Neuropediatrics 2022; 53(01): 052-060
DOI: 10.1055/s-0041-1740549
Original Article

Treatment of Plexiform Neurofibromas with MEK Inhibitors: First Results with a New Therapeutic Option

Pia Vaassen
1   Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
,
Nikola Reinhard Dürr
2   Department of Neuroradiology, Sana Kliniken Duisburg, Duisburg, Germany
,
Thorsten Rosenbaum
1   Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany
› Author Affiliations

Abstract

Neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PN) are peripheral nerve sheath tumors that can significantly affect the quality of life. Until recently, surgery was the only treatment for these tumors. However, in most cases, surgery cannot achieve complete tumor removal and carries a high risk of postoperative deficits. Therefore, the recent approval of the MEK inhibitor selumetinib for the treatment of NF1-associated PN provides a long-awaited novel therapeutic option. Here, we report our experience with MEK inhibitor treatment in 12 pediatric NF1 patients with inoperable symptomatic PN. Eight patients received trametinib (median therapy duration 12.13 months and range 4–29 months), and four patients received selumetinib (median therapy duration 6.25 months and range 4–11 months). Volumetric magnetic resonance imaging (MRI) after 6 months of treatment was available for seven trametinib patients (median tumor volume reduction of 26.5% and range 11.3–55.7%) and two selumetinib patients (21.3% tumor volume reduction in one patient and +3% tumor volume change in the other one). All patients reported clinical benefits such as improved range of motion or reduced disfigurement. Therapy-related adverse events occurred in 58.3% of patients and mainly consisted of skin toxicity, paronychia, and gastrointestinal symptoms. Two patients discontinued trametinib treatment after 14 and 29 months when severe skin toxicity occurred and no further reduction of tumor size was observed. In one patient, discontinuation of therapy resulted in a 27.2% tumor volume increase as demonstrated on volumetric MRI 6 months later. Our data show that MEK inhibition is a novel therapeutic approach for inoperable PN with promising results and a manageable safety profile.



Publication History

Received: 31 May 2021

Accepted: 04 November 2021

Article published online:
14 December 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Huson SM, Compston DA, Clark P, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet 1989; 26 (11) 704-711
  • 2 Poyhonen M, Kytölä S, Leisti J. Epidemiology of neurofibromatosis type 1 (NF1) in northern Finland. J Med Genet 2000; 37 (08) 632-636
  • 3 Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005; 141 (01) 71-74
  • 4 Denayer E, Legius E, Brems H. Genetics and Pathway in Neurofibromatosis Type 1. In: Tadini G, Legius E, Brems H. eds. Multidisciplinary Approach to Neurofibromatosis Type 1. Switzerland: Springer Nature; 2020: 5-14
  • 5 Akshintala S, Baldwin A, Liewehr DJ. et al. Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: growth analysis of plexiform neurofibromas and distinct nodular lesions. Neuro-Oncol 2020; 22 (09) 1368-1378
  • 6 Gross AM, Singh G, Akshintala S. et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro-Oncol 2018; 20 (12) 1643-1651
  • 7 Nguyen R, Kluwe L, Fuensterer C, Kentsch M, Friedrich RE, Mautner VF. Plexiform neurofibromas in children with neurofibromatosis type 1: frequency and associated clinical deficits. J Pediatr 2011; 159 (04) 652-5.e2
  • 8 Needle MN, Cnaan A, Dattilo J. et al. Prognostic signs in the surgical management of plexiform neurofibroma: the Children's Hospital of Philadelphia experience, 1974-1994. J Pediatr 1997; 131 (05) 678-682
  • 9 Canavese F, Krajbich JI. Resection of plexiform neurofibromas in children with neurofibromatosis type 1. J Pediatr Orthop 2011; 31 (03) 303-311
  • 10 Jessen WJ, Miller SJ, Jousma E. et al. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 2013; 123 (01) 340-347
  • 11 Dombi E, Baldwin A, Marcus LJ. et al. Activity of selumetinib in neurofibromatosis type-1 related plexiform neurofibromas. N Engl J Med 2016; 375 (26) 2550-2560
  • 12 Gross AM, Wolters PL, Dombi E. et al. Selumetinib in children with inoperable plexiform neurofibromas. N Engl J Med 2020; 382 (15) 1430-1442
  • 13 Vaassen P, Dürr N, Röhrig A, Willing R, Rosenbaum T. Trametinib induces neurofibroma shrinkage and enables surgery. Neuropediatrics 2019; 50 (05) 300-303
  • 14 Ferner RE, Huson SM, Thomas N. et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007; 44 (02) 81-88
  • 15 McCowage GB, Mueller S, Pratilas CA. et al. Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)-associated plexiform neurofibroma: A phase I/IIa study. J Clin Oncol 2018; 36 (15, Suppl): 10504
  • 16 Common Terminology Criteria for Adverse Events (CTCAE). v5.0. 2017
  • 17 Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D. et al; REiNS International Collaboration. Recommendations for imaging tumor response in neurofibromatosis clinical trials. Neurology 2013; 81 (21, Suppl 1): S33-S40
  • 18 Toledano H, Dotan G, Friedland R. et al. Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1. Childs Nerv Syst 2021; 37 (06) 1909-1915
  • 19 Perreault S, Larouche V, Tabori U. et al. A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC Cancer 2019; 19 (01) 1250
  • 20 Gross AM, Dombi E, Widemann BC. Current status of MEK inhibitors in the treatment of plexiform neurofibromas. Childs Nerv Syst 2020; 36 (10) 2443-2452
  • 21 Geoerger B, Moertel CL, Whitlock J. et al. Phase 1 trial of trametinib alone and in combination with dabrafenib in children and adolescents with relapsed solid tumors or neurofibromatosis type 1 (NF1) progressive plexiform neurofibromas (PN). J Clin Oncol 2018; 36 (15, Suppl): 10537
  • 22 Baldo F, Grasso AG, Cortellazzo Wiel L. et al. Selumetinib in the treatment of symptomatic intractable plexiform neurofibromas in neurofibromatosis type 1: a prospective case series with emphasis on side effects. Paediatr Drugs 2020; 22 (04) 417-423
  • 23 Jackson S, Baker EH, Gross AM. et al. The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas. Neurooncol Adv 2020; 2 (01) a095
  • 24 Galvin R, Watson AL, Largaespada DA, Ratner N, Osum S, Moertel CL. Neurofibromatosis in the era of precision medicine: development of MEK inhibitors and recent successes with selumetinib. Curr Oncol Rep 2021; 23 (04) 45
  • 25 O'Sullivan Coyne G, Gross AM, Dombi E. et al. Phase II trial of the MEK 1/2 inhibitor selumetinib (AZD 6244, ARRY-142886 hydrogen sulfate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN). J Clin Oncol 2020; 38 (15, Suppl): 3612
  • 26 Lehmann B. Regulation (EC) no 1901/2006 on medicinal products for paediatric use & clinical research in vulnerable populations. Child Adolesc Psychiatry Ment Health 2008; 2 (01) 37
  • 27 Kernell JW, DePaola RV, Maglione AM, Ahern LN, Penney NG, Addiss DG. Risk of adverse swallowing events and choking during deworming for preschool-aged children. PLoS Negl Trop Dis 2018; 12 (06) e0006578
  • 28 Tse Y, Vasey N, Dua D. et al. The KidzMed project: teaching children to swallow tablet medication. Arch Dis Child 2020; 105 (11) 1105-1107
  • 29 Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to improve antiretroviral medication adherence in pediatric patients with HIV/AIDS. Pediatrics 2007; 119 (04) e893-e899
  • 30 Patel A, Jacobsen L, Jhaveri R, Bradford KK. Effectiveness of pediatric pill swallowing interventions: a systematic review. Pediatrics 2015; 135 (05) 883-889
  • 31 Boulva K, Apte S, Yu A. et al. Contemporary neoadjuvant therapies for high-risk melanoma: a systematic review. Cancers (Basel) 2021; 13 (08) 1905
  • 32 Méndez-Martínez S, Calvo P, Ruiz-Moreno O. et al. Ocular adverse events associated with MEK inhibitors. Retina 2019; 39 (08) 1435-1450
  • 33 Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol 2015; 7 (02) 122-136
  • 34 Modak S, Asante-Korang A, Steinherz LJ, Grana N. Trametinib-induced left ventricular dysfunction in a child with relapsed neuroblastoma. J Pediatr Hematol Oncol 2015; 37 (06) e381-e383
  • 35 Banks M, Crowell K, Proctor A, Jensen BC. Cardiovascular effects of the MEK inhibitor, trametinib: a case report, literature review, and consideration of mechanism. Cardiovasc Toxicol 2017; 17 (04) 487-493
  • 36 Boull C, Hook K, Moertel C, Maguiness S. Cutaneous reactions in children treated with the mitogen-activated protein kinase extracellular signal-regulated kinase inhibitor trametinib for neural tumors. Pediatr Dermatol 2017; 34 (01) 90-94
  • 37 Klesse LJ, Jordan JT, Radtke HB. et al. The use of MEK inhibitors in Neurofibromatosis type 1-associated tumors and management of toxicities. Oncologist 2020; 25 (07) e1109-e1116
  • 38 Ronsley R, Hounjet CD, Cheng S. et al. Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma. Cancer Med 2021; 10 (11) 3556-3564
  • 39 Sun Q, Antaya RJ. Treatment of MEK inhibitor-induced paronychia with doxycycline. Pediatr Dermatol 2020; 37 (05) 970-971