Targeted Therapy in Pediatric Low-Grade Gliomas: Advances and Future Outlook

Abstract

Pediatric low-grade gliomas (pLGG) are the most frequent central nervous system (CNS) neoplasms in children and are largely motivated by genetic mutations in the RAS-RAF-mitogen-activated protein kinase (MAPK) pathway. Identification of these molecular drivers has significantly altered treatment protocols with the realization of targeted therapies like MEK and RAF kinase inhibitors. Although conventional chemotherapy is still the first line for unresectable pLGG, recurrence after cytotoxic treatment has led to the need for alternate strategies. The use of targeted inhibitors has shown excellent efficacy and increased tolerability in refractory and relapsed settings with further ongoing work investigating their application as a first-line agent. This article presents the clinician-friendly realities of using MEK and RAF inhibitors in everyday clinical practice, ranging from administration and toxicity control through monitoring responses to ensuring appropriate equitable access to such therapies. In addition, we also discuss the possible use of these agents outside of pLGG given their applicability in other RAS-pathway-mutated malignancies. The future promises more phase 3 trials, maximizing the combination therapy, and optimizing personalized treatment strategies to maximize long-term outcomes in pediatric patients.

Introduction

Pediatric low-grade gliomas (pLGG) represent the most common CNS tumors in children and are typically characterized by a good prognosis. Nevertheless, their treatment is still problematic because they tend to recur and the possible long-term sequelae of therapy. Historically, LNG has been managed with surgery if possible, and then chemotherapy or radiotherapy in the event of incomplete resection or recurrence. Identification of the central pathway of the MAPK pathway in the pathogenesis of these cancers has opened up the possibility of targeted therapy, specifically MEK and RAF inhibitors, as an attractive alternative to traditional chemotherapy.

Genetic Basis of pLGG and Targeted Therapy

The MAPK pathway is essential for cell growth and differentiation, and its dysregulation is central to pLGG tumorigenesis. Constitutive activation of the pathway is caused by genetic alterations including BRAF fusions, BRAF V600E mutations, NF1 mutations, and FGFR alterations, which promote tumor growth. MEK and RAF kinase inhibitors selectively target these aberrations, providing a more targeted and effective therapeutic strategy than traditional cytotoxic therapies.

Current Treatment Paradigm

For the majority of pLGG, surgical resection is the mainstay of treatment. Yet, because many tumors are located in functionally important areas of the brain, total resection is frequently not feasible. For these situations, chemotherapy protocols, such as carboplatin, vincristine, and thioguanine, have been the mainstay of therapy. Yet, the toxicities of chemotherapy and the potential for tumor recurrence make alternative approaches necessary.

Emerging Role of MEK and RAF Inhibitors

MEK and RAF inhibitors have emerged as promising second-line and salvage therapies for pLGG patients who experience disease progression following chemotherapy. Agents such as selumetinib, trametinib, dabrafenib, and vemurafenib have shown significant clinical efficacy, particularly in tumors harboring BRAF alterations.

MEK Inhibitors

• Selumetinib: A MEK1/2 inhibitor with promising results in clinical trials, demonstrating prolonged progression-free survival and tumor shrinkage.

• Trametinib: Another MEK inhibitor with favorable response rates, particularly in patients with NF1-associated pLGG.

RAF Inhibitors

• Dabrafenib: Specifically targets BRAF V600E-mutant tumors, showing durable responses in pediatric trials.

• Vemurafenib: An alternative BRAF inhibitor with efficacy in BRAF-mutant pLGG cases.

Toxicity Management and Mitigation Strategies

Despite their efficacy, targeted therapies can be associated with unique toxicities, requiring careful management.

• Dermatologic Toxicity: Skin rash and photosensitivity are common with MEK and RAF inhibitors. Preventive measures include dermatologic consultations, sun protection, and topical steroids.

• Ocular Toxicity: Retinal toxicity is a concern with MEK inhibitors, necessitating regular ophthalmologic evaluations.

• Cardiovascular Effects: Some patients may experience hypertension or cardiac dysfunction, requiring close monitoring and potential dose adjustments.

• Gastrointestinal Symptoms: Nausea, diarrhea, and hepatotoxicity are possible side effects, which can be managed with supportive care and dose modifications.

Clinical Implementation and Patient Access

The integration of targeted therapies into routine clinical practice requires addressing challenges related to drug availability, financial constraints, and treatment accessibility.

• Geographic Barriers: Access to specialized neuro-oncology centers can be limited, necessitating telemedicine and shared-care models.

• Financial Considerations: High costs of targeted agents may be a barrier; insurance approvals and patient assistance programs are critical for affordability.

• Off-Label Use Considerations: While ongoing clinical trials aim to establish definitive indications for MEK and RAF inhibitors, their off-label use in refractory pLGG cases must be carefully considered based on individual risk-benefit assessments.

Future Directions and Ongoing Clinical Trials

Ongoing phase 3 trials are investigating the efficacy of MEK inhibitors as frontline therapy for pLGG, potentially shifting the treatment paradigm. Additionally, research efforts are exploring:

• Combination Therapies: Synergistic approaches combining MEK inhibitors with other targeted agents or immunotherapy to enhance efficacy.

• Histology-Agnostic Approaches: Expanding the use of MEK inhibitors beyond pLGG to other RAS-pathway-driven tumors.

• Personalized Medicine: Tailoring treatment based on genetic profiling to optimize outcomes while minimizing toxicities.

Conclusion

The arrival of MEK and RAF inhibitors has revolutionized the treatment profile of pediatric low-grade gliomas, providing an efficient and safe alternative to conventional chemotherapy. As tumor biology is better understood, future research and clinical trials will continue to refine the application of these agents, leading to an increasingly personalized and targeted treatment strategy for pLGG. Having fair and widespread access, while overcoming real-world implementation challenges, will be essential in deriving the most from these new treatments for every patient.

Read more such content on @ Hidoc Dr | Medical Learning App for Doctors