This new analysis of the data from multiple previous clinical trials is already informing upcoming clinical trials like ‘Low Grade Glioma In Children’ (LOGGIC), which is being set up across Europe and the UK.
This analysis is the largest that has been done looking at the benefits of using trametinib to block the mitogen activated protein kinase (MAPK) pathway in this tumour type. MAPK is a key area for study because there are lots of changes within the pathway that are seen in low grade gliomas (LGG). One particular type of LGG, called pilocytic astrocytoma, has overactive MAPK in 100% of cases.
What did they look at?
Dr Till Milde, and his team at the German Cancer Research Centre (DKFZ) in Heidelberg, looked at data from 18 children, between the ages of six months and 10 years, who were given trametinib between 2015 and 2019. The analysis, published in the scientific Journal of Neuro-Oncology , combines molecular information about the tumours with images showing how the tumour responded and records of any reactions the children had to the drug.
What did the drug do to the tumours?
MRI images were used to assess changes in the volume of the tumour (how big it was). In each of the 18 children their best responses were noted, six had a partial response (PR; a reduction of more than 50%) two had a minor response (MR; a reduction of 25-50%) and 10 stable disease (SD; didn’t shrink by more than 25% nor grow by more than 25%). These best responses happened at a median of four months into treatment.
While some of these best responses didn’t last for the full course of treatment it does show that blocking MAPK, and learning more about how it works, is a valuable area of study.
What else did the drug do?
Known as ‘adverse events’ or side effects, these are the things that the drug causes, that are not directly about treating the tumour. In this case 16 of the 18 children experienced at least one of these adverse effects, which mostly effected the children’s skin, such as rashes or infection that caused swelling in either the face or toes.
For two children their rashes were so severe that trametinib treatment was stopped. For the other 16, a short interruption in the drug treatment, or other supportive care, meant that they were able to continue with the trial.
What happened when the drug treatment stopped?
An interesting finding was that in some cases within two to four months of stopping trametinib use, some tumours began to progress. This is evidence that it was the drug slowing/stopping growth in the first place.
One child in particular was put back on trametinib again and the tumour growth stopped and slowed again. This shows that their tumour had not become resistant to the drug during the first treatment.
All of these children received the treatment ‘off label’ because it is not currently approved for used in progressive paediatric low grade brain tumours. This goes to show the importance of doing retrospective studies like this, looking back at data collected on people receiving non-approved treatments.
But this also highlights the need for more prospective trials (analysing information as the treatment is given) to test promising new treatments for these children.
The upcoming LOGGIC trial plans to this by comparing trametinib to the current standard of care drug combination (carboplatin and vincristine) as well as vincristine alone in children with newly-diagnosed low grade gliomas.
Find out more about the vital work The Everest Centre is undertaking, here