Article: Targeted Therapies for Relapsing/Remitting Pediatric Low-Grade Glioma (R/R pLGG)

Pediatric low-grade glioma (pLGG) is characterized by near-universal activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which includes rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), mitogen-activated extracellular signal-regulated protein kinase (MEK), and extracellular signal-regulated kinase (ERK).¹ The most common drivers of this activation are BRAF gene alterations—either fusions or point mutations—making BRAF a key therapeutic target.

Targeting MAPK hyperactivation has become central to pLGG treatment. BRAF inhibitors (vemurafenib, dabrafenib), MEK inhibitors (trametinib, selumetinib), and pan-RAF inhibitors (tovorafenib) are Food and Drug Administration (FDA) approved for pLGG. These agents address the distinct biological behavior of MAPK alterations through tailored mechanisms.

Mechanism of Action of Targeted Therapies for pLGG

BRAF inhibitors target pLGG driven by BRAF^V600E mutations, which are present in ~20% of pLGG tumors.² These mutations result from a single nucleotide change that replaces valine with glutamate at codon 600,² driving potent MAPK pathway activation and aggressive tumor biology.³BRAF inhibitors specifically bind to the mutated BRAF protein, blocking its activity to prevent downstream activation of MEK and ERK, which, in turn, reduces signaling linked to tumor growth and survival.⁴ A MEK inhibitor (eg, trametinib) can be added to the BRAF inhibitor to block MEK directly, further dampening MAPK signaling that may persist despite BRAF inhibition.⁵

Monotherapy with a BRAF inhibitor does not work effectively against fusions, most notably the KIAA1549-BRAF fusion found in 70–80% of pilocytic astrocytoma and 30–40% of pLGG.¹ This genetic rearrangement fuses a portion of the KIAA1549 gene with the BRAF gene, eliminating BRAF’s typical regulatory control.^1,2 The resulting fusion protein remains constitutively active and signals continuously through the MAPK pathway. Treatment with first-generation BRAF inhibitors—designed to inhibit monomeric BRAF^V600E—can paradoxically enhance MAPK signaling in the case of BRAF fusions, which function as dimers. In contrast, the pan-RAF inhibitor, tovorafenib, binds to inactive RAF subtypes, including both wild-type and mutant forms, and inhibits RAF dimerization.¹ This broad inhibition blocks MAPK pathway activation in both fusions and BRAF^V600E point mutations, reducing tumor cell growth across pLGG subtypes.^6,7

Efficacy and Safety of Targeted Therapies for pLGG
BRAF Inhibitors ± MEK Inhibitors: BRAF^V600E-Mutant Tumors

BRAF^V600E mutations are associated with more aggressive pLGG tumors but typically respond well to BRAF inhibitors, such as dabrafenib and vemurafenib. Dabrafenib is FDA-approved as a monotherapy in patients aged ≥1 year with BRAF^V600E-mutant pLGG requiring systemic therapy.⁴ Additionally, adding MEK inhibition with trametinib improves outcomes. In a randomized trial, dabrafenib/trametinib outperformed chemotherapy in response rate (47% vs 11%), progression-free survival (20.1 vs 7.4 months), and grade 3 adverse events (47% vs 94%).^2,8   

MEK Inhibitors: KIAA-BRAF Fusion-Driven Tumors

MEK inhibitors have been studied for BRAF fusion-driven pLGG. Selumetinib, the first such agent approved for pLGG, was associated with a 20% partial response rate in a phase I trial, with 80% of patients having BRAF aberrations. In phase II, among 25 patients with either BRAF^V600E mutations or fusions (KIA1549-BRAF, or the less common neurofibromatosis type 1 (NF1) fusion), 36% had partial responses, 36% had stable disease, and 28% progressed. Selumetinib was well tolerated. Common side effects included elevated creatine kinase and maculopapular rash.²

Trametinib, an oral MEK1/2 inhibitor, is the most studied of these agents and has shown positive outcomes in pLGG. In a retrospective study of 18 patients, 6 had partial and several minor responses, mostly in KIAA1549-BRAF fusion and NF1-associated tumors. In the TRAM-01 trial, among 43 evaluable patients, 4 had partial responses, 18 had minor responses, 17 had stable disease, and 4 had progressive disease. The median time to response was 5.5 months, with the median duration of response being 6.1 months. Early-phase trials showed good tolerability, and evaluations are ongoing in multiple tumor groups.²

Pan-RAF Inhibitors

Pan-RAF inhibitors have been developed to address the limitations of first-generation BRAF inhibitors in fusion-driven pLGG. Tovorafenib is an oral selective, type II RAF inhibitor that blocks all RAF isoforms, including dimers formed by BRAF fusions. In a phase 1 trial of 137 patients with relapsed/refractory (R/R) BRAF-altered pLGG, tovorafenib achieved a 51% objective response rate (ORR) (RAPNO) and 67% ORR (RANO-HGG), including a 17% complete response rate.⁶ The median response duration was 13.8 months, even in this heavily pretreated population.⁶

The most frequently reported treatment-related adverse events included hair color changes in 76% of patients, elevated creatine phosphokinase levels in 56%, and anemia in 49%. Severe (grade ≥3) adverse events occurred in 42% of patients. Tovorafenib was discontinued due to adverse events in 7% of cases.⁶ In 2024, tovorafenib received FDA-accelerated approval for pLGG with either BRAF^V600E mutations or BRAF fusions.⁷ It is now being evaluated as first-line therapy in head-to-head trials versus standard chemotherapy regimens.⁹

What the Future Holds

Despite major advances in our understanding of the molecular biology of pLGG and the increased availability and use of targeted therapies, several challenges persist. Chief among these are: a) a lack of robust preclinical models that would accelerate the development of novel agents; b) inconsistent early-phase trial designs, which would lead to nonstandardized patient eligibility, clinical assessment, radiographic evaluation, and response criteria; and c) challenges posed by resistance, rebound after treatment discontinuation, and recurrence. Long-term data on toxicity in pediatric populations are also missing.³

References:

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