Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1

Toledano, Helen; Dotan, Gad; Friedland, Rivka; Cohen, Rony; Yassur, Iftach; Toledano‐Alhadef, Hagit; Constantini, Shlomi; Rootman, Mika Shapira

doi:10.1007/s00381-021-05127-6

Cited by 8 publications

(20 citation statements)

References 21 publications

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“…In concert with several reports published elsewhere, our data show that MEK inhibitors such as selumetinib or trametinib reliably lead to a significant reduction of PN volume but will not result in the complete disappearance of the tumor. 11 12 13 18 19 20 21 22 23 24 25 For many NF1 patients even this partial response will be a therapeutic success since it might effectively reduce PN-related morbidity or facilitate surgical removal of the remaining tumor. 13 23…”

Section: Discussionmentioning

confidence: 99%

“…31 In pediatric NF1 patients treated with MEK inhibitors, gastrointestinal symptoms such as nausea, vomiting, and diarrhea, as well as skin toxicities were the most frequently reported AEs. 11 12 18 19 36 37 38 In most cases, these AEs were mild, did not lead to MEK inhibitor discontinuation, and could be controlled by dose reductions, treatment breaks, or standard therapies. 12 37 38 39 In our set of NF1 patients on MEK inhibitor treatment, dermatitis and paronychia were the most common AEs, whereas gastrointestinal symptoms only occurred in two out of seven patients (28.6%).…”

Section: Discussionmentioning

confidence: 99%

“…Other severe AEs such as reduced cardiac ejection fraction 34 35 could easily be monitored by echocardiography in all age groups but did not occur in our patient cohort and have only rarely been reported in pediatric NF1 patients on selumetinib or trametinib. 11 12 18 19 This might be a consequence of the younger patients' age and might also be caused by the combined use of MEK and BRAF inhibitors in adult cancer patients. 31 In pediatric NF1 patients treated with MEK inhibitors, gastrointestinal symptoms such as nausea, vomiting, and diarrhea, as well as skin toxicities were the most frequently reported AEs.…”

Section: Discussionmentioning

confidence: 99%

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

2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2021

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“…In recent years, there has been a greater focus on the use of MEK inhibitors for the treatment of nerve sheath tumors, based on promising preclinical studies ( Jessen et al, 2013 ; Ramkissoon et al, 2019 ). Clinical trials using the MEK inhibitor, selumetinib, revealed decreased pNF and spinal neurofibroma burden ( Jackson et al, 2020 ) with minimal side effects ( Baldo et al, 2021 ), and another MEK inhibitor, trametinib, decreased tumor size ( Toledano et al, 2021 ; Weiss et al, 2021 ). These exciting results culminated in MEK inhibitors, specifically selumetinib, becoming the first U.S. Food and Drug Administration (FDA)-approved agents for the treatment of progressive pNFs.…”

Section: Neurofibromin and Canonical Ras-dependent Signalingmentioning

confidence: 99%

RAS and beyond: the many faces of the neurofibromatosis type 1 protein

Anastasaki

Orozco

Gutmann

2022

Disease Models &Amp; Mechanisms

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Neurofibromatosis type 1 is a rare neurogenetic syndrome, characterized by pigmentary abnormalities, learning and social deficits, and a predisposition for benign and malignant tumor formation caused by germline mutations in the NF1 gene. With the cloning of the NF1 gene and the recognition that the encoded protein, neurofibromin, largely functions as a negative regulator of RAS activity, attention has mainly focused on RAS and canonical RAS effector pathway signaling relevant to disease pathogenesis and treatment. However, as neurofibromin is a large cytoplasmic protein the RAS regulatory domain of which occupies only 10% of its entire coding sequence, both canonical and non-canonical RAS pathway modulation, as well as the existence of potential non-RAS functions, are becoming apparent. In this Special article, we discuss our current understanding of neurofibromin function.

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“… 16 Due to the recent approval by regulatory agencies, relatively few cases have been published regarding the use of MEKi in the treatment of PNs. 17 - 23 …”

Section: Introductionmentioning

confidence: 99%

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study

et al. 2023

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Introduction Plexiform neurofibromas (PN) represent the main cause of morbidity in patients affected by Neurofibromatosis Type 1 (NF1). Until recently, surgery has been the main treatment option in these patients, but it is burdened with a low efficacy rate and a high incidence of side effects as well as recurrence. In recent years, MEK inhibitors (MEKi) such as selumetinib and trametinib have shown great promise. Methods We retrospectively describe a single center cohort of NF1 patients affected by PN1 and treated with MEKi since 2019 to 2021. Patients recruited in the study were affected by PN that were not eligible to complete surgical excision, symptomatic or with major cosmetic deformation or functional neurological deficits. Results Most patients experienced improvement in clinical symptoms and quality of life, with reduction or stabilization of lesions. However, no complete response was achieved. The most common adverse effects involved the skin, affecting every patient. Importantly, no life-threatening adverse effects occurred. Conclusions In our experience, MEKi treatment has been shown to be both safe and effective in improving symptomatology and quality of life.

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Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1

Cited by 8 publications

References 21 publications

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

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

RAS and beyond: the many faces of the neurofibromatosis type 1 protein

Safety and Efficacy of Mek Inhibitors in the Treatment of Plexiform Neurofibromas: A Retrospective Study

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