Home Forums Melanoma Diagnosis: Stage IV Systemic Treatments for Brain Mets

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  • #21281
    Catherine Poole
    Keymaster

    I’ve been bothered lately by many statements that certain therapies from TIL to IPI to BRAF drugs were effective against brain mets. I’ve not seen this in the scientific data so I turned to our scientific board member with this expertise and here is her response:

    There are clearly anecdotal reports of all of these agents having some effect on the brain metastases – they just can’t be relied upon to provide complete or durable response especially when compared with radiosurgery. We believe that in ipilimumab, the CNS mechanism is in fact that the primed T-cells do cross into the brain and can be effective.

    for Vemurafenib we are in fact starting up a trial looking to see if we we can use it to shrink lesions before definitive radiosurgery thus trying to cut down toxicity.

    a similar trial may be starting soon for anti-PD1.

    #60777
    kylez
    Participant

    Thank you for asking, posting about and researching brain mets, Catherine.

    The paucity of phase III (especially) clinical trials that accept active brain mets, I guess makes everything about this subject anecdotal. And even rarer (non-existent?) would be any trial that combines radiation with systemic treatments — while doing that would likely be no worse than radiation (and/or resection) alone, would that be viewed as introducing too main variables to even begin to analyze the trial results?

    I remember reading somewhere that of melanoma patients who unfortunately passed away, at autopsy the majority had known or unknown brain mets. From a patient’s point of view (as opposed to that of a trial designer), shouldn’t real world studies of sytemic treatments include active brain mets? And for that matter, radiation tx being part of the real world too, shouldn’t simultaneous treatment with either radiation and/or resection be allowed too? Or are such trials simply impossible to design?

    Likewise , with (very new) treatments now available, could those now be used in different arms for brain mets patients, rather than a placebo or DTIC arm? But I guess this is all very complicated to devise trials for. But is it totally impossible? Either today or at some point in the future?

    Here’s a few brain met + systemic treatment articles, but as you say, none of these are blinded phase III trial results. Some include Dr. Rosenberg as an author — I will be excited to listen to your upcoming webinar with him, in part because his work on IL-2 and immunotherapy is almost certainly a major part of why I’ve been able to stay alive.

    Successful Treatment of Melanoma Brain Metastases with Adoptive Cell Therapy (Rosenberg et al): http://www.ncbi.nlm.nih.gov/pubmed/20719934” class=”bbcode_url”>http://www.ncbi.nlm.nih.gov/pubmed/20719934

    Study of Ipilimumab to Treat Melanoma in Patients with Brain Metastases: http://clinicaltrials.gov/show/NCT00623766” class=”bbcode_url”>http://clinicaltrials.gov/show/NCT00623766

    Safety and Efficacy of High-Dose Interleukin-2 in Patients with Brain Metastases: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424228/” class=”bbcode_url”>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2424228/

    Melanoma Drug GSK2118436 Shrinks Brain Metastases in Australian Phase I/II Study http://oncozine.com/profiles/blogs/melanoma-drug-gsk2118436” class=”bbcode_url”>http://oncozine.com/profiles/blogs/melanoma-drug-gsk2118436

    Abstract B234: LY2835219, a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts: http://mct.aacrjournals.org/cgi/content/short/10/11_MeetingAbstracts/B234?rss=1” class=”bbcode_url”>http://mct.aacrjournals.org/cgi/content/short/10/11_MeetingAbstracts/B234?rss=1

    #60778
    Catherine Poole
    Keymaster

    The problem with these studies is not just they aren’t phase III randomized, but they are such small samples of melanoma patients. For instance, the one by Rosenberg/TIL has 26 patients.

    I would give your own immune system credit Kyle, since IL2 has a low response rate in 94% of the population. You must be part of the 6% who respond. I am always happy when that happens but lean towards the less toxic therapies and certainly all of these new ones hitting the pipeline!

    One additional note, about Rosenberg’s trials is he sometimes criticized by the scientific community for only allowing the healthiest to participate in his trials which of course could skew the results.

    #60779
    benp
    Participant

    Hi Catherine,

    I think it is known that these articles kylez gives (and myself on a recent thread) don’t provide definitive, rock solid results. What they do show, however, is scientific proof that these therapies CAN show results for brain mets. Having brain mets is a very scary thing. Most of the time we can’t afford to wait for the rigorous randomized phase 3 trial results to come out. The fact that the treatments can be significantly beneficial is the main point, albeit it in retrospective, relatively small single institution studies. It may not show p << 0.00001, but would be p < 0.01. This is definitely "good enough" (for me, and I would imagine others with brain mets) when you know the existing pre-Ipi systemic treatments show dismal results for brain disease. Personally, my brain is very happy to have been the recipient of them! I look forward to hearing more about this during Rosenberg’s upcoming webinar. Thank you so much for organising these! Thanks, Ben.

    #60780
    Anonymous
    Guest

    I think this is a good discussion topic.

    There is also to consider how some of theses agents, such as IPI, may help to delay the onset of brain mets, which is huge from a trial entry point of view. Fortemistine, which is approved over in europe but not here in the states, has been shown to rather effectively delay brain mets over Temodar as it readily crosses the blood/brain barrier but it can have increased neurological effects, relative to Temodar, as a result.

    Good topic.

    Jeff

    #60781
    Catherine Poole
    Keymaster

    Jeff: I would like to see more information on fortemestine as well. My training with Dr. Guerry included the knowledge that no agent can truly cross the blood-brain barrier. Our bodies were engineered this way for a reason, to protect us. It exists for the testicular region as well. I am not not trying to dash anyone’s hopes as I would more than anyone like to see something work systemically for brain mets. But MIF is under the HonCode designation, as well as my own strict standards of not providing false hope. We need significant scientific proof to state an agent works for brain mets. For right now, the only definitive way to treat brain mets is through radiation and that is stated here by our expert neurosurgeon:. [quote][there are clearly anecdotal reports of all of these agents having some effect on the brain metastases – they just can’t be relied upon to provide complete or durable response especially when compared with radiosurgery/quote]The systemic agents so far have not worked in a large population of people.

    Yes, it does make for an interesting discussion, but always look at how the study is run, how many people were in the study, who paid for the study, and whether there was randomization and overall survival measured. Then you will know whether to believe it or not.

    #60782
    Anonymous
    Guest

    Catherine:

    Here is the Fotemustine study that caught my attention first showing a dely in brain mets where there wer’nt any befor but no improvement for brain mets that were there at the start of treatment:

    http://jco.ascopubs.org/content/22/6/1118.full

    And another:

    http://www.mdpi.com/2072-6694/4/1/77

    This one was funded by BMS combining Fotemustine and IPI but to me, the size of the study was a little small:

    http://www.ncbi.nlm.nih.gov/pubmed/22894884

    And this one was another combination but did not show any advantage for Fotemustine even for onset of brain mets but the drug was given rather differently that usual.

    And there was this retrospective study I picked up here:

    http://www.hindawi.com/journals/jsc/2013/735282/

    Eventually, fotemustine (Muphoran), a non-FDA-approved drug available in Europe, is known to rapidly cross the blood-brain barrier and to display encouraging activity in patients with brain metastases [80]. Also, in a phase 3 trial involving patients with metastatic melanoma () [81], fotemustine compared to DITC was associated with (i) an improved overall RR (15.5% versus 6.8%, resp.); (ii) a trend toward improved OS (7.3 versus 5.6 months, resp.); (iii) a longer median time to development of brain metastases (22.7 months versus 7.2 months, resp.) in patients without brain metastases at inclusion; (iv) a similar MDR (5.8 months versus 6.9 months); (v) a similar time to progression (1.8 months versus 1.9 months); (vi) a similar quality of life; (vii) more adverse events such as myelosuppression (i.e., grade 3 to 4 neutropenia 51% versus 5%, resp. and thrombocytopenia 43% versus 6%, resp.) and alopecia. Interestingly, a recent open-label, single-arm phase 2 trial (NIBIT-M1 study) is investigating the efficacy and safety of ipilimumab plus fotemustine in adult patients () with metastatic melanoma and with or without asymptomatic brain metastases [82]. As primarily results, this medicinal combination achieved disease control in 40 patients (46.5%) with metastatic melanoma, including those with brain metastases. Nevertheless, the treatment-related adverse effects (e.g., grade 3 or 4 myelotoxicity and hepatotoxicity) were present in 47 patients (55%).

    Again by itself, there seems to be little clear advantage to Fotemustine except maybe the onset of brain mets and it’s not approved for use in the US.

    But you’re right, the only treatment shown to kill brains mets outright is radiation.

    Jeff

    #60783
    benp
    Participant

    HI Jeff and Catherine,

    I agree this is a very good discussion topic. Targeted radiation does seem the best way by far to control local disease, much better than any of the above. Though comparing SRS/GK to the above systemic treatments is asking a very different question as to whether the above are able to effectively treat brain disease (systemically) in a suitably large proportion of patients. This issue becomes greater if there are several brain sites, and does not consider the fact that targeted radiation is not able to treat mets outside of the radiation field or prevent new lesions popping up. While the above does not definitively prove systemic efficacy in the brain, it comes very close to it.

    Thanks,

    Ben.

    #60784
    kylez
    Participant

    Here’s one of the 2013 ASCO abstracts, “Survival of melanoma patients with brain metastases treated with ipilimumab combined with stereotactic radiosurgery.” http://abstracts2.asco.org/AbstView_132_113893.html” class=”bbcode_url”>http://abstracts2.asco.org/AbstView_132_113893.html

    What the (of course) small (n = 30) study found was that overall survival of patients w/brain mets and treated with IPI + SRS, was comparable with OS of patients w/o brain mets, treated with IPI. I believe the benefits of IPI during or after SRS/resection will, eventually, be proven beyond anecdotal status, if a larger multi-institution version of this study could be done. IMO this deserve a high priority so that if proven, the combination could become, even for “brain met only” pts, standard of care.

    #60785
    kylez
    Participant

    Not to wear this out, but here’s one more article, from 2012, in the Journal of Neurosurgery proposing essentially the same thing, this time N=77 (again small). Authors include Mario Sznol and Veronica Chiang (of the MIF webinar).

    http://thejns.org/doi/abs/10.3171/2012.5.JNS111929” class=”bbcode_url”>http://thejns.org/doi/abs/10.3171/2012.5.JNS111929

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