Clinical trial gives hope for children with rare gliomas

These results follow on from the publication of results from the same study in patients with BRAF mutated high-grade gliomas.

The “TADPOLE-G” study, published in the New England Journal of Medicine and the Journal of Clinical Oncology, demonstrates for the first time a clear clinical benefit of the combination therapy of the medications Dabrafenib and Trametinib (Novartis) in BRAF mutated low- and high-grade paediatric gliomas respectively.

A senior author on the study, Professor Darren Hargrave (pictured), receives funding from GOSH Charity.

Researchers showed that the combination therapy significantly improved response and survival in children with BRAF mutated low-grade gliomas (BM-LGG) and had fewer side effects when compared to chemotherapy.

For children with relapsed/refractory BRAF mutated high-grade glioma (BM-HGG), the treatment had an improved overall response rate than previous chemotherapy trials.

The study leaders argue that these trials demonstrate a clear clinical benefit of the dual treatment, with the recommendation being that it become a first-line treatment for BM-LGG and a clinical option for those with relapsed/refractory BM-HGG.

Evidence from these trials is now being used as part of a NICE scoping review to appraise the clinical and cost effectiveness of the treatments and the Food and Drug Administration have already approved the treatment for children with low-grade glioma.

Professor Darren Hargrave, GOSH Charity Clinical Professor in Paediatric Neuro-Oncology at the UCL Great Ormond Street Institute of Child Health and Honorary Consultant Paediatric Oncologist at GOSH, chaired the Clinical Trial Steering group and led recruitment at GOSH for this trial and earlier phase I arm of the trial.

He says of the trial:

“The results of these studies highlight how targeted drug therapies can offer patients new treatment avenues that not only improve outcomes but reduce the side effects often associated with cancer therapies.”

Mutations in the BRAF gene were first identified as drivers of cancer in the early 2000s and now targeted therapies such as Dabrafenib and Trametinib are being used for treatment of melanoma and non-small cell lung cancer in patients with mutations in the BRAF gene.

The BRAF mutation is present in around 15-20% of paediatric low-grade gliomas and around 5-10% of high-grade gliomas in children. These studies are the first to investigate the effectiveness of the combination therapy in paediatric gliomas.

“It has been incredible to watch research move our ability to treat specific cancers forward at such a rapid pace,” says Professor Hargrave.

“I was involved in the original study that identified BRAF gene mutations as drivers of cancer and so it has been fantastic to now be able to see treatments that target the mutation in clinical trials for paediatric gliomas.

“These studies demonstrate the power of collaborative, global research to find new treatments for rare cancers. We’d like to thank all the patients and families who make research like this possible.”

Paediatric low-grade glioma

For children with paediatric low-grade glioma, the normal course of treatment is a full surgical removal. However, for children where this is not possible, additional treatments like chemotherapy are required. These patients often experience multiple relapses, further progression and serious side effects.

In this randomised trial, 73 children with BRAF mutated low-grade gliomas (BM-LGG) were treated with Dabrafenib and Trametinib and their outcomes were compared to 37 patients treated with standard chemotherapy drugs.

As well as decreased side effects from the chemotherapy, the new treatment also improved overall response rate by over four-fold and increased median progression free survival from 7.4 months with chemotherapy to 20.1 months with the new treatment. (Median progression free survival means the length of time that patients go for once they are on the treatment without their disease progressing.)

Paediatric high-grade glioma

Children with high-grade gliomas often undergo full surgical resections, followed by radiotherapy and chemotherapy. Unfortunately, overall response rates to treatments are less than 20% and two-year survival is less than 35%, with many patients developing recurrent disease.

41 children who had previously received treatment for their BRAF mutated high-grade glioma (BM-HGG) took part in this study. The treatment led to an overall response rate of 56% - this was a significant improvement when comparing to chemotherapy trials run previously - and a median duration of response of 22.2 months.

“New treatments that help improve outcomes and reduce side effects for young patients living with BRAF V600 low- and high-grade gliomas address unmet patient need, where treatment options are very limited,” says Gerrit Zijlstra, Chief Medical Officer, Novartis UK. “We welcome the results of the TADPOLE-G clinical trial and are humbled to be a part of international scientific community effort in developing targeted therapies based on the unique genetic features of a patient’s tumour.”

Paediatric gliomas, although the most common type of brain tumour, are still rare, especially when divided into specific molecular subtypes such as BRAF mutated tumours. Global collaboration is therefore essential to achieve timely and scientifically significant results. The TADPOLE-G study enrolled patients from 58 sites in 20 countries demonstrating truly effective collaboration.

GOSH Charity’s Build it. Beat it. appeal, is raising money to help build a world-leading new Children’s Cancer Centre at GOSH, to help drive transformation in children’s cancer care and save more lives.

A national resource for children with the hardest-to-treat cancers, the Children’s Cancer Centre will help to increase research capacity, so there can be more clinical trials like this to pioneer new cures and treatment options.