Home Forums Melanoma Diagnosis: Stage IV Newly diagnosed melanoma stage IV- Zelboraf+IPI?

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    I am 34 years old and generally in good health. I like to run long distance runs and I even participated in the last Tel Aviv marathon on March 2013.

    Last month I was diagnosed with a Metastatic Melanoma at Stage IV with metastasis in the liver, bones, lungs and spleen, following a back pain felt for a few weeks prior to the diagnosis. The disease progression has been very fast and aggressive. Within 3 days of the diagnosis my physical condition deteriorated to the point of not being able to walk and hardly being able to get up from bed.

    Since my Melanoma was tested positive for the BRAF mutation, I was immediately treated with Vemurafenib (Zelboraf). The clinical improvement was immediate. Currently, the liver function tests returned to normal values including most of the CBC tests and LDH levels. I can now walk normally again .

    In my last meeting with my oncologyst regarding the next treatment steps it was made clear to me that due to the aggressiveness of my Melanoma, the treatment possibilities are very limited. He strongly suggested to combine Ipilimumab (Yervoy) with Zelboraf since once a resistance to the Zelboraf will be developed there is a high risk the Melanoma will aggressively strike again not giving the time to receive a response from Yervoy. I read that such a combination might create liver toxicity.

    I wanted to ask if such a combination has been tried before and what were the results.

    I would appreciate any comments regarding such a combination or a method that can be applied before Zelboraf resistance is developed a point that might be too late for any treatment.

    Thank you very much,


    Catherine Poole

    Hello Michel,

    Sorry to hear of your bout with melanoma. You are correct that the trial combining zelboraf with yervoy was halted due to liver toxicity. However the sequential trials have resumed, whereas you do one agent and then follow it by the other. I would like you to think about the PD1 trials available in Israel. You would need to do Yervoy (15-20 response) first I believe and progress. There are currently three trials accruing for PD1 (38% response): Haifa, Jerusalem, and Ramat Gen. So I would give the Yervoy a try and see how it works for you. But I agree, that combining them is not a good idea.


    Thank you very much for your answer.

    It seems that stopping the zelboraf can be very risky due to the Melanoma aggressiveness. My oncologist made it clear to me that until the yervoy will have an effect the tuomor might errupt again. Is there any experience in combining these two treatments maybe by reducing doses or something similar? I know that the literature does not support such a protocol by I wonder how can I combine the Zelboraf with any other treatment that has a long response time.

    Thank you for the information about the PD1 trials in Israel. They all require Yervoy resistance (meaning halting the Zelboraf) but my tumor aggressiveness does not allow me to take this chance, this is why i am looking at the possibility of combining the Zelboraf and the Yervoy.



    Catherine Poole

    I might guess that reducing dosage of both would lower toxicity. But I am not a doctor expert in this matter. So discuss your concerns with your doctor further and maybe get another opinion. If you progress on both, you would then be eligible for the PD1 which acts fairly quickly. I would possibly at least get on the list for those trials, although you would need 20-30 washout.


    Hi, Michel!

    From what I know and experience the best melanoma team for Stage IV is Ella Institute in Tel Hashomer. Clinical trials for Ramat Gan are for this institution. The only downside is that this place is overloaded, but it is nuts!

    Who is treating you?

    P.S. TIL therapy is also available there as a last resort.

    P.P.S. Your story reminds mine so much…


    P.P.P.s. there was a clinical trial( Phase I) of combining Vemurafenib and Ipillimumab. It was halted early due to the liver toxicity.


    Hi, Michel-

    I can see that you are in a difficult situation right now– very aggressive tumors but also wanting to go for a longer-acting immune therapy like Yervoy. As I recall, not everyone who was in the BRAF + ipi trial experienced liver toxicity– I think that about 30% did and another 30% got severe skin rashes–both of which were reversible when the patients stopped taking the medications.

    I expect that what you want to do is to shrink the melanoma tumors enough that you could risk going through a wash-out period and then an immune treatment– either anti-PD1 as Catherine suggested or the Yervoy your oncologist suggested. I wonder if it is possible in Israel to take a BRAF inhibitor and a MEK inhibitor at the same time. Both of those drugs were just approved in the US as single agents. Doctors here can prescribe both at once (called an “off label” use) but most US insurance companies won’t pay for both at once. We hope to have the combination FDA approved soon so insurance companies will pay for it.

    The good thing about taking BRAF+MEK is that the combination acts like a 1-2 punch against the melanoma. The combination works in more patients than does either drug alone and with fewer side effects. Tumors shrink more and the effect lasts longer than either drug alone. If you could take BRAF+MEK for a month or two perhaps you would be in a better position to switch to an immune-based treatment.


    The timing of IPI and Braf inhibitors has been the topic of intense discussions in the oncology community for a while.

    My impression is that for aggressive disease and/or individuals with extensive disease, use the Braf drug first to reduce tumor load quickly and prime the immune system with the antigens that are produced as the tumors die off. Then induce with IPI to ramp up the immune system T cell response to those antigens. My gut feeling is that this may help delay spread to the brain but that’s just a W.A.G.

    The key would seem to be the timing of the two treatments(like everything in life, I guess). Braf works quickly but typically resistance to it is developed by the disease some months into the treatment. IPI seems to need at least two to three infusions to begin the deregulation of the immune system and ramp up of the T cells, takes 9 weeks to complete all four infusions, and then you watch and wait.

    So, if it were me, I wouldn’t want to wait to see if I’d progress on the Braf before starting the IPI, especially if my disease is deemed aggressive. I’d like an overlap of the two if it were me, maybe IPI a few months after starting Braf. Then, in the mean time, set myself up to get enrolled in a PD1 trial. A layered approach.

    But it’s not me. Everybody is different in what they feel comfortable with and your course of action is a highly personnal choice. But I do know that this damned disease needs to be treated aggressively and smacked down early and often.

    I hope this helps.



    Thank you for all your comments!

    Im treated in “Sheba” hospital but Unfortunately because I started taking Zelboraf there isnt a tumor that fits to take the TIL from.

    It seems like the combination of the 2 drugs (IPI + Zelboraf) are my only option, therefore I would like to know if someone else tried the same protocol? and if so how was it implemented?


    I totally agree with Jeff. You need to attack this disease more aggressively than it attacks you. Pursue all possible treatments as early as possible. Fear of toxicity fears be damned! Good luck and God bless.

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