Tovorafenib has received conditional marketing authorization in Europe for patients at least 6 months of age with BRAF-positive relapsed/refractory pLGG.
The European Commission (EC) has granted conditional marketing authorization to tovorafenib (Ojemda) as monotherapy for the treatment of patients at least 6 months of age with relapsed or refractory pediatric low-grade glioma (pLGG) harboring a BRAF fusion or rearrangement, or a BRAF V600 mutation, following at least 1 prior systemic therapy.1
This regulatory decision establishes the agent as the first systemic therapy indicated specifically for patients with pLGG harboring BRAF rearrangements, including fusions, across all 27 European Union member states.
Data from the pivotal, multicenter, open-label phase 2 FIREFLY-1 trial (NCT04775485) supported the approval, which demonstrated an overall response rate (ORR) of 71% according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, with a clinical benefit rate (CBR) of 77%. Additionally, the ORR per Response Assessment in Pediatric Neuro-Oncology LGG (RAPNO-LGG) criteria was 53%, with a CBR of 58%. Furthermore, among responders, the median time to response was 5.4 months, and the median duration of response was 18.0 months, per RAPNO-LGG criteria.
“Families affected by LGG often endure years of uncertainty, difficult treatment decisions, and the fear of long-term consequences,” François Doz, MD, MSc, a professor of pediatrics at Paris Descartes University, deputy director of Clinical Research, Innovation and Teaching in the SIREDO Oncology Centre of the Curie Institute (Care, Innovation and research in Cancer of the child, adolescent and young adult), and director of Teaching of the Hospital Ensemble of the Institut Curie in France, stated in a news release. “The approval of a targeted therapy like tovorafenib represents a major step forward, offering families not only a new treatment option, but a renewed optimism.”
The trial enrolled 137 patients 6 months to 25 years of age with relapsed or progressive pLGG harboring an activating BRAF alteration.2 Patients were required to have received at least 1 prior line of systemic therapy and have documented evidence of radiographic progression. The efficacy-evaluable cohort consisted of 76 patients in arm 1, and arm 2 provided safety data for an additional 60 patients.
Updated 3-year results presented suggest that tovorafenib prolonged clinical stability beyond the planned treatment duration of at least 26 cycles. In an exploratory analysis, the median time to next treatment was 42.6 months (95% CI, 36.7-not evaluable [NE]).
Among 39 patients who entered a post-treatment observation period after completing at least 26 cycles of tovorafenib, 77% remained treatment free for at least 12 months. The median treatment-free interval had not yet been reached (95% CI, NE-NE) at the time of the data cutoff. Furthermore, minimal tumor rebound was observed within the first 6 months of stopping therapy, and early evidence suggested that patients who eventually required retreatment with tovorafenib remained sensitive to the agent, with all 8 retreated patients remaining on therapy at the time of analysis.
Tovorafenib, a type II RAF kinase inhibitor, demonstrated a manageable safety profile in FIREFLY-1. The most common treatment-related adverse effects (TRAEs) across the study population included hair color changes, increased blood creatine phosphokinase levels, fatigue, anemia, vomiting, and headache. Other frequently reported toxicities included rash, pyrexia, dry skin, and growth retardation.
The 3-year safety analysis revealed that 66% of evaluable patients (n = 137) experienced grade 3 or higher TRAEs.2 The most frequent grade 3 or higher TRAEs were decreased growth velocity (34%), anemia (14%), and increased creatine phosphokinase levels (11%). The rate of treatment discontinuation due to TRAEs was 13%.
In 2024, the FDA
