Dr Leary on the FDA Approval of Tovorafenib for Pediatric R/R BRAF+ Low-Grade Glioma

Sarah E. S. Leary, MD, MS, attending physician, medical director, Pediatric Brain Tumor Program, Seattle Children’s Hospital; professor, Department of Pediatrics, University of Washington School of Medicine, discusses the significance of the FDA approval of tovorafenib (Ojemda) for pediatric patients with relapsed/refractory, 

granted accelerated approval to tovorafenib

 for the treatment of pediatric patients 6 months of age or older who have relapsed/refractory low-grade glioma with a 

 V600 mutation. This regulatory decision was based on findings from the single-arm, multicenter, open-label, phase 2 FIREFLY-1 trial (NCT04775485), in which the agent elicited an overall response rate per Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma criteria of 51% (95% CI, 40%-63%) among 76 pediatric patients with relapsed/refractory low-grade glioma harboring an activating 

alteration who had prior exposure to at least 1 line of systemic therapy. Furthermore, the median duration of response was 13.8 months (95% CI, 11.3–not estimable). Patients received the agent once per week at doses ranging from 290 mg/m

, up to a maximum dose of 600 mg, according to body surface area. The recommended dose of tovorafenib based on body surface area is 380 mg/m

 once weekly, with a maximum recommended dose of 600 mg once weekly.

Low-grade glioma is the most common pediatric tumor, Leary says. Although low-grade glioma is described as a benign tumor, Leary cautions against considering this disease benign. Glioma is a brain tumor, and the brain is crucial and central to many human functions, Leary emphasizes. Furthermore, low-grade glioma may be life threatening for some patients, Leary explains.

Prior to the approval of tovorafenib, no FDA-approved medical therapies existed for patients with pediatric low-grade glioma, Leary notes. Tovorafenib was the first drug in this indication to be considered for approval by the FDA and is therefore the first FDA-approved therapy for this patient population, Leary concludes.

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Sarah E. S. Leary, MD, MS, discusses the FDA approval of tovorafenib for pediatric patients with relapsed/refractory, BRAF-mutant low-grade glioma.

Sarah E. S. Leary, MD, MS, attending physician, medical director, Pediatric Brain Tumor Program, Seattle Children’s Hospital; professor, Department of Pediatrics, University of Washington School of Medicine; medical director, Clinical Research, Ben Towne Center for Childhood Cancer Research, discusses findings from the phase 2 FIREFLY-1 trial (NCT04775485) in pediatric patients with low-grade glioma.

Dr Leary on the Rationale for Evaluating Tovorafenib in

The FIREFLY-1 trial is investigating the efficacy and safety of the pan-RAF inhibitor tovorafenib in pediatric and young adult patients aged 6 months to 25 years who have 

-altered tumors that have progressed on at least 1 prior line of systemic therapy. The registrational arm includes patients with recurrent or progressive low-grade glioma harboring an activating 

 alteration, as low-grade gliomas are driven by the BRAF pathway. An extension arm includes patients with recurrent or progressive low-grade glioma harboring an activating 

 alteration, and a third arm includes patients with locally advanced or metastatic 

-altered solid tumors outside the central nervous system.

The ongoing phase 1b PNOC014 trial (NCT03429803) is investigating tovorafenib in pediatric patients with 

-altered low-grade glioma. Previously reported findings from this trial demonstrated that of 8 pediatric patients with relapsed low-grade glioma harboring 

 fusions who received tovorafenib, 2 achieved a complete response (CR), 3 achieved a partial response (PR), 2 had prolonged stable disease (SD), and 1 had progressive disease (PD).

The preliminary efficacy data from FIREFLY-1 align with the previously reported findings from PNOC014, Leary says.

Of the 69 evaluable patients in the registrational arm of FIREFLY-1, the overall response rate was 67%, with 6% of patients achieving a CR and 61% of patients achieving a PR. Additionally, 26% and 6% of patients had best responses of SD and PD, respectively.

No new safety signals occurred with tovorafenib in this trial beyond known adverse effects (AEs) associated with RAF inhibitors, Leary notes. Treatment-emergent AEs (TEAEs) of any grade occurred in 100% of patients in the registrational arm, and any-grade treatment-related AEs occurred in 98% of patients. The most common TEAEs of grade 3 or higher were maculopapular rash, fatigue, decreased appetite, and vomiting.

These encouraging findings emphasize the efficacy of tovorafenib in patients with 

-mutant low-grade glioma who have progressed on other therapies, Leary concludes.

Sarah E. S. Leary, MD, MS, discusses findings from the phase 2 FIREFLY-1 trial in pediatric patients with low-grade glioma.

Sarah E. S. Leary, MD, MS

Articles

Dr Leary on the FDA Approval of Tovorafenib for Pediatric R/R BRAF+ Low-Grade Glioma

Dr Leary on Tovorafenib in Pediatric Low-Grade Glioma