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Selumetinib Shows Durable Tumour Shrinkage and Clinical Benefit in Neurofibromatosis

MEK inhibition is a rational treatment strategy for neurofibromatosis type 1–related tumours
23 Mar 2020
Anticancer agents & Biologic therapy;  Cancer in Special Situations / Population;  Central nervous system malignancies

Selumetinib resulted in sustained neurofibroma shrinkage in the majority of patients and provided clinically meaningful benefit in a phase II trial in children and adolescents with neurofibromatosis type 1 and symptomatic plexiform neurofibroma. The toxicity level and absence of cumulative toxic effects permit long-term treatment according to investigators from the US National Cancer Institute (NCI).

Neurofibromatosis type 1 is an autosomal dominant genetic disorder characterised by multiple progressive tumour and non-tumour manifestations. There are limited treatment options. Because of overactivation of the RAS pathway, targeted inhibition with MEK inhibitors is a logical treatment approach that has been successful in a preclinical model of neurofibromatosis type 1. Plexiform neurofibromas are histologically benign peripheral-nerve sheath tumours that occur in up to 50% of persons with neurofibromatosis type 1 and can cause substantial complications.

In a phase I trial of the oral selective MEK inhibitor selumetinib involving 24 children with inoperable neurofibromatosis type 1–related plexiform neurofibromas, the study team found previously a median change in tumour volume of −31%, a confirmed partial response in 71% and anecdotal evidence of clinical improvement but no complete responses.

Determining clinical benefit in this population is a challenging task, given that neurofibromas occur in various locations, patients have a wide variety of neurofibroma-related symptoms, and few validated patient-reported or functional outcome measures for neurofibromatosis type 1 exist.

The primary objective of this phase II trial was to confirm the objective response rate of plexiform neurofibromas to selumetinib and key secondary objectives were to assess whether treatment was associated with clinical benefit.

The trial was coordinated by the NCI and was conducted at four participating sites in US. The study protocol was designed and written by the NCI investigators.

Children and adolescents with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule of 28 day cycles. Volumetric magnetic resonance imaging and clinical outcome assessments of pain, quality of life, disfigurement, and function were performed at least every four cycles. Patients rated tumour pain intensity on a scale from 0 meaning no pain to 10 meaning worst pain imaginable.

A total of 50 patients, median age 10.2 years (range, 3.5 to 17.4) were enrolled. The most frequent neurofibroma-related symptoms were disfigurement in 44 patients, motor dysfunction in 33 patients, and pain in 26 patients. A total of 35 patients (70%) had a confirmed partial response and 28 of these patients had a durable response lasting at least 1 year.

After 1 year of treatment, the mean decrease in reported tumour pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in patient-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients).

Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhoea, an asymptomatic increase in the creatine phosphokinase level, acneiform rash, and paronychia.

A limitation of this study is that, with the exception of the Pain Interference Index and the measurements of visual acuity, the other outcome measures that were used have not yet been validated for the population with neurofibromatosis type 1. The study team also did not find a direct correlation between change in neurofibroma size and patient-reported outcomes or functional responses.

The authors concluded that most patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumour shrinkage and clinical benefit from selumetinib.

Recently, other MEK inhibitors have also resulted in partial responses in patients with neurofibromatosis type 1–related neurofibroma, and selumetinib treatment resulted in shrinkage in neurofibromatosis type 1–related gliomas in the optic pathway. These findings confirm MEK inhibition as a rational treatment strategy for neurofibromatosis type 1–related tumours.

The study was supported by the US National Institute of Health, NCI, AstraZeneca which provided selumetinib and funding for the pharmacokinetic analysis and clinical-trial support, a grant from the Developmental and Hyperactive Ras Tumor Specialized Program of Research Excellence for pharmacodynamic studies and the Neurofibromatosis Therapeutic Acceleration Program for funding of trial conduct. 


Gross AM, Wolters PL, Dombi E, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. NEJM; Published online 18 March 2020. DOI: 10.1056/NEJMoa1912735.

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