Tovorafenib produced responses in pediatric and adolescent/young adult patients with progressive or recurrent BRAF-altered low-grade glioma (LGG) in a phase 2 trial. 

Results from this trial were presented in a poster at the Society for Neuro-Oncology 27th Annual Meeting.

Arm 1 of the trial, FIREFLY-1 ( Identifier: NCT04775485), enrolled patients with recurrent or progressive LGG harboring an activating BRAF alteration. All patients received treatment with tovorafenib, a pan-RAF inhibitor. 

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At the data cutoff of April 2022, 25 patients had at least 6 months of follow-up. These patients had a median age of 8 (range, 3-18) years, 52% were male, 60% were White, 96% had a Karnofsky/Lansky performance status of 80-100, 56% had received 3 or more previous lines of therapy, and 72% had received prior MAPK-targeted therapy.

The patients had tumors located in the optic pathway (52%), deep midline structures (12%), hypothalamus (8%), brain stem (8%), cerebellum (4%), or other brain regions (16%). Most tumors had BRAF fusions (84%), and 16% had a BRAF V600E mutation (16%).

There were 22 patients who were evaluable for response with Response Assessment in Neuro-Oncology (RANO) criteria. In this group, the overall response rate (ORR) was 64%. The ORR was 100% for those with a BRAF V600E mutation and 60% for those with a BRAF fusion. 

Overall, 59% of patients had a partial response, 5% had an unconfirmed partial response, and 27% had stable disease per RANO criteria.

According to Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria, the ORR was 50%, with 23% of patients achieving a partial response and 27% having a minor response. The other 50% of patients had stable disease.

The most common treatment-emergent adverse events were blood creatine phosphokinase increase (80%), hair color changes (68%), anemia (56%), increased aspartate aminotransferase (56%), vomiting (56%), rash (52%), increased blood lactate dehydrogenase (48%), and headache (40%). 

Grade 3 or higher treatment-related adverse events included rash (12%), increased blood creatine phosphokinase (8%), anemia (8%), vomiting (4%), and increased alanine aminotransferase (4%). As of the data cutoff, no patient discontinued treatment due to adverse events.

“Tovorafenib showed encouraging anticancer activity in pediatric patients with BRAF-altered recurrent or progressive LGG,” the researchers concluded, adding that the treatment “was generally well tolerated.” 

Disclosures: This research was supported by Day One Biopharmaceuticals, Inc. Some study authors are employed by the company. 


Kilburn L, Landi D, Leary S, et al. FIREFLY-1 (PNOC026): Phase 2 study of pan-RAF inhibitor tovorafenib in pediatric and young adult patients with RAF-altered recurrent or progressive low-grade glioma or advanced solid tumors. Presented at SNO 2022; November 16-20, 2022. Abstract CTNI-68.