In the phase II PNOC001 trial reported in the Journal of Clinical Oncology, Daphne A. Haas-Kogan, MD, MBA, and colleagues found that everolimus showed activity in pediatric patients with recurrent or progressive low-grade glioma. PI3K/AKT/mTOR pathway activation was not correlated with clinical outcomes.
Daphne A. Haas-Kogan, MD, MBA
Study Details
In the multicenter international trial, 65 patients aged 3 to 21 years enrolled between 2012 and 2019 received everolimus at 5 mg/m2 once daily. The primary endpoint of the study was 6-month progression-free survival. Association of outcome with PI3K/AKT/mTOR pathway activation was assessed, with activation measured by phosphorylated-ribosomal protein S6.
Key Findings
Median follow-up was 57.5 months. Progression-free survival at 6 months was 67.4% (95% confidence interval [CI] = 60.0%–80.0%). Median progression-free survival was 11.1 months (95% CI = 7.6–19.8 months). Overall survival at 6 months was 100%; at 48 months, it was 91.9% (95% CI = 85.3%–99.0%).
PI3K/AKT/mTOR pathway activation vs nonactivation was not associated with differences in 6-month progression-free survival (68.4% vs 63.3%) or median progression-free survival (11.2 months vs 11.1 months, P = .80). Pathway activation was also not associated with differences in overall survival (P = .35).
Rare/novel KIAA1549::BRAF fusion breakpoints were most frequent in supratentorial midline pilocytic astrocytomas, and were correlated with poorer outcome vs presence of common KIAA1549::BRAF fusion breakpoints (median progression-free survival = 6.1 vs 16.7 months, P < .05). Rare pathogenic germline variants in homologous recombination genes were identified in 6.8% of the study population.
The most common grade ≥ 3 treatment-related adverse events in patients receiving everolimus were hypertriglyceridemia (16.9%), oral mucositis (7.7%), and diarrhea (6.2%).
The investigators concluded, “Everolimus is a well-tolerated therapy for progressive/recurrent pediatric low-grade gliomas. Rare/novel KIAA1549::BRAF fusion breakpoints may define biomarkers for progressive disease and should be assessed in future clinical trials.”
Sabine Mueller, MD, PhD, MAS, of the Departments of Neurology, Neurosurgery, and Pediatrics, University of California, San Francisco, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Pacific Pediatric Neuro-Oncology Consortium Foundation and the Pediatric Brain Tumor Foundation. For full disclosures of the study authors, visit ascopubs.org.
