Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas

Abstract

BACKGROUND Effective medical therapies are lacking for the treatment of neurofibromatosis type 1– related plexiform neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling. METHODS We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1–related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.)

Genomic Status ofMETPotentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors

“…The recent clinical success of MEK inhibition (i.e. selumetinib) in NF1-related plexiform neurofibromas highlights the therapeutic potential of targeting MEK in NF1-related peripheral nerve tumors such as MPNSTs (41). We used the MEK inhibitor trametinib (Mekinist) which is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2, and is FDA approved for metastatic melanoma.…”

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

“…Previously, NF1 molecular testing was not routinely recommended unless needed for reproductive decision making in patients with a clinical diagnosis of NF1, as molecular diagnosis would not alter management for individuals with an established clinical diagnosis. This classic paradigm is shifting, however, based on new knowledge that a variety of syndromes have overlapping features with NF1 but a very different clinical course and on the emerging therapeutic benefits observed with targeted therapies aimed at the RAS/MAPK pathway in children with NF1 (57). A child who meets one or more clinical criterion (as outlined in Table 1) should now have NF1 molecular genetic testing (sequencing and deletion/duplication analysis) offered to confirm if NF1 is the correct diagnosis, as a misdiagnosis could lead to inappropriate surveillance.…”

Not so mass effect? Finding of a remarkable ‘incidentaloma’ in a teenager with neurofibromatosis

“…As previously discussed, tumour growth associated with a dysregulated MAPK signalling, key component of which are the enzymes mitogen-activated protein kinase 1 and 2 (MEK1 and 2). Dombi et al have recently described a phase 1 trial in 24 affected children of selumetinib, a selective MEK1 and 2 inhibitor and report that 71% of patients exhibited a ≥20% reduction in tumour volume 12. Further fields of research include the use of agents such as 13-cis-retinoic acid, thalidomide and interferon α-2a 6.…”