Article: Selecting Second-Line Therapy for Relapsing/Remitting Pediatric Low-Grade Glioma (pLGG)

The Age of Molecular Profiling in pLGG Management

In 2021, World Health Organization (WHO) incorporated molecular diagnostics into the classification of central nervous system (CNS) malignancies, stating that molecular features were required for a diagnosis and, in some cases, override histological features.¹ This shift reflects an evolving understanding that pediatric low-grade glioma (pLGG) that appear similar under a microscope may have molecular profiles that influence clinical outcomes and therapeutic responses. Integrating molecular profiling into diagnosis and management decisions has laid the groundwork for adopting precision treatment strategies.¹

Specifically, recent in-depth molecular profiling has revealed that pLGG almost universally involves activation of the RAS/mitogen-activated protein kinase (Ras/MAPK) and mammalian target of rapamycin (mTOR) signaling pathways.² Targeted therapies aimed at these pathways show encouraging efficacy and, in some studies, superior response rates compared to chemotherapy. For example, a combination of dabrafenib and trametinib significantly improved progression-free survival and had a more favorable safety profile than carboplatin and vincristine in BRAF^V600E-mutated pLGG.³ These findings support the emerging role of targeted therapies as first-line and second-line treatments for pLGGs with specific molecular profiles.³

The choice of therapy is increasingly shaped by specific genetic alterations. While BRAF inhibitors are effective for tumors with BRAF^V600E mutations, they are not used in cases with BRAF fusions, which may paradoxically progress on these agents.³ MEK inhibitors, such as selumetinib and trametinib, and pan-RAF inhibitors like tovorafenib, offer additional options for tumors with MAPK pathway alterations other than the BRAF^V600E mutation.²

Guiding Treatment Decisions: Prior Treatment and Tumor Characteristics

Prior treatment history substantially impacts the choice of targeted therapies for second-line or later treatment. In this respect, molecular profiling is proving invaluable in determining the most appropriate therapies by identifying genetic alterations that determine susceptibility. For example, retreating KIAA1549-BRAF fusion-driven tumors with MEK inhibitors, like selumetinib, after progression suggests that resistance to these agents may be reversible. BRAF^V600E mutation-driven tumors rechallenged with BRAF inhibitors or BRAF/MEK inhibitor combinations have also shown positive response to retreatment. In contrast, chemotherapies can seldom be reused after progression.³

Tumor location influences the risk of progression in pLGG, with supratentorial midline, brainstem, spinal cord, and diencephalon sites linked to higher risk. Nonetheless, the impact of tumor location is not entirely clear. In a multi-institutional study of 798 patients, hypothalamic/chiasmatic tumors showed the highest tendency to progress. However, multivariate analysis did not confirm tumor location as an independent risk factor, likely due to the confounding impact of resection extent, which is often limited in brain regions surrounded by eloquent tissue. Supporting this, tumor growth rate did not vary significantly by location preoperatively, though postoperative growth was highest with midline tumors, which had the lowest resection extent. In contrast, a prospective study of 1031 patients identified the supratentorial midline location as an independent predictor of highly progressive disease. Emerging molecular factors, such as histone H3 mutations and enhancer of zeste homologs inhibitory protein (EZHIP) overexpression, may also influence outcomes but, as yet, have not been accounted for in earlier studies.²  

Despite these considerations, complete surgical resection remains a cornerstone in pLGG treatment due to its ability to delay or eliminate the need for further therapy. Still, molecular profiling and the emergence of targeted therapies have changed the treatment landscape. For example, while optic pathway gliomas (OPGs)—which account for 40% of pLGGs—were traditionally managed without biopsy due to their sensitive location, the emergence of molecular targets has led to increased consideration of surgical biopsy, particularly in sporadic cases where targeted therapies may be viable.⁴

Assessing Treatment Response to Targeted Therapies

Historically, radiological progression has been the primary trigger for treatment decisions, but challenges remain, particularly for tumors that are amorphous or located near critical structures like the optic pathway. In these areas, even minor growth may lead to treatment changes despite not meeting formal progression criteria. Moreover, radiographic response does not always align with functional outcomes—especially in cases of optic pathway gliomas—making it harder to assess true therapeutic benefit.⁴

Beyond objective tumor assessment, it is crucial to assess how the emergence of MAPK-targeted therapies may affect chronic pLGG-related morbidities, including vision impairment and neurocognitive outcomes. For example, unlike traditional chemotherapy, MEK inhibitors may improve visual acuity. Ongoing studies evaluate a broader array of effects using quality of life measures, patient-reported outcomes, functional assessments, adaptive behavior tools, activities of daily living scores, and additional metrics to better define the overall risk-benefit profile and impact of newer treatments.³

What Might the Future Hold?

Targeted therapies have changed the pLGG landscape, but limited data exist on the risk of recurrence or rebound after discontinuing MAPK inhibition. For example, in trials of dabrafenib/trametinib, 23% of responders discontinued treatment before progression, after which the median time to progression was 3.7 months. However, recurrence rates vary dramatically, ranging from 0% to 69% with median times to progression of 2.5 to 22 months. It remains unclear how progression-free survival in pLGG is affected by treatment duration. Predictive markers, like plasma cell-free tumor DNA, may eventually guide decisions about treatment duration, although challenges remain with blood-based analysis for brain tumors. Cerebrospinal fluid analysis may be more sensitive, but it is also invasive and likely to burden children.⁵

Nonetheless, the future of pLGG treatment is improving due to the emergence of oral MAPK-targeted therapies, which offer convenience, reduced financial burden, improved efficacy, and fewer side effects compared to chemotherapy. These therapies—including MEK, BRAF, and pan-RAF inhibitors—provide flexibility in administration, potentially improving access to care in rural and underserved areas. The emergence of telehealth allows for remote therapy and monitoring, reducing travel requirements and the accompanying financial strain. In low-resource settings, however, targeted therapies and molecular testing remain limited. Still, initiatives like the WHO Global Initiative for Childhood Cancer may address these disparities by improving global access to molecular diagnostics and treatments.³

References:

1. Trinder SM, McKay C, Power P, et al. BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience. Front Oncol. 2023;13:1154246. doi:10.3389/fonc.2023.1154246.
2. Gorodezki D, Schuhmann MU, Ebinger M, Schittenhelm J. Dissecting the natural patterns of progression and senescence in pediatric low-grade glioma: from cellular mechanisms to clinical implications. Cells. 2024;13(14):1215. doi:10.3390/cells13141215. PMID: 39056798; PMCID: PMC11274692.
3. Crotty EE, Sato AA, Abdelbaki MS. Integrating MAPK pathway inhibition into standard-of-care therapy for pediatric low-grade glioma. Front Oncol. 2025;15:1520316. doi:10.3389/fonc.2025.1520316.
4. Manoharan N, Liu KX, Mueller S, Haas-Kogan DA, Bandopadhayay P. Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era. Neoplasia. 2023;36:100857. doi:10.1016/j.neo.2022.100857.
5. O'Hare P, Cooney T, de Blank P et al. Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions-International Pediatric Low-Grade Glioma Coalition. Neuro Oncol. 2024;26(8):1357-1366. doi:10.1093/neuonc/noae074.