Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.

Abstract

10506 Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.