Selumetinib in Children with Inoperable Plexiform Neurofibromas

Abstract

Background: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1.

Methods: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children 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 (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable).

Results: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-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 diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia.

Conclusions: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

Figure 1.. Target Plexiform Neurofibroma Progression–free Survival during Selumetinib Treatment as Compared with Natural History of Neurofibromatosis Type 1.

At 3 years of follow-up, the progression-free survival was 15% in the natural-history group and 84% in the selumetinib group.

Figure 2.. Change in Plexiform Neurofibroma–Related Complications between Baseline and the Evaluation before Cycle 13 of Treatment with Selumetinib.

Most patients had some degree of improvement or no change and few had any worsening in functional, patient-reported, and observer-reported outcome measures of plexiform neurofibroma–related symptoms (Panel A). FEV₁ denotes forced expiratory volume in 1 second, NRS-11 the 11-item Numerical Rating Scale, PedsQL the Pediatric Quality of Life Inventory, PROMIS Patient-Reported Outcomes Measurement Information System, R5 airway resistance at 5 Hz, and R20 airway resistance at 20 Hz. On the Global Impression of Change scale (Panel B), 86% of parents (37 of 43) and 72% of children (21 of 29) (blue shaded areas) who completed the form reported some level of improvement with respect to the child’s plexiform neurofibroma–related complications (other than pain) at the evaluation before cycle 13. Percentages may not total 100 because of rounding.

Figure 3.. Examples of Specific Patients.

Panels A through C relate to an 8-year-old boy (Patient 1) with a large plexiform neurofibroma in the left neck, arm, and trunk (Panel A) that had a baseline volume of 1748 ml (Panel B). The patient received ibuprofen daily for tumor pain, and the tumor caused limitations in range of motion and strength at baseline (Panel C), with values marked in red indicating range of motion more than 2 SD below age- and sex-matched expected normal values. He had a 24.6% decrease in plexiform neurofibroma volume (Panel B) at the evaluation before cycle 13 with resolution of pain, allowing him to discontinue ibuprofen. In addition, the strength and range of motion of the muscles and joints in the body quadrant of the target plexiform neurofibroma increased by 5.3% and 50.5%, respectively, with normalization of his neck and shoulder movement (Panel C). NRS-11 scores range from 0 (no pain) to 10 (worst pain imaginable). Scores on the Pain Interference Index range from 0 to 6, with higher scores indicating greater interference of pain in daily functioning. Scores on the strength scale reflect the average strength of muscles in the quadrant of the target plexiform neurofibroma; scores range from 0 to 10, with higher scores indicating greater strength. The value for range of motion is the sum of degrees of motion in the joints in the body quadrant of the target plexiform neurofibroma. Panels D through F relate to a 10-year-old boy (Patient 2) with a plexiform neurofibroma in the right neck (baseline volume, 185 ml). The tumor shrank 36.2% after 12 cycles of treatment (Panel F), with a visible decrease in the disfigurement caused by the neurofibroma (Panels D and E). MRI denotes magnetic resonance imaging.