MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

Peter M K de Blank¹, Andrea M Gross², Srivandana Akshintala², Jaishri O Blakeley³, Gideon Bollag⁴, Ashley Cannon⁵, Eva Dombi², Jason Fangusaro⁶, Bruce D Gelb⁷, Darren Hargrave⁸, AeRang Kim⁹, Laura J Klesse¹⁰, Mignon Loh¹¹, Staci Martin², Christopher Moertel¹², Roger Packer⁹, Jonathan M Payne¹³, Katherine A Rauen¹⁴, Jonathan J Rios¹⁵, Nathan Robison¹⁶, Elizabeth K Schorry¹, Kevin Shannon¹¹, David A Stevenson¹⁷, Elliot Stieglitz¹¹, Nicole J Ullrich¹⁸, Karin S Walsh⁹, Brian D Weiss¹, Pamela L Wolters², Kaleb Yohay¹⁹, Marielle E Yohe², Brigitte C Widemann², Michael J Fisher²⁰

Affiliations

¹ Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
² Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
³ Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
⁴ Plexxikon Inc., Berkeley, California, USA.
⁵ Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Children's Hospital of Atlanta, Emory University and the Aflac Cancer Center, Atlanta, Georgia, USA.
⁷ Department of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Department of Oncology, Great Ormond Street Hospital for Children, London, UK.
⁹ Center for Neuroscience and Behavioral Medicine and Center for Cancer and Blood Disorders, Children's National Hospital, Washington, DC, USA.
¹⁰ Department of Pediatrics, Division of Hematology/Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.
¹¹ Benioff Children's Hospital, University of California San Francisco, San Francisco, California, USA.
¹² Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
¹³ Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
¹⁴ Department of Pediatrics, University of California Davis, Sacramento, California, USA.
¹⁵ Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
¹⁶ Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁷ Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, California, USA.
¹⁸ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁹ Department of Neurology and Pediatrics, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Division of Oncology, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 35788692
PMCID: PMC9629420
DOI: 10.1093/neuonc/noac165

Review

MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

Peter M K de Blank et al. Neuro Oncol. 2022.

. 2022 Nov 2;24(11):1845-1856.

doi: 10.1093/neuonc/noac165.

Authors

Affiliations

¹ Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
² Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
³ Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
⁴ Plexxikon Inc., Berkeley, California, USA.
⁵ Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁶ Children's Hospital of Atlanta, Emory University and the Aflac Cancer Center, Atlanta, Georgia, USA.
⁷ Department of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Department of Oncology, Great Ormond Street Hospital for Children, London, UK.
⁹ Center for Neuroscience and Behavioral Medicine and Center for Cancer and Blood Disorders, Children's National Hospital, Washington, DC, USA.
¹⁰ Department of Pediatrics, Division of Hematology/Oncology, UT Southwestern Medical Center, Dallas, Texas, USA.
¹¹ Benioff Children's Hospital, University of California San Francisco, San Francisco, California, USA.
¹² Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
¹³ Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia.
¹⁴ Department of Pediatrics, University of California Davis, Sacramento, California, USA.
¹⁵ Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, Texas, USA.
¹⁶ Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA.
¹⁷ Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, California, USA.
¹⁸ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
¹⁹ Department of Neurology and Pediatrics, New York University Grossman School of Medicine, New York, New York, USA.
²⁰ Division of Oncology, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 35788692
PMCID: PMC9629420
DOI: 10.1093/neuonc/noac165

Abstract

The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 have made it the first medical therapy approved for this indication in the United States, the European Union, and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefits for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low-grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.

Keywords: MEK inhibitors; RASopathy; low-grade glioma; neurofibromatosis type 1; plexiform neurofibromas.

Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.

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References

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MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

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MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus

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