Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity

Abstract

Background: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity.

Methods: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart.

Results: 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment.

Conclusions: Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results.

Clinical trial registration: ClinicalTrials.gov NCT01362803.

Keywords: MEK inhibitor; neurofibromatosis type 1; patient-reported outcome measures; plexiform neurofibroma; selumetinib.

Fig. 1

Examples of types of target plexiform neurofibromas (PN). PN are shown on axial STIR (short T1 inversion recovery) MRI sequences. (A) Typical appearing PN of the right pelvic wall displaying the characteristic central dot sign (dark center surrounded by bright rim) within individual small nodules. (B) Nodular pelvic PN consists of typical appearing and large distinct nodular components that account for ≥30% of total PN volume. (C) A solitary distinct nodular lesion (DNL) of the right carotid sheath. Arrows highlight DNLs defined as a single nodule ≥3 cm longest diameter, often with loss of the central dot sign.

Fig. 2

Tumor volumetric response through February 27, 2021 data cutoff (DCO). Black bars indicate the best response of tumor and gray bars indicate the response at the last restaging evaluation subject had prior to DCO. Asterisks (*) indicate progressive disease (≥20% increase from best response after a partial response).

Fig. 3

Progression-free survival (PFS) curve. Median PFS has not been reached. PFS at 48 cycles was 86.6% (95% CI: 55.2%-96.6%). Of note, though the maximum duration of treatment was 67 cycles, due to limitations from the COVID-19 pandemic the last evaluable restaging evaluation for that subject was performed after 60 cycles. Number at risk (# at risk) indicates the number of subjects remaining in the study at each time point.