Dabrafenib plus trametinib significantly increases overall response rate in paediatric low-grade gliomas

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Published: 6 Jun 2022
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Dr Eric Bouffet - The Hospital for Sick Children, Toronto, Canada

Dr Eric Bouffet speak to ecancer about his study findings, where he found two targeted therapies, dabrafenib (taflinar) plus trametinib (mekinst), significantly increased the overall response rate compared to the standard-of-care chemotherapy combination of carboplatin plus vincristine in paediatric patients with BRAF V600 mutation-positive low-grade gliomas.

The next steps for this study are that researchers hope to learn more about the optimal duration of treatment.

Also, the researchers hope to determine if this treatment fits into the World Health Organisation (WHO) global initiative for childhood cancer.

Read the news story here

Watch Dr Bouffet's press conference video here

Watch Dr Hudson comment on the study here

 

At this ASCO meeting I’m presenting on the results of a randomised study of targeted treatment,

dabrafenib plus trametinib, versus chemotherapy in children with low-grade glioma associated with a

BRAF V600E mutation. It needs a bit of background, obviously, about low-grade glioma, about the

mutation. Low-grade glioma is by far the most common paediatric brain tumour. It is benign, it is low

grade but the behaviour is very diverse depending on a number of factors: first, resectability –

whether the tumour can be removed or not – and, second, response to treatment when the tumour

cannot be resected. The common treatment in paediatric low-grade glioma when the tumour is non-

surgical is chemotherapy. The response to chemotherapy is very viable and there are many factors

that can affect the response and, in particular, the molecular biology of the tumour. Within the

spectrum of molecular alterations, BRAF V600E mutation accounts for 15-20% of the mutations and

is associated with a lower response to chemotherapy, a shorter response to chemotherapy and a

higher risk of transformation to higher-grade glioma.

 

In this context drugs that target the BRAF V600E mutation but have been developed first for

melanoma patients and non-cancer patients have been tested in this tumour type. We have

conducted phase I and phase II studies that have shown safety and efficacy. So this was the last

stage of the study which was is this combination of dabrafenib and trametinib better than the standard

treatment. So this was the rationale for this randomised study and this was an international study that

was conducted in Europe and North America and with a profile that was a 2:1 randomisation – two

children treated with targeted treatment versus one with chemotherapy. A total number of 110

patients. The principle was to treat patients who were chemotherapy or treatment naïve as a first line

treatment.

 

The study accrued over a short period of time, over a period of two years, and we have now results

after a follow-up of nearly 19 months. The results are very, very exciting. First I have to say that the

criteria that have been used were very stringent. We used the RANO criteria but there was also

central review that was very, very stringent. I will present the results from the central review. There is

some discrepancy between the investigator assessed response and the central review that is causing

some issues. But, basically, what we see is a clear benefit of the targeted treatment versus

chemotherapy in many aspects. First, in terms of response rate with a response rate which is 47% in

the targeted treatment arm versus 11% in the chemotherapy arm. Response is more than 50% and

up to complete response but when we see the decrease in tumour size overall we also see a large

difference with nearly a 90% decrease in tumour size in the targeted treatment arm versus around

60% of the tumour that decreases in size in the chemotherapy treatment.

 

When we look at the event free survival, the event free survival at one year is 66% in the targeted

treatment arm versus 26.1% in the chemotherapy arm – a major difference which shows that for the

first time we can see that a targeted treatment is providing better results than chemotherapy.

 

The safety profile is also interesting to look at. The toxicity of the chemotherapy is essentially on

haematology – neutropenia, anaemia and thrombocytopenia – whereas the toxicity of the targeted

treatment is mostly general toxicity – fever and also skin reactions that are classical with this type of

medication. But when we look at the quality of life that has been measured during the study we see

that the quality of life of the patients who are on targeted treatment has been stable throughout the

study whereas the quality of life of the patients who were on chemotherapy had seen a gradual

decrease.

 

So overall we can say that this is the first ever randomised study of targeted treatment in children with

low-grade glioma, or in children with brain tumour, that for the first time is showing a clear advantage

of the targeted treatment. A very exciting prospect because we can anticipate now a gradual switch

from the standard chemotherapy management to a more targeted treatment in paediatric low-grade

glioma. The first one is this subgroup of patients with the BRAF V600E mutation but we can anticipate

that there will be more to come because we know that there are many other alterations that are seen

in paediatric low-grade glioma and targeted treatment that can be used for this, using the same

design as this randomised study.

 

I want to say that it’s not really specific of the paediatric population and that’s also an important

message because life doesn’t stop at 18 years old. In fact, when we look at this population first we

can see that these patients, with the treatment that we offer, live longer and their life expectancy is

relatively good. They may need treatment during adulthood if the tumour is still active. But we also

identify, and we have identified in a number of adult patients with low-grade glioma, the same

characteristics as we see in paediatric low-grade glioma with also a number of patients who have the

BRAF V600E mutation. So the result of this paediatric study can certainly apply to adult patients. So

we hope that this will be taken into account when the drug will be considered for approval, that it’s not

going to be limited to a specific population because this is more a broad result that can also impact on

the general oncology practice.

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