Pediatric Low-Grade Glioma With BRAF Alterations: Stories, Science, and Strategies Authors: Darren Hargrave, MBChB, MD; Cameron Miller; Enrico Opocher, MD; Sébastien Perreault, MD, FRCPC

https://www.medscape.org/viewarticle/pediatric-low-grade-glioma-braf-alterations-stories-science-2025a1000x3w?page=1&sso=true&uac=148436CN&src=mkmcmr_reeng_recap_mscpedu_activity Pediatric Low-Grade Glioma With BRAF Alterations: Stories, Science, and Strategies Below are some key learning points to help reinforce the impact of this activity. ☑ Pediatric low-grade glioma (pLGG) • Although classified as low-grade, it can have serious long-term consequences; due to the fact that the disease manifestation can be unpredictable, patients describe their disease as a “ticking time bomb” leading to a permanent state of fear and anxiety. • Beyond the physical manifestations of pLGG, which can include blindness, nausea, seizures and personality changes, patients also face social challenges, which include difficulties reentering work or school, and difficulties within their social lives. • Furthermore, pLGG can also have a large mental health burden for both patients and caregivers. ☑ Epidemiology and characteristics • pLGG is the most common central nervous system (CNS) tumor in children and adolescents, with an incidence estimated at 10 to 12/1,000,000 for children < 15 years. • pLGGs are distinguished from high-grade gliomas based on specific morphologic features and/or the absence of necrosis, mitoses, and microvascular proliferation. • Although slow-growing and rarely fatal, treatment is needed, especially for symptomatic cases. • Surgery is indicated whenever feasible; in case of incompletely resected disease or if surgery is not possible, standard treatments include radiotherapy (with potential neurocognitive and endocrine complications) and chemotherapy (which does not provide a durable effect). ☑ BRAF alterations • MAPK pathway alterations are common in pLGG and are present in 2/3 cases, with BRAF alterations as the most common. • BRAF alterations are also a negative prognostic factor. ☑ Targeted therapy for pLGG with BRAF alterations. • The TADPOLE-G phase 2 trial showed improved overall response rates (ORR) with daBRAFenib (BRAF inhibitor) + trametinib (MEK inhibitor) vs chemotherapy (47% vs 11%) and improved PFS in patients with pLGG and BRAF V600 mutations who did not receive prior targeted therapy. ◦ Adverse events more common with daBRAFenib + trametinib included pyrexia and skin toxicities. • Single-agent MEK inhibitors have also been assessed, including trametinib and selumetinib, and showed positive results in clinical trials, however, none of these options has received regulatory approval. • The FIREFLY phase 2 trial assessed single-agent tovorafenib, a pan-RAF inhibitor, in children and young adult patients with recurrent/progressive disease and BRAF V600 mutations, BRAF fusions, and other RAF alterations. ◦ The ORR with tovorafenib was 51% to 67% (depending on method of evaluation), with responses observed regardless of the BRAF alteration type (mutation vs fusion) and treatment with a prior MEK inhibitor. ◦ Adverse events typical with tovorafenib include change in hair color (unique adverse event), as well as nail/cutaneous and gastrointestinal toxicities. • At the time of the recording, daBRAFenib + trametinib was approved by the FDA, EMA and MHRA for pLGG with BRAF V600E mutations, while tovorafenib was approved in patients with relapsed/refractory pLGG with BRAF fusion or rearrangement, or BRAF V600 mutations by the FDA only.