The FDA announced on Thursday that it has approved the BRAF inhibitor dabrafenib (Tafinlar) combined with the MEK inhibitor trametinib (Mekinist) for the treatment of pediatric patients 1 year and older with low-grade glioma with a BRAF V600E mutation who require systemic therapy.
The agency also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.
Approval was based on data from the phase II/III TADPOLE trial, the results of which were presented by Eric Bouffet, MD, of the Hospital for Sick Children in Toronto, at last year’s American Society of Clinical Oncology annual meeting.
“Pediatric cancer research is vital to uncover new treatment methods for a population,” said Bouffet in a press release from Novartis, the maker of the drugs. “Developing targeted therapies based on the unique genetic features of a patient’s tumor is the future of pediatric cancer care.”
In the TADPOLE study, which included 110 children harboring BRAF V600E mutations with progressive disease following surgery, the 73 patients randomized to the dual targeted therapy had an overall response rate more than four times higher than that of the 37 children treated with carboplatin plus vincristine (46.6% vs 10.8%, P<0.001).
At a median follow-up of 18.9 months, the median progression-free survival was 20.1 months with the combination compared with 7.4 months with chemotherapy (HR 0.31, 95% CI 0.17-0.55, P<0.001). At 1 year, about two-thirds of children in the combination arm were alive without disease progression compared with 26% in the chemotherapy arm.
At the time of the interim analysis of overall survival (OS) — when all patients had completed at least 32 weeks of treatment or had discontinued — there was one death in the chemotherapy arm. OS results at the interim analysis did not reach statistical significance.
“It is more important than ever to test for genetic mutations in patients living with low-grade glioma. This FDA approval may offer new hope to pediatric patients living with BRAF V600E low-grade glioma,” said TADPOLE co-investigator Roger Packer, MD, senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital in Washington, D.C., in the press release. “This has the potential to change the way healthcare providers treat these pediatric patients, offering a significant advancement compared to chemotherapy.”
Regarding safety, the most common adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%).
The most common grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).
The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight; dabrafenib is administered orally twice daily and trametinib is administered orally once daily.