The Evolution of Targeted Treatments for Pediatric Low-Grade Brain Tumors

Table of Contents

• Introduction: Understanding Pediatric Low-Grade Gliomas
• The Evolution of pLGG Treatment Approaches
• Molecular Breakthrough: The MAPK Pathway Discovery
• Targeted Therapies for pLGG: BRAF and MEK Inhibitors
• Clinical Trial Results and Effectiveness Data
• Current Challenges and Limitations of Targeted Therapy
• Side Effects and Toxicity Management
• Future Directions and Ongoing Research
• What This Means for Patients and Families
• Source Information

Introduction: Understanding Pediatric Low-Grade Gliomas

Pediatric low-grade gliomas (pLGG) are the most common brain tumors in children. While these tumors are not typically aggressive, they present significant challenges because they often regrow after initial treatment and many patients require multiple treatment courses over time.

The long-term survival rate for children with pLGG exceeds 90%, which is excellent news for families. However, this positive outlook comes with a significant caveat: children often experience cumulative toxicity from multiple treatments, leading to serious long-term health problems and reduced quality of life.

Surgical removal remains the primary treatment when possible, achieving cure in approximately 60% of cases. For tumors that cannot be completely removed or that recur after surgery, additional treatments are necessary. This is where the field has seen remarkable advances in recent years.

The Evolution of pLGG Treatment Approaches

The approach to treating pLGG has evolved dramatically over the decades. In the 1970s and 1980s, radiation therapy was the standard treatment for tumors that couldn't be completely removed or that recurred after surgery. However, researchers eventually discovered that radiation caused significant long-term damage that was sometimes more severe than the disease itself.

A major database review of 4,040 pediatric LGG cases treated between 1973 and 2008 revealed startling data: receiving radiation therapy was the greatest risk factor for death in multivariate analysis of 20-year overall survival, with a hazard ratio of 3.9. This means children who received radiation were nearly four times more likely to die over a 20-year period compared to those who didn't receive radiation.

As a result, chemotherapy became the preferred treatment over radiation. A pivotal phase 3 clinical trial showed that chemotherapy resulted in 5-year event-free survival of 45 ± 3.2% and overall survival of 86 ± 2.2%. While these numbers represented progress, nearly half of patients still experienced tumor progression within five years, requiring additional treatment.

Molecular Breakthrough: The MAPK Pathway Discovery

The treatment landscape began to change dramatically in the early 2000s when researchers made a crucial discovery about the molecular mechanisms driving pLGG. Through genome-wide analysis, scientists identified that the majority of these tumors have genetic alterations in what's called the MAPK pathway.

Specifically, researchers found that 84% of pediatric low-grade gliomas harbor a genetic alteration in the MAPK pathway, and nearly universal upregulation of this pathway occurs in these tumors. The most common genetic abnormalities identified were:

• KIAA1549-BRAF fusions (occurring in many pilocytic astrocytomas)
• BRAF-V600 mutations (occurring in approximately 19% of pediatric LGG)

This discovery was groundbreaking because it meant that instead of using broad-acting chemotherapy that affected both cancerous and healthy cells, doctors could now use targeted therapies that specifically block the abnormal signals causing tumor growth.

Targeted Therapies for pLGG: BRAF and MEK Inhibitors

The identification of MAPK pathway alterations led to the development of targeted treatments specifically designed to block these abnormal signals. The main categories of targeted drugs include:

BRAF-V600E Inhibitors

Drugs like dabrafenib specifically target the BRAF-V600 mutation. In clinical trials, dabrafenib showed an overall response rate of 44% with a 1-year progression-free survival rate of 85%. Importantly, these inhibitors only work for tumors with the specific BRAF-V600 mutation and can actually cause paradoxical acceleration of growth in tumors with BRAF fusions.

MEK Inhibitors

Since MEK is the downstream gene in the MAPK pathway, MEK inhibitors like selumetinib can target multiple types of MAPK alterations. Clinical trials have shown impressive results:

• Selumetinib achieved 2-year progression-free survival of 69 ± 9.8%
• 36% of patients with BRAF-altered tumors had sustained partial responses
• 40% of patients with neurofibromatosis type 1-associated pLGG had sustained partial responses

Combination Therapy

Based on adult cancer research, combining BRAF and MEK inhibitors has shown better outcomes than single agents. In pediatric trials, the combination of dabrafenib and trametinib demonstrated:

• Overall response rate of 47% compared to 11% with chemotherapy
• Clinical benefit in 86% of patients versus 46% with chemotherapy
• Grade 3 or higher adverse events in only 47% of patients versus 94% with chemotherapy

Clinical Trial Results and Effectiveness Data

The effectiveness of various treatments for pLGG has been extensively studied in clinical trials. The data shows a clear advantage for targeted therapies over traditional approaches:

Traditional Chemotherapy Results:

• Vincristine/carboplatin: 5-year progression-free survival of 39 ± 4%
• TPCV regimen: 5-year progression-free survival of 52 ± 5%
• Vinblastine: 5-year progression-free survival of 53.2%
• Multiple drug combinations: 5-year progression-free survival of 34%
• Avastin/irinotecan: 2-year progression-free survival of 47.8 ± 9.27%

Targeted Therapy Results:

• Dabrafenib: 1-year progression-free survival of 85%
• Selumetinib: 2-year progression-free survival of 70%
• Trametinib: 1-year progression-free survival of 83.1%
• Dabrafenib + Trametinib: 1-year progression-free survival of 67% versus 26% with chemotherapy

These results were so compelling that in March 2023, the FDA approved dabrafenib and trametinib combination for treating pLGG with BRAF-V600E mutation, effectively replacing chemotherapy as first-line treatment for this specific subgroup.

Current Challenges and Limitations of Targeted Therapy

Despite the remarkable progress, targeted therapies for pLGG face several significant challenges that researchers are working to address:

Treatment Resistance

Some tumors develop resistance to targeted therapies through various mechanisms. Research has identified several resistance pathways:

• MEK/ERK-dependent resistance (can sometimes be overcome with combination therapy)
• MEK/ERK-independent resistance (including EGFR-mediated resistance)
• Autophagy (a cellular recycling process that helps tumors survive treatment)

Researchers are testing combination approaches, such as adding hydroxychloroquine (an autophagy inhibitor) to MAPK inhibitors, to overcome these resistance mechanisms.

Rebound Growth After Stopping Treatment

A particularly concerning phenomenon is rapid tumor regrowth after discontinuing targeted therapy. A study of 56 BRAF-V600E mutant pLGGs found that 76.5% experienced rapid progression after stopping BRAF inhibitors, with rebound growth occurring at a median of 2.3 months.

The good news is that 90% of these patients responded again when retreated with BRAF inhibition. However, this raises difficult questions about how long children need to continue these medications—possibly indefinitely.

Side Effects and Toxicity Management

While targeted therapies generally have fewer severe side effects than chemotherapy, they still cause specific toxicities that require careful management:

Skin Toxicity

Skin problems are the most common side effect, affecting many patients taking MAPK inhibitors. These can include:

• Maculopapular rash (red, raised bumps on skin)
• Follicular eruptions (hair follicle inflammation)
• Erythema (skin redness)
• Keratosis pilaris-like changes (rough, bumpy skin)
• Photosensitivity (increased sun sensitivity)

Fortunately, doctors have developed effective prevention and management strategies including sunscreen, moisturizers, topical corticosteroids, and sometimes oral antibiotics or steroids.

Other Significant Side Effects

Targeted therapies can also cause:

• Cardiac issues: Approximately 10% of adult patients experience decreased heart function
• QTc prolongation: A heart rhythm issue seen in 3% of patients
• Ophthalmologic problems: Various eye inflammations and vision changes
• Fever and gastrointestinal symptoms

Additionally, because these drugs are metabolized by liver enzymes, they can interact with many other medications, requiring careful monitoring.

Future Directions and Ongoing Research

The field of pLGG treatment continues to evolve rapidly with several promising developments:

Second-Generation Inhibitors

New drugs like tovorafenib show promise for treating both BRAF fusions and BRAF-V600 mutations without causing paradoxical activation. Early studies show:

• 67% overall response rate for BRAF-altered tumors
• Weekly dosing schedule (better for children than daily dosing)
• Tolerable safety profile with main side effects being hair color changes and elevated muscle enzymes

Based on this data, tovorafenib received FDA approval in April 2024 for children over 6 months with recurrent low-grade glioma harboring BRAF alterations.

Ongoing Clinical Trials

Multiple phase 3 trials are currently comparing targeted therapy to standard chemotherapy:

• COG studies comparing first-line chemotherapy to selumetinib monotherapy (NCT04166409, NCT03871257)
• Study comparing selumetinib alone versus selumetinib plus vinblastine for recurrent pLGG (NCT04576117)
• Trial combining trametinib and everolimus for recurrent gliomas (NCT04485559)

What This Means for Patients and Families

For families facing a pLGG diagnosis, these advances represent truly transformative progress. The shift from chemotherapy to targeted therapies means:

Better treatment outcomes with higher response rates and longer progression-free survival. Reduced severe side effects—grade 3 or higher adverse events dropped from 94% with chemotherapy to 47% with targeted combinations. More personalized treatment based on the specific genetic alterations in each child's tumor.

However, important questions remain that families should discuss with their medical team:

1. How long will treatment last? The optimal duration of targeted therapy is unknown, and rebound growth is a real concern.
2. What are the long-term effects? Since these drugs are relatively new, their impact on growth, development, fertility, and secondary cancer risk over decades is not fully understood.
3. How will side effects be managed? While generally better tolerated than chemotherapy, targeted therapies still require careful monitoring and management of specific toxicities.
4. What about cost and access? These newer treatments are expensive, and access may vary depending on insurance and geographic location.

The era of targeted therapy for pediatric low-grade glioma has truly arrived, offering new hope for children with these tumors while presenting new challenges that researchers continue to address.

Source Information

Original Article Title: Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era

Authors: Ashley S. Plant-Fox, Uri Tabori

Publication: Child's Nervous System (2024)

DOI: https://doi.org/10.1007/s00381-024-06504-7

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible to patients and families while preserving all significant scientific findings and data points from the original publication.