Reference Detail

Ref Type

PMID

Authors

Eric Bouffet, Jordan Hansford, Maria Luisa Garré, Junichi Hara, Ashley Plant-Fox, Isabelle Aerts, Franco Locatelli, Jasper Van der Lugt, Ludmila Papusha, Felix Sahm, Uri Tabori, Kenneth J. Cohen, Roger J. Packer, Olaf Witt, Lali Sandalic, Ana Bento Pereira da Silva, Mark W. Russo, Darren R. Hargrave

Title

Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG).

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	40	no. 17_suppl	June 10, 2022

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA2002

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References