A new study found that combining the targeted therapies, dabrafenib and trametinib, considerably improved the overall response rate (ORR) in paediatric patients with BRAF V600 mutation-positive low-grade gliomas.
The ORR of dabrafenib and trametinib was compared to the ORR of usual chemotherapy combination of carboplatin and vincristine.
The American Society of Clinical Oncology (ASCO) said: “Secondary findings showed an improved clinical benefit rate and prolonged progression-free survival for dabrafenib plus trametinib compared to carboplatin plus vincristine.”
In children, the most common tumours are central nervous system tumours, with an expected 4,170 new cases of childhood brain tumours being diagnosed in the United States in 2022. Around 50 per cent of these 4,170 cases will be gliomas.
It is not always possible for paediatric low-grade gliomas to be removed surgically, due to their location, and patients with residual, progressive, or recurrent disease often need systemic therapy. Despite a five-year survival rate of around 95 per cent using existing treatment approaches, there is still a likelihood of tumour progression with numerous patients needing various lines of treatment.
The BRAF V600 mutation is identified in approximately 15 to 20 per cent of low-grade gliomas cases and could be linked to a higher risk of progression to high-grade glioma. At the start of the study, the researchers noted that using the existing standard of care could result in worse outcomes for patients with the BRAF V600-mutant disease compared to those with non-mutated disease.
The study
Melissa M. Hudson, MD, a Fellow of and expert in paediatric cancers at ASCO, said: “This study shows that a new, oral targeted therapy combination can significantly improve outcomes for the most common type of brain tumour in children over standard-of-care chemotherapy that often requires frequent visits to the hospital or clinic and can result in health problems later in life.
“It is exciting to see success in developing targeted treatments based on the unique genetic features of a tumour in a young patient.”
The focus of the phase II/III trial, according to ASCO, was “to determine if a combination of targeted therapies is better at treating paediatric low-grade gliomas than a combination of standard chemotherapy drugs”.
The double-blind trial took place in 57 investigative centres across 20 countries. It involved 110 patients aged one to 17 with BRAF V600 mutation-positive low-grade gliomas. The participants were randomly assigned either dabrafenib twice and trametinib once per day or standard-of-care doses of carboplatin and vincristine.
The overall response rate was the primary endpoint and the secondary endpoints were the clinical benefit rate, duration of response, time to response, progression-free survival, overall survival and safety.
Results
The median follow-up for the pre-planned primary analysis was 1 year and 6.9 months. The researchers collected the ORR, the clinical benefit rate (CBR) and the median progression-free survival (PFS).
The ORR is defined as the number of patients who showed a complete or partial response and the CBR is defined as the number of patients who showed a full response, partial response, or had stable disease for at least six months.
Results for dabrafenib with trametinib showed:
- ORR = 47 percent
- CBR = 86 per cent
- PFS = 20.1 months
Results for carboplatin with vincristine showed:
- ORR = 11 percent
- CBR = 46 per cent
- PFS = 7.4 months
Lead author of the study, Eric Bouffet, MD, Fellow of the Royal College of Physicians of Canada and Director of the Pediatric Neuro-Oncology Program at The Hospital for Sick Children in Toronto, explained: “For paediatric patients with BRAF V600-mutant low-grade glioma, dabrafenib plus trametinib may offer an improved standard of care.
“This represents an important advance for the youngest patients with brain cancer, as this is the first combination of targeted therapies developed for patients as young as one year of age.”
Significance
The outcome of this study “supports the use of dabrafenib plus trametinib as a new potential standard of care in paediatric patients with low-grade glioma with BRAF V600 mutations,” according to ASCO. “These results highlight the importance of early molecular testing in paediatric low-grade glioma to determine if patients may benefit from targeted therapy.”
This study will be used by researchers to further their understanding about the ideal duration of treatment. The study is still in progress and will gather long-term safety data which will be displayed in a companion study.
The researchers are also hoping that this combination of targeted therapies will be accepted into the World Health Organization (WHO) global initiative for childhood cancer.
The research was published in the Journal of Clinical Oncology and was presented at the 2022 ASCO Annual Meeting.
