Long-Term Safety and Efficacy of Selumetinib in Children with Neurofibromatosis Type 1 on a Phase 1/2 Trial for Inoperable Plexiform Neurofibromas

Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cut-off (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. This manuscript includes data from the Phase 1 and Phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle=28 days). Safety and efficacy data through 2/27/2021 are included. PN response assessed by volumetric MRI analysis: confirmed partial response (cPR) =20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (Pain Interference Index). For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting = 12 cycles. Tumor pain intensity (n=19, p=0.015) and pain interference (n=18, p=0.0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at one year. No new safety signals were identified, however ongoing monitoring for known selumetinib-related AEs is needed while treatment continues. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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