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. 2020 May 20:4:PO.19.00298.
doi: 10.1200/PO.19.00298. eCollection 2020.

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

Liana Nobre  1 , Michal Zapotocky  1   2 , Vijay Ramaswamy  1   3   4 , Scott Ryall  1 , Julie Bennett  1 , Daniel Alderete  5 , Julia Balaguer Guill  6 , Lorena Baroni  5 , Ute Bartels  1 , Abhishek Bavle  7 , Miriam Bornhorst  8 , Daniel R Boue  9 , Adela Canete  6 , Murali Chintagumpala  10 , Scott L Coven  11 , Ofelia Cruz  12 , Sonika Dahiya  13 , Peter Dirks  14   15 , Ira J Dunkel  16 , David Eisenstat  17 , Cecile Faure Conter  18 , Elizabeth Finch  19 , Jonathan L Finlay  9 , Didier Frappaz  18 , Maria Luisa Garre  20 , Karen Gauvain  13 , Anne Grete Bechensteen  21 , Jordan R Hansford  22 , Inga Harting  23 , Peter Hauser  24 , Lili-Naz Hazrati  25 , Annie Huang  1   14 , Sarah G Injac  10 , Valentina Iurilli  20 , Matthias Karajannis  16 , Gurcharanjeet Kaur  16 , Martin Kyncl  2 , Lenka Krskova  2 , Normand Laperriere  1 , Valerie Larouche  26 , Alvaro Lassaletta  27 , Sarah Leary  28 , Frank Lin  10 , Samantha Mascelli  20 , Tara McKeown  1 , Till Milde  23 , Andres Morales La Madrid  12 , Giovanni Morana  20 , Helena Morse  29 , Naureen Mushtaq  30 , Diana S Osorio  9 , Roger Packer  8 , Zdenek Pavelka  31 , Eduardo Quiroga-Cantero  32 , James Rutka  14   15 , Magnus Sabel  33 , Duarte Salgado  34 , Palma Solano  32 , Jaroslav Sterba  31 , Jack Su  10 , David Sumerauer  2 , Michael D Taylor  3   14   15   25   35   4 , Helen Toledano  36 , Derek S Tsang  1 , Mariana Valente Fernandes  34 , Frank van Landeghem  17 , Cornelis M van Tilburg  23 , Bev Wilson  17 , Olaf Witt  23 , Josef Zamecnik  2 , Eric Bouffet  1 , Cynthia Hawkins  14   25   37 , Uri Tabori  1   14
Affiliations

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

Liana Nobre et al. JCO Precis Oncol. .

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.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Vijay RamaswamyHonoraria: AstraZenecaMiriam BornhorstConsulting or Advisory Role: AstraZeneca/MedImmuneDaniel R. BoueStock and Other Ownership Interests: Vertex Pharmaceuticals, Intuitive Surgical, IlluminaAdela CaneteConsulting or Advisory Role: EUSA Pharma, Bayer Speakers’ Bureau: EUSA PHarma Research Funding: EUSA Pharma (Inst) Travel, Accommodations, Expenses: EUSA PharmaIra J. DunkelConsulting or Advisory Role: Bayer, Apexigen, Celgene, Roche/Genentech, AstraZeneca Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Novartis (Inst)Karen GauvainEmployment: Iqvia Biotech Consulting or Advisory Role: Bayer, Axiom Health Care SciencesJordan R. HansfordConsulting or Advisory Role: BayerSarah G. InjacResearch Funding: TakedaMatthias KarajannisConsulting or Advisory Role: Bayer, Recursion Pharma Research Funding: Novartis Travel, Accommodations, Expenses: Bayer Uncompensated Relationships: Debiopharm (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/710370/summaryNormand LaperriereHonoraria: Merck/Schering Plough Consulting or Advisory Role: AbbVieAlvaro LassalettaConsulting or Advisory Role: Shire, Jazz Pharmaceuticals, Roche Travel, Accommodations, Expenses: Shire, Gilead SciencesRoger PackerHonoraria: Novartis Consulting or Advisory Role: Novartis, AstraZenecaJaroslav SterbaResearch Funding: Roche/Genentech (Inst) Travel, Accommodations, Expenses: Bristol-Myers SquibbDerek S. TsangOther Relationship: Varian Medical Systems (Inst), Mevion Medical Systems (Inst), Hitachi (Inst), RaySearch Laboratories (Inst), IBA (Inst), ProTom (Inst)Cornelis M. van TilburgConsulting or Advisory Role: Novartis, BayerOlaf WittConsulting or Advisory Role: Novartis, AstraZeneca, Janssen Research & Development, Bristol-Myers Squibb, Roche, BayerEric BouffetResearch Funding: Roche (Inst), Bristol-Myers Squibb (Inst)Cynthia HawkinsConsulting or Advisory Role: Bayer Patents, Royalties, Other Intellectual Property: IP for low-grade glioma and sarcoma fusion panels as well as medulloblastoma subgrouping panel No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Response of BRAF V600E–mutated gliomas to BRAF inhibition. (A) Waterfall plot of best response in pediatric low-grade gliomas (PLGGs) to BRAF inhibition as measured by the products of perpendicular measures in T2 or fluid-attenuated inversion recovery magnetic resonance imaging. (B) Spider plot revealing time to response of PLGGs to BRAF inhibition. (C) Waterfall plot of response at 6 months in PLGGs treated with (C) chemotherapy or (D) BRAF inhibition. CR, complete response; MR, minor response; PD, progressive disease; PR, partial response; SD, stable disease.
FIG 2.
FIG 2.
Swimmer plot for BRAF V600E–mutated gliomas treated with BRAF inhibition. Legend describes parameters of response, progression, and ongoing therapy. CR, complete response; MR, minor response; PD, progressive disease; PR, partial response; SD, stable disease.
FIG 3.
FIG 3.
Survival plot for BRAF V600E–mutated pediatric low-grade gliomas (PLGGs). Progression-free survival (PFS) for (A) 56 patients with PLGG treated with BRAF inhibition, (B) those in whom BRAF inhibition therapy was continued for ≥ 10 months, and (C) those in whom BRAF inhibition was discontinued after ≥ 10 months. (D) PFS for patients with BRAF V600E–mutated PLGG treated with chemotherapy.
FIG 4.
FIG 4.
Outcomes of BRAF V600E–mutated pediatric high-grade gliomas (PHGGs) treated with BRAF inhibition. (A) Waterfall plot of best response, (B) swimmer plot, and (C) Kaplan-Meier plot for progression-free survival (PFS) comparing children with pediatric low-grade glioma (PLGG) and PHGG. CR, complete response; MR, minor response; PD, progressive disease; PR, partial response; SD, stable disease.
See this image and copyright information in PMC

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