Efficacy Study of Vemurafenib in Children With Recurrent or Progressive BRAF^V600E- or BRAF^InsT-Mutant Brain Tumors: PNOC002

Pediatric gliomas constitute the most prevalent central nervous system tumors in children, and aberrations in BRAF signaling contribute to their pathogenesis by disrupting the MAPK pathway. Targeted inhibition of this pathway using agents such as vemurafenib may hold therapeutic promise.

PNOC002 was a multicenter trial conducted through the Pediatric Neuro-Oncology Consortium in patients younger than 25 years with recurrent or progressive BRAF^V600E-mutant brain tumors. This combined phase 0/1 study aimed to establish the recommended phase II dose (RP2D) and assess preliminary efficacy, including tumor growth trajectories and rebound (defined as ≥25% increase in lesion size within 6 months, usually within 3 months, of stopping therapy).

Thirty-patients (range, 3-23 years) were treated at the RP2D of 550 mg/m² twice a day: 22 low-grade glioma (LGG) and 8 high-grade glioma (HGG). PFS at 6 months (PFS6) for the entire cohort was 80% (95% CI, 67 to 96). In patients with LGG, PFS6 was higher at 86% (95% CI, 73 to 100), compared with 63% (95% CI, 37 to 100) in patients with HGG. The best responses were stable disease (13 patients) and partial responses (13 patients). Four patients experienced PD, with three patients in the HGG cohort. Responsiveness varied by lesion type, with cystic lesions showing a larger and longer-lasting decrease in tumor size than solid lesions. Of 13 patients with LGG who discontinued treatment and had follow-up imaging, 3 (23%) experienced rebound within 78-97 days. The most common grade 3 adverse event was maculopapular rash (57%).

Vemurafenib showed efficacy in children with recurrent or progressive BRAF^V600E-mutant brain tumors with acceptable toxicity. However, the rebound rate of 23% warrants further investigation.