Targeted Therapy

Somatic BRAF V600E variants are present in a small subset of patients. While many of these tumors are responsive to BRAF and/or MEK inhibitors, responses in the recurrent setting are typically not sustained long term. A median progression-free survival of approximately 3 months was reported in one retrospective series.[6] In a multicenter, open-label, single-arm, phase II trial that evaluated dabrafenib plus trametinib, 15 of 45 adult patients with BRAF V600E variants and high-grade gliomas had an objective response. There were three complete responses and 12 partial responses, with a median overall survival of 17.6 months.[7]

The U.S. Food and Drug Administration (FDA) approved the combination of dabrafenib (BRAF inhibitor) plus trametinib (MEK inhibitor) for adult and pediatric patients aged 1 year and older with unresectable or metastatic solid tumors with BRAF V600E variants who have progressed following prior treatment and have no satisfactory alternative treatment options.[8,9] This approval includes pediatric patients aged 1 year and older with BRAF V600E variants and high-grade gliomas. The approval for this patient population was based on the results described below:[8-10]

Activating gene fusions (ALK, NTRK1, NTRK2, NTRK3, ROS1, and MET) are characteristic of infant-type diffuse gliomas.[11,12] Data from case reports and recent prospective clinical trials suggest that these tumors are highly responsive to targeted therapies.[13]

Tumor sample sequencing was done in pediatric (n = 54) and young adult patients (n = 15) with recurrent or refractory high-grade gliomas who were enrolled in the National Cancer Institute (NCI)–Children's Oncology Group (COG) Pediatric MATCH trial. The test revealed genomic alterations that were considered actionable for treatment on MATCH study arms in 36 of 69 tumors (52.2%).[14] Alterations in MAPK pathway genes were detected in 17 of 69 tumors (24.6%), most frequently BRAF V600E variants or fusions (n = 11, 15.9%). FGFR1 variants or fusions were identified in 6 of 69 tumors (8.7%).