Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG).
Authors: Bouffet Eric , Hansford Jordan , Garré Maria Luisa , Hara Junichi , Plant-Fox Ashley , Aerts Isabelle , Locatelli Franco , Van der Lugt Jasper , Papusha Ludmila , Sahm Felix , Tabori Uri , Cohen Kenneth J. , Packer Roger J. , Witt Olaf , Sandalic Lali , Bento Pereira da Silva Ana , Russo Mark W. , Hargrave Darren R. 
Published: June 2022

LBA2002 Background: LGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. Most patients (pts) with pLGG have disease progression and require post-surgical therapy. The standard of care is chemotherapy, such as carboplatin + vincristine (C+V), which may be less effective in BRAF V600–mutant disease; thus, alternative treatment options are needed. Dab + tram showed encouraging efficacy in a Phase I/II study (NCT02124772) in pts with previously treated BRAF V600–mutant pLGG. We describe the results of a randomized Phase II study (NCT02684058) of first-line dab + tram vs C+V in BRAF V600–mutant pLGG. Methods: Pts aged 1 to <18 y with BRAF V600 mutation–positive gliomas and Karnofsky/Lansky performance status ≥50% were enrolled. In the pLGG cohort, pts with progressive disease after surgery or nonsurgical pts requiring systemic treatment were randomized (2:1) to receive either dab twice daily (<12 y, 5.25 mg/kg/d; ≥12 y, 4.5 mg/kg/d) + tram once daily (<6 y, 0.032 mg/kg/d; ≥6 y, 0.025 mg/kg/d) or C+V (standard dosing). The primary endpoint was overall response rate (ORR; independent review, RANO criteria). Secondary endpoints included investigator-assessed ORR, clinical benefit rate (CBR), duration of response, time to response, progression-free survival (PFS), overall survival, and safety. Results: A total of 110 pts were randomized to receive dab + tram (n=73) or C+V (n=37); 4 pts in the C+V arm withdrew before treatment. Baseline characteristics were well balanced between treatment arms. At data cutoff (August 23, 2021; median follow-up, 18.9 mo), 61 pts (84%) in the dab + tram arm and 8 (22%) in the C+V arm remained on treatment; in the C+V arm, 9 completed planned treatment and 16 discontinued before completion. The primary endpoint was met: the independently assessed ORR (CR+PR) was 47% (95% CI, 35%-59%) with dab + tram vs 11% (95% CI, 3%-25%) with C+V ( P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]), and the clinical benefit rate (CR+PR+SD ≥24 wk) was 86% (95% CI, 76%-93%) vs 46% (95% CI, 30%-63%). Median PFS was 20.1 mo (95% CI, 12.8 mo-not estimable) with dab + tram vs 7.4 mo (95% CI, 3.6-11.8 mo) with C+V ( P<.001; HR, 0.31 [95% CI, 0.17-0.55]); 12-mo Kaplan-Meier PFS rates were 67% vs 26%. There were no deaths in the dab + tram arm and 1 in the C+V arm due to LGG. Pts in the dab + tram arm had fewer grade ≥3 adverse events (AEs; 47% vs 94%) and fewer discontinuations due to AEs (4% vs 18%) than pts in the C+V arm. The most frequent AEs in the dab + tram vs chemotherapy arms were pyrexia (68% vs 18%), headache (47% vs 27%), and vomiting (34% vs 48%). Conclusions: Dab + tram significantly increased ORR and CBR and prolonged PFS compared with C+V in pts with BRAF V600 mutation–positive pLGG. These encouraging results and the tolerable safety profile suggest that dab + tram may be a promising first-line systemic treatment option for this pt population. Clinical trial information: NCT02684058.