Selumetinib in children with recurrent or refractory low-grade glioma

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Published: 4 Jun 2017
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Dr Jason Fangusaro - Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, USA

Dr Fangusaro speaks with ecancer at ASCO 2017 about the results of a phase II multicentre prospective study of the efficacy of the MEK I/II inhibitor selumetinib in children with recurrent and refractory low-grade glioma. There was a 30-40% response rate in patients for whom multiple previous therapies had failed.

He notes that selumetinib was fairly well tolerated by patients. The most common toxicities were Grade 1 and 2, and included nausea, diarrhoea, asymptomatic CPK elevation, rashes and paronychia.

Other arms of the trial have been expanded based on results in the early groups. Dr Fangusaro is hopeful selumetinib will soon be used as a first-line therapy.

The trial is conducted by the Paediatric Brain Tumour Consortium, an NCI funded group overseen by CTEP.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

I am presenting some very exciting research, it’s a phase II study looking at a drug named selumetinib which is a MEKI/II inhibitor in patients with recurrent and refractory low grade glioma, particularly children. So it’s one of the first targeted biological therapies that we’re using in children with low grade glioma and we’re very excited about it because the data is very optimistic. So we’re seeing lots of responses in children who have a particular abnormality in their tumour that this drug targets and then children who have a diagnosis called neurofibromatosis which is a genetic disorder. They’re often predisposed to developing brain tumours, typically low-grade gliomas, and they’ve had excellent results. So we’re seeing in a group of patients who have failed multiple therapies close to a 30-40% response rate which is pretty much unheard of so we’re very enthusiastic.

Could you tell us more about the mechanism there? You said it was a MEK inhibitor and we’ve heard lots about RAF MEK and other indications before.

Yes, it’s a drug. We know that these tumours, these low grade gliomas, seem to be activated by this MAP kinase pathway and what this drug does is downstream of an oncogene called BRAF is called MEK, so it blocks the downstream target of BRAF called MEK and it blocks both forms of MEK, MEKI and II. That seems to, for whatever reason, dysregulate the MAP kinase pathway and lead to tumour regression.

The inevitable question there is what about toxicity, because it will happen.

Yes, it’s a great question and it’s an important one for us because so far we’ve been using standard cytotoxic chemotherapy for these children and radiotherapy and those obviously have acute and late effects. So this drug is fairly well tolerated, most of the side effects are what we classify as grade 1 and 2 toxicity, so they’re fairly well tolerated. The ones that we see commonly are a little bit of nausea and vomiting, some diarrhoea, there’s some elevation in a blood level called CPK but it’s usually asymptomatic. The ones that become probably the most difficult and are tolerable are rash, so children can get a kind of non-descript rash or an acne-like rash, and then also they can get something called paronychia which is an infection or irritation of the nail bed, most commonly in the toes.  Those oftentimes will need antibiotics or rest from the drug and some of those children will need a decrease in the dose of the drug. But even when they’ve needed to decrease the drug it seems to still be effective for many of those children.

Do you think this could then go on to be useful outside of the low grade gliomas for children, looking at either adult patients or other indications?

I’m not an expert on all of those areas but there are many studies ongoing looking at adult cancers; I believe there are some large colon cancer studies that have recently completed. We’re also looking at it where it’s been very effective is in that same group of children with the genetic disorder neurofibromatosis, outside of brain tumours they also develop something called plexiform neurofibromas which are growths usually on parts of their body, it can be their arm, their thigh, it can be in their orbit. This drug has been used to decrease the size of those growths and it’s been very effective. Historically even classic chemotherapy has never really shrunk these lesions and now these lesions are shrinking and the quality of life and the disfigurement in these children has improved greatly. That’s work that has been recently published in The New England Journal of Medicine by Dr Brigitte Widemann from the NCI. So that’s very exciting and along with our group of patients with neurofibromatosis we really feel for many children but particularly for those children there seems to be a very specific indication and benefit.

Are there plans for expansion, further recruitment or taking this forward to another stage of trials?

That’s a great question. The trial that we are evaluating there are other arms besides the children with neurofibromatosis and the children who have low grade glioma with the BRAF aberrations. There are a few other arms and we recently found out in the last week that those have been expanded because there have been enough responses in the early groups of patients. So even in children with pilocytic astrocytoma, which is the most common type of low grade glioma in children, who don’t have the two most common BRAF aberrations we’re seeing responses. What that suggests is that even though we’re not seeing the most common abnormalities there are probably other abnormalities in the MAP kinase pathway and because of that, even though we haven’t detected it or looked for it, the drug is effective in those patients.

We’re also looking at a group of patients with not pilocytic astrocytomas but other low grade gliomas such as things called ganglioglioma or xanthoastrocytoma. That group of patients, who have the BRAF aberration, when we’ve tested the drug they’ve had responses as well and now that has recently expanded to include more patients. But probably your bigger question and what I’m most excited about is we’re really working with the drug company to start thinking about using this drug as a first line therapy in children with newly diagnosed low grade glioma, particularly that group of patients with neurofibromatosis. Ideally, if I had my druthers, we would do a comparison directly with the standard, gold standard, carboplatin vincristine which is the chemotherapy that’s classically used and do a head-to-head comparison. If we can show that it’s just as effective and less toxic it could ideally become the new standard of care. I’m projecting a little bit but that’s my optimism, as a paediatric neuro-oncologist it kind of comes through.

Optimism is a byline at ASCO, it’s what we’re here for.