In the FIREFLY-1 trial, tumors shrank or vanished in almost 70% of the 77 children given tovorafenib. On April 23, the Food and Drug Administration used that result to grant accelerated approval to the drug, sold as Ojemda, for children aged 6 months or older with a type of brain tumor called low-grade glioma.
The approval covers tumors that have changes in the BRAF gene and either cannot be fully removed by surgery or have come back after it. A child must also have already had one prior systemic treatment, such as chemotherapy, after surgery.
A gap the older drugs left open
A pairing of dabrafenib (Tafinlar) and trametinib (Mekinist) won a similar approval last year. It does not work for tumors with BRAF rearrangements or fusions, where pieces of the gene are shuffled or attached to other genes. Lindsay Kilburn, M.D., of Children’s National Hospital, who led the study behind the new approval, said fusions are the most common BRAF change in children and teens with these tumors. “So the dabrafenib/trametinib combination can’t be used in many children who need treatment,” she said.
Tovorafenib can target cancer cells with specific BRAF fusions as well as other changes in the gene, including mutations.
What the trial found
Participants ranged from 6 months to 25 years old and took the drug in cycles of four weekly doses for as long as it seemed to help. Many had been through several treatments already, including other BRAF-targeted drugs. When early results appeared in November 2023, they had been on tovorafenib for a median of almost 16 months, and two-thirds were still taking it.
About 70% of children whose tumors carried a BRAF fusion, and 50% of those with a BRAF mutation called V600, had some measurable shrinkage. Of the 46 children whose tumors shrank, 12 saw them disappear entirely. Some responses had lasted nearly 2 years by the time those results were published, and the team is still tracking how long they hold. “Seeing [responses last] into 1 or 2 years [so far] is really exciting,” Kilburn said.
Side effects were real. The most common were changes in hair color, anemia, changes in blood markers that can signal early kidney injury, and skin problems such as a severe rash. Most were considered manageable, but 9 participants quit treatment early because of them. Investigators also noted that normal growth slowed during treatment. Brain tumors can delay growth too, Kilburn said, so the children will be followed to see whether growth picks up again afterward.
Why a weekly pill matters
Low-grade gliomas are the most common brain tumor in children. They grow slowly and damage the brain by pressing on nearby tissue. Sadhana Jackson, M.D., of NCI’s Pediatric Oncology Branch, who was not part of the study, said some can be cured by surgery alone, but those near sensitive structures cannot be fully removed. “And an issue with low-grade gliomas is that some of them like to grow back,” she said.
Most children in that position now get chemotherapy, which can hold a tumor in check for a long time but carries substantial side effects and means regular hospital visits. Tovorafenib is taken at home, once a week, as a pill or a liquid. Kilburn called that “an exciting advance from a quality-of-life perspective.”
What comes next
A larger randomized trial, FIREFLY-2, is comparing tovorafenib with chemotherapy as an initial treatment for children whose tumors have fusions, rearrangements or mutations in BRAF or several related genes. A separate trial is testing selumetinib (Koselugo) against chemotherapy after surgery, whether or not a tumor has BRAF changes. Jackson said that until the last 10 years there was no way to directly target some of the known genetic changes in these tumors, and that more tools “in our toolbox” is good for children.
Families should talk to their child’s doctor about whether a treatment like this fits their situation.
