About 10% of children with low-grade gliomas have the BRAF V600E mutation, and preliminary studies suggest that the BRAF inhibitor dabrafenib (Tafinlar) may play an important role in treating this group of patients. A phase I/II trial presented at the 2016 European Society for Medical Oncology (ESMO) Congress found that dabrafenib achieved excellent responses in children with relapsed or refractory low-grade gliomas whose tumors harbor the BRAF V600E mutation.1
According to experts, this preliminary study shows an excellent response with dabrafenib and sets the stage for combination therapy with a MEK inhibitor plus dabrafenib, which is presumably less toxic than either drug alone based on studies in adults with melanoma.
The finding that dabrafenib can shrink tumors or stop them growing is exciting and has led to trials combining it with a MEK inhibitor. This combined therapy may completely change the way we treat low-grade gliomas in children with this mutation.— Mark Kieran, MD, PhD
Although pediatric low-grade glioma has a high cure rate and most children live a normal life span, radiation therapy used to treat the tumor causes cognitive damage and secondary malignancies. “Current therapies for low-grade glioma have significant long-term morbidity. The development of drugs that target the specific causative mutation of the tumor and avoid long-term toxicities may revolutionize the treatment of pediatric brain cancer,” said lead investigator Mark Kieran, MD, PhD, Director of Pediatric Medical Neuro-Oncology at Dana-Farber Cancer Institute, Boston.
Glioma accounts for about 50% of all pediatric central nervous system tumors. With the recognition that approximately 10% of tumors have BRAF mutations, the investigators wanted to study whether a therapy targeted to the BRAF mutation could achieve tumor responses. “Exciting data in BRAF-mutated melanoma suggested that dabrafenib could have activity in other tumor types driven by the BRAF V600E mutation,” Dr. Kieran said, providing a rationale for the phase I/II study.
The phase I dose-escalation study enrolled 15 patients with low-grade glioma positive for BRAF V600E. The recommended dose for the phase II phase was set at 4.5 mg/kg/d for patients aged 12 years and older and 5.25 mg/kg/d for younger patients.
In the phase II study, 17 patients were added, bringing the total to 32 patients treated with dabrafenib. Ages ranged from 2 to 17 years, and the median age was 9 years. About 60% were male, and 78% were white. The median duration of exposure to dabrafenib was 55 weeks. At the time of data cutoff, 22 patients (69%) were still on therapy.
Toxicity and Response
The majority of adverse events were grades 1 and 2 and were easily managed, said Dr. Kieran. Eighteen patients required treatment interruption for adverse events, and 13 were restarted at the same dose, whereas 5 were restarted on a lower dose. Only two patients had a serious adverse event. No cases of squamous cell carcinoma, which was found in adult patients with melanoma treated with dabrafenib, were reported. One patient had an allergic reaction.
Response rates were encouraging. Among 29 evaluable patients, there was 1 complete response, 11 partial responses, 14 with stable disease, and 3 with progressive disease. The clinical benefit rate was 75% (responses plus stable disease). “We saw significant tumor shrinkage. The majority of patients are still on therapy and are doing well,” Dr. Kieran said.
Dr. Kieran and co-investigators are now studying dabrafenib in combination with a MEK inhibitor in an effort to reduce toxicity. “We want to make the response rate with dabrafenib even higher by combining it with a MEK inhibitor, since that works in adults. Adding two drugs together normally produces twice as much toxicity, but much of the toxicity of the BRAF drug is inhibited by the MEK drug, so the combination in children may be less toxic than either drug alone, which is unusual.”
Trials of Combination Therapy
“The finding that dabrafenib can shrink tumors or stop them growing is exciting and has led to trials combining it with a MEK inhibitor. This combined therapy may completely change the way we treat low-grade gliomas in children with this mutation. The caveat is these personalized drugs are relatively new, so we need to make sure they don’t have any long-term developmental toxicities in children,” Dr. Kieran stated. ■
Disclosure: The study was sponsored by Glaxo/Novartis. Dr. Kieran is on an advisory board for Novartis.
1. Kieran MW, Bouffet E, Tabori U, et al: The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas. 2016 ESMO Congress. Abstract LBA19_PR. Presented October 7, 2016.
I was impressed by this first study of dabrafenib in pediatric patients with BRAF V600E–mutated relapsed, refractory low-grade glioma.— Guido Reifenberger, MD
“Low-grade gliomas are biologically and clinically heterogeneous entities with different genetic drivers,” said ...!-->!-->