Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

Abstract

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low‐grade glioma

“…6,9,[43][44][45] It is difficult to make comparative statements regarding other targeted agents like selumetinib and trametinib, however, for whom the early data are descriptive in terms of sustained PRs or includes combined cohorts of low-grade patients treated with different BRAF/MEK inhibitors. [46][47][48] In conclusion, everolimus does demonstrate activity in pediatric patients with radiographically progressive LGGs and provides another potential option for patients with recurrent disease. Its limited, reversible toxicity and administration as a pill or liquid preparation obviates the need for intravenous access.…”

“…Taking into consideration the 5‐year OS and PFS, this drug compares similarly to other standard chemotherapy trials for refractory disease utilizing vinblastine or upfront trials utilizing carboplatin/vincristine 6,9,43–45 . It is difficult to make comparative statements regarding other targeted agents like selumetinib and trametinib, however, for whom the early data are descriptive in terms of sustained PRs or includes combined cohorts of low‐grade patients treated with different BRAF/MEK inhibitors 46–48 …”

Salvage chemotherapy after failure of targeted therapy in a child with BRAF V600E low‐grade glioma

“…2,3 Response rates are promising and appear to be superior to those observed with chemotherapy. 4 However, little is known regarding the management of patients who fail to respond or progress while treated with MEK or BRAF inhibitors. We describe a patient with BRAF V600E mutated PLGG who progressed on a combination of dabrafenib and tramatenib, and eventually responded to thioguanine, procarbazine, lomustine, and vincristine (TPCV) resulting in reversal of life-threatening symptoms.…”

“…Early trials have shown efficacy of BRAF and MEK inhibitors in recurrent/refractory PLGG 2,3 . Response rates are promising and appear to be superior to those observed with chemotherapy 4 . However, little is known regarding the management of patients who fail to respond or progress while treated with MEK or BRAF inhibitors.…”

“…A trial of dabrafenib in children with BRAF mutated PLGG reported a partial response in 19/27 evaluable patients, and a 1‐year event‐free survival of 85% 2 . More recently, Nobre et al compared two cohorts of patients with BRAF mutated PLGG treated with chemotherapy or BRAF inhibitors and demonstrated a clear advantage for targeted treatments 4 …”