Selumetinib 10mg capsules

Background: Selumetinib is the first approved treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in the EU and US, as well as in multiple other countries. Evidence for the management of selumetinib-associated adverse events (AEs) is mostly limited to clinical trials and expanded-access programs. We gathered a panel of European healthcare practitioners with clinical experience prescribing selumetinib and/or managing pediatric patients with NF1-PN to provide recommendations on the prevention and management of AEs. Methods: A modified Delphi approach was used to develop the recommendations among the group of experts. Initial statements were developed from a literature review of current management recommendations and regulatory reports. The panel refined the statements and rated the extent to which they agreed with them in 2 sessions and a follow-up survey. The panel comprised 2 pediatric neuro-oncologists, 1 pediatric oncologist, 1 pediatrician, 1 neuropediatrician, 1 oncologist, 1 neurologist, 2 psychologists, and 1 dermatologist. Results: The experts agreed on the relative frequency and impact of AEs potentially associated with selumetinib. Consensus-level agreement was reached for 36 statements regarding the prevention and management of AEs potentially associated with selumetinib. Experts recommended treatments for AEs based on their experience. Conclusions: The development of a variety of consensus statements indicates expert agreement on best practices for the prevention and management of AEs potentially associated with selumetinib in pediatric patients with NF1-PN. These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained.

Abstract licence: CC BY-NC

BACKGROUND: 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 cutoff (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. METHODS: 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 February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging 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). RESULTS: 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 was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .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. CONCLUSIONS: 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 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Abstract licence: Public domain

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a wide range of clinical manifestations, including café-au-lait macules, cutaneous neurofibromas, and an increased risk of certain malignancies. Historically, there has been no approved medical therapy specifically aimed at achieving tumor shrinkage or regression. Surgical intervention is often limited by factors such as the inaccessibility of the tumor location, involvement of critical tissues, suboptimal timing, or the inability to achieve complete resection. Recent advancements in targeted therapies, particularly MEK inhibitors, have introduced promising treatment options for patients with severe manifestations of NF1. This review highlights the pathophysiology of NF1 and the therapeutic role of MEK inhibitors and presents a detailed case study of a patient treated with selumetinib, a novel MEK inhibitor. While the therapeutic potential of selumetinib has been demonstrated in preclinical and clinical studies, including those involving Japanese patients, this review aims to evaluate its application in real-world clinical practice. A comprehensive discussion of the case study provides insights into the efficacy, safety, and clinical challenges associated with selumetinib treatment, offering valuable perspectives for its use in managing NF1.

Abstract licence: CC BY

WHAT IS THIS SUMMARY ABOUT?: Neurofibromatosis type 1 (also called NF1) is a rare genetic condition. It causes a range of symptoms that develop from childhood onwards and worsen over time. Some children with NF1 develop non-cancerous nerve tumors called plexiform neurofibromas. Plexiform neurofibromas can grow large and compress nearby tissues. This can cause severe pain, reduced movement, vision and hearing loss, and other medical problems. Some children can have plexiform neurofibromas removed surgically. Most children have tumors that cannot be removed by surgery (known as inoperable tumors). Children with inoperable plexiform neurofibromas can receive a medicine called selumetinib. This plain language summary includes important findings from two selumetinib studies in children with NF1 and inoperable plexiform neurofibromas: The SPRINT selumetinib studies are part of a clinical study program that looked at how well selumetinib works in treating children with symptomatic, inoperable plexiform neurofibromas. The SPRINT studies program included the first studies of this medicine done in children, called phase 1 and phase 2 studies. For the phase 2 study, some children had severe symptoms and some children did not. The group of children with severe symptoms is called group 1, and their results are included in this summary. The researchers monitored the participating children for up to 5 years in a long-term study to better understand how the treatment works over time. The NF1 caregivers experience study is a related study where caregivers shared their experiences of caring for children with NF1and plexiform neurofibromas. WHAT WERE THE RESULTS?: A total of 74 children took part in the SPRINT phase 1 and phase 2 (group 1) study. Their ages ranged from 3 to 18.5 years, and their average age was 10.3 years. After more than 4 years of treatment, around 70% of the children (52 out of 74) had smaller tumors. For most children, the responses lasted beyond 1 year. There was a significant and lasting reduction in the intensity of the children';s tumor pain, noticeable as early as 2 months after starting the treatment. After 12 months, children reported their pain dropped from an average score of 2.2 to 0.6 and stayed low at 0.58 over 4 years. There was also an improvement in how much their pain affected the children's ability to do daily tasks. Some children had side effects related to selumetinib, although these were generally manageable. Results from the NF1 caregivers experience study showed caregivers of children with plexiform neurofibromas face significant impacts in physical, psychological, economic, and social aspects. These effects often result in a loss of productivity and difficulties with daily activity. WHAT DO THE RESULTS OF THE STUDY MEAN?: Children with NF1 who have symptomatic, inoperable plexiform neurofibromas can benefit from selumetinib treatment. Selumetinib is generally well-tolerated, but it is important to monitor side effects during treatment. Caring for a child with NF1 and symptomatic, inoperable plexiform neurofibromas has a significant impact on family members and others providing daily care. This highlights the importance of improving treatment and quality of life for both children with the condition and their caregivers.

Abstract licence: CC BY-NC-ND

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1 manifestations (eg, neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase II trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hours for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22 ± 5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P < .05). Prepubertal patients showed increases in height score and growth velocity (P < .05). Café-au-lait spot intensity decreased significantly (P < .05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSIONS: Selumetinib decreases PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in nonmalignant diverse NF1 manifestations. TRIAL REGISTRATION: Cris.nih.go.kr Identifier (KCT0003700).

Abstract licence: CC BY-NC