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3D illustration of cancer cells attacking a human brain as in gliomas.
Researchers found that the combination therapy not only lessened chemotherapy side effects but also improved the overall response rate over four-fold.
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Combination Therapy Improves Rare Brain Tumors in Children

Trials showed the effect of combination therapy on survival and quality of life in children with low- and high-grade gliomas

Great Ormond Street Hospital
Published:Nov 21, 2023
|2 min read
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A collaboration of researchers, led by University College London (UCL) and Great Ormond Street Hospital (GOSH), have published successful results from a Phase 2 trial for the treatment of BRAF-mutated low-grade pediatric gliomas—brain tumors that start in glial cells.

The results from the TADPOLE-G study, published in The New England Journal of Medicine and the Journal of Clinical Oncology, are the first to demonstrate a clear clinical benefit of combining the therapies of dabrafenib and trametinib in BRAF-mutated low- and high-grade pediatric gliomas respectively.

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

In the randomized trial, 73 children with BRAF-mutated low-grade gliomas (BM-LGG) were treated with dabrafenib and trametinib. Their outcomes were compared to 37 patients who were treated with standard chemotherapy drugs.

Researchers found that the combination therapy not only lessened chemotherapy side effects, but also improved the overall response rate over four-fold and increased median progression-free survival from 7.4 months with chemotherapy to 20.1 months with the new treatment.

Dual treatment for BRAF-mutated high-grade glioma

The new research follows the publication of results from the same study in patients with BRAF-mutated high-grade gliomas (BM-HGG). Children with BM-HGG often undergo full surgical resections, followed by radiotherapy and chemotherapy. Unfortunately, overall, less than one in five children respond well to treatment and two-year survival is less than 35 percent as in many cases the cancer relapses.

Some 41 children who had previously received treatment for their BM-HGG took part in the second study. The treatment led to 56 percent of patients responding to treatment overall—a significant improvement compared to previous chemotherapy trials—and a median duration of response of 22.2 months.

The study leaders say that these trials demonstrate a clear clinical benefit of the dual treatment, recommending that it become the 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. The FDA has already approved the treatment for children with low-grade glioma.

Darren Hargrave, MBChB (Hons), MD, MRCP, FRCPCH, professor at the UCL Great Ormond Street Institute of Child Health and GOSH, said: “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.”

Significance of BRAF mutations

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 to treat melanoma and non-small cell lung cancer in patients with mutations in the BRAF gene.

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

Pediatric gliomas, although the most common type of brain tumor, are still rare, especially when divided into specific molecular subtypes, such as BRAF-mutated tumors. Global collaboration is, therefore, essential to achieve timely and scientifically significant results, which led to the TADPOLE-G study enrolling patients from 58 sites in 20 countries.

- This press release was originally published on the Great Ormond Street Hospital website