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

Peter M.K. De Blank; Andrea M. Gross; Srivandana Akshintala; Jaishri O. Blakeley; Gideon Bollag; Ashley Cannon; Eva Dombi; Jason Fangusaro; Bruce D. Gelb; Darren Hargrave; Ae Rang Kim; Laura J. Klesse; Mignon Loh; Staci Martin; Christopher Moertel; Roger Packer; Jonathan M. Payne; Katherine A. Rauen; Jonathan J. Rios; Nathan Robison; Elizabeth K. Schorry; Kevin Shannon; David A. Stevenson; Elliot Stieglitz; Nicole J. Ullrich; Karin S. Walsh; Brian D. Weiss; Pamela L. Wolters; Kaleb Yohay; Marielle E. Yohe; Brigitte C. Widemann; Michael J. Fisher

doi:10.1093/neuonc/noac165

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

Peter M.K. De Blank, Andrea M. Gross, Srivandana Akshintala, Jaishri O. Blakeley, Gideon Bollag, Ashley Cannon, Eva Dombi, Jason Fangusaro, Bruce D. Gelb, Darren Hargrave, Ae Rang Kim, Laura J. Klesse, Mignon Loh, Staci Martin, Christopher Moertel, Roger Packer, Jonathan M. Payne, Katherine A. Rauen, Jonathan J. Rios, Nathan RobisonElizabeth K. Schorry, Kevin Shannon, David A. Stevenson, Elliot Stieglitz, Nicole J. Ullrich, Karin S. Walsh, Brian D. Weiss, Pamela L. Wolters, Kaleb Yohay, Marielle E. Yohe, Brigitte C. Widemann, Michael J. Fisher

Research output: Contribution to journal › Review article › peer-review

29 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1845-1856
Number of pages	12
Journal	Neuro-oncology
Volume	24
Issue number	11
DOIs	https://doi.org/10.1093/neuonc/noac165
State	Published - Nov 1 2022

Keywords

MEK inhibitors
RASopathy
low-grade glioma
neurofibromatosis type 1
plexiform neurofibromas

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

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10.1093/neuonc/noac165

Cite this

De Blank, P. M. K., Gross, A. M., Akshintala, S., Blakeley, J. O., Bollag, G., Cannon, A., Dombi, E., Fangusaro, J., Gelb, B. D., Hargrave, D., Kim, A. R., Klesse, L. J., Loh, M., Martin, S., Moertel, C., Packer, R., Payne, J. M., Rauen, K. A., Rios, J. J., ... Fisher, M. J. (2022). MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro-oncology, 24(11), 1845-1856. https://doi.org/10.1093/neuonc/noac165

De Blank, PMK, Gross, AM, Akshintala, S, Blakeley, JO, Bollag, G, Cannon, A, Dombi, E, Fangusaro, J, Gelb, BD, Hargrave, D, Kim, AR, Klesse, LJ, Loh, M, Martin, S, Moertel, C, Packer, R, Payne, JM, Rauen, KA, Rios, JJ, Robison, N, Schorry, EK, Shannon, K, Stevenson, DA, Stieglitz, E, Ullrich, NJ, Walsh, KS, Weiss, BD, Wolters, PL, Yohay, K, Yohe, ME, Widemann, BC & Fisher, MJ 2022, 'MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus', Neuro-oncology, vol. 24, no. 11, pp. 1845-1856. https://doi.org/10.1093/neuonc/noac165

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title = "MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus",

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",

author = "{De Blank}, {Peter M.K.} and Gross, {Andrea M.} and Srivandana Akshintala and Blakeley, {Jaishri O.} and Gideon Bollag and Ashley Cannon and Eva Dombi and Jason Fangusaro and Gelb, {Bruce D.} and Darren Hargrave and Kim, {Ae Rang} and Klesse, {Laura J.} and Mignon Loh and Staci Martin and Christopher Moertel and Roger Packer and Payne, {Jonathan M.} and Rauen, {Katherine A.} and Rios, {Jonathan J.} and Nathan Robison and Schorry, {Elizabeth K.} and Kevin Shannon and Stevenson, {David A.} and Elliot Stieglitz and Ullrich, {Nicole J.} and Walsh, {Karin S.} and Weiss, {Brian D.} and Wolters, {Pamela L.} and Kaleb Yohay and Yohe, {Marielle E.} and Widemann, {Brigitte C.} and Fisher, {Michael J.}",

note = "Publisher Copyright: {\textcopyright} 2022 Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2022",

month = nov,

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doi = "10.1093/neuonc/noac165",

language = "English (US)",

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T1 - MEK inhibitors for neurofibromatosis type 1 manifestations

T2 - Clinical evidence and consensus

AU - De Blank, Peter M.K.

AU - Gross, Andrea M.

AU - Akshintala, Srivandana

AU - Blakeley, Jaishri O.

AU - Bollag, Gideon

AU - Cannon, Ashley

AU - Dombi, Eva

AU - Fangusaro, Jason

AU - Gelb, Bruce D.

AU - Hargrave, Darren

AU - Kim, Ae Rang

AU - Klesse, Laura J.

AU - Loh, Mignon

AU - Martin, Staci

AU - Moertel, Christopher

AU - Packer, Roger

AU - Payne, Jonathan M.

AU - Rauen, Katherine A.

AU - Rios, Jonathan J.

AU - Robison, Nathan

AU - Schorry, Elizabeth K.

AU - Shannon, Kevin

AU - Stevenson, David A.

AU - Stieglitz, Elliot

AU - Ullrich, Nicole J.

AU - Walsh, Karin S.

AU - Weiss, Brian D.

AU - Wolters, Pamela L.

AU - Yohay, Kaleb

AU - Yohe, Marielle E.

AU - Widemann, Brigitte C.

AU - Fisher, Michael J.

PY - 2022/11/1

Y1 - 2022/11/1

N2 - 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.

AB - 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.

KW - MEK inhibitors

KW - RASopathy

KW - low-grade glioma

KW - neurofibromatosis type 1

KW - plexiform neurofibromas

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DO - 10.1093/neuonc/noac165

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AN - SCOPUS:85141308428

SN - 1522-8517

VL - 24

SP - 1845

EP - 1856

JO - Neuro-oncology

JF - Neuro-oncology

IS - 11

ER -

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

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