FDA Approval Summary: Tovorafenib for Relapsed or Refractory BRAF-altered Pediatric Low-Grade Glioma.

in Clinical cancer research : an official journal of the American Association for Cancer Research by Sonia Singh, Diana Bradford, Somak Chatterjee, Xiaoxue Li, Stephanie L Aungst, Amy M Skinner, Claudia P Miller, Sarah Kim-McOlash, Jeanne Fourie Zirkelbach, Ye Xiong, Youwei Bi, Ying-Hong Wang, Yuching Yang, Jielin Sun, Jeffrey Kraft, Rosane Charlab, Stacy S Shord, Shenghui Tang, Barbara Scepura, Ilynn Bulatao, Opeyemi Udoka, Haleh Saber, Nam Atiqur Rahman, Richard Pazdur, Harpreet Singh, Martha Donoghue, Nicole Drezner

TLDR

  • The FDA granted accelerated approval to tovorafenib for the treatment of relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.
  • The study found that tovorafenib was effective in inducing a response in patients with relapsed or refractory pLGG, with a overall response rate of 51% and a median duration of response of 13.8 months.
  • This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements, providing a new treatment option for patients with this rare and aggressive brain tumor.

Abstract

On April 23, 2024, FDA granted accelerated approval to tovorafenib, a type II RAF kinase inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation. Efficacy was evaluated in FIREFLY-1 (NCT04775485), a single-arm, open-label, multicenter trial that enrolled patients 6 months to 25 years of age with relapsed or refractory pLGG with an activating BRAF alteration who had received prior systemic therapy. The major efficacy outcome measure was radiologic overall response rate (ORR), defined as the proportion of patients with complete response, partial response, or minor response as determined by blinded independent central review using Response Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. A key secondary endpoint was duration of response (DoR). In an efficacy population of 76 patients, the ORR was 51% (95% confidence interval (CI): 40, 63), and the median DoR was 13.8 months (95% CI: 11.3, not estimable). The required post-marketing clinical trial (FIREFLY-2) was well underway at the time of accelerated approval. This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements.

Overview

  • The FDA granted accelerated approval to tovorafenib for the treatment of relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or BRAF V600 mutation.
  • The efficacy was evaluated in the FIREFLY-1 trial, a single-arm, open-label, multicenter trial that enrolled patients 6 months to 25 years of age with relapsed or refractory pLGG with an activating BRAF alteration.
  • The primary objective of the study was to evaluate the radiologic overall response rate (ORR) and duration of response (DoR) in patients with relapsed or refractory pLGG.

Comparative Analysis & Findings

  • The study found that the overall response rate (ORR) was 51% (95% CI: 40, 63), and the median duration of response (DoR) was 13.8 months (95% CI: 11.3, not estimable) in the efficacy population of 76 patients.
  • The study did not include a control group, as tovorafenib was given to patients who had previously received systemic therapy and had relapsed or refractory disease.
  • The study found a significant response rate and duration of response, indicating the potential efficacy of tovorafenib in treating patients with relapsed or refractory pLGG.

Implications and Future Directions

  • This represents the first FDA approval of a systemic therapy for the treatment of patients with pLGG with BRAF fusions or rearrangements, providing a new treatment option for patients with this rare and aggressive brain tumor.
  • The required post-marketing clinical trial (FIREFLY-2) will continue to evaluate the safety and efficacy of tovorafenib in patients with relapsed or refractory pLGG.
  • Future studies may investigate the combination of tovorafenib with other therapeutic agents to improve response rates and overall survival in patients with relapsed or refractory pLGG.
Read Full Article