data saying that if you are responding to a BRAF inhibitor, adding a MEKi will delay resistance compared to staying on the BRAFi alone. (From the data we have my personal opinion is that it will, and the earlier you are in the course, the larger the effect- besides, would YOU want to be on a trial like this?!! There are luckily ethical limits on scientific curiosity). So you can wait until someone designs a trial to test this- or get an oncologist to prescribe you both drugs. As the combo works longer with fewer side effects and there were no reported disadvantages of adding a MEKi to a BRAFi, I know what I personally would choose!

    Wishing you all the best,

    Bettina

    #61462
    Johnfdc7
    Participant

    Hi Bettina – very good summary of the dilemma there. I guess we should be grateful for these dilemmas – we wouldnt have been concerned with these only a few years ago! I’m in agreement with your conclusion too.

    #61463
    Johnfdc7
    Participant

    Hi All

    Just an update to my original question here.

    After 8.5 months on the GSK BRAFi Tafinlar (Dabrafenib), we have this week (after much discussion) added Mekinist (Trametinib) to the treatment mix – so now on the combo. Feeling is that it was better to do this now rather than wait until Tafinlar stops working.

    Up to now the Tafinlar on its own has been extremely successful at eradicating some body mets, reducing other body mets, stabilising brain mets (along with SRS) so I’m hoping for continued good news.

    One slight blip is most recent brain scan shows a little more activity around site of one of brain mets that previously received SRS vs last scan – so more investigation required here to ascertain if we are looking at regrowth or radiation effects

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