selumetinib
Fuentes regulatorias consultadas
Indicaciones aprobadas
- Adultos y pacientes pediátricos desde 1 año con neurofibromatosis tipo 1 y neurofibromas plexiformes sintomáticos e inoperables.
Contraindicaciones
Absolutas
- CIMA: hipersensibilidad al principio activo o excipientes e insuficiencia hepática grave; la etiqueta FDA indica que no hay dosis establecida para hepatopatía grave.
Advertencias clínicas
- Controla FEVI al inicio, cada 3 meses el primer año y luego cada 6 meses. Examen oftalmológico basal y periódico: oclusión venosa retiniana exige suspensión; desprendimiento del epitelio pigmentario exige retención. — OpenFDA, set_id 7d042c61-f28f-4ab5-ab10-d7558c0d49ff
- Vigila diarrea, toxicidad cutánea y CPK/rabdomiólisis. Las cápsulas contienen vitamina E: calcula la ingesta total, evita suplementos sobre el límite y vigila sangrado con antagonistas de vitamina K o antiagregantes. — OpenFDA, set_id 7d042c61-f28f-4ab5-ab10-d7558c0d49ff
Interacciones medicamentosas
- SeveraInhibidores o inductores CYP3A y fluconazol
Mecanismo: Pueden alterar la exposición a selumetinib.
Recomendación: Evita inhibidores CYP3A fuertes/moderados, fluconazol e inductores. Si un inhibidor o fluconazol es inevitable, no inicies ni continúes sin que el equipo oncológico seleccione la reducción específica de cápsulas por superficie corporal.
OpenFDA, set_id 7d042c61-f28f-4ab5-ab10-d7558c0d49ff
Eventos adversos
Comunes (≥1%)
vómitos · diarrea · aumento de creatina fosfoquinasa · piel seca · paroniquia · náuseas · dermatitis acneiforme · fiebre
Embarazo y lactancia
Verifica embarazo. Mujeres y hombres deben usar anticoncepción durante y 1 semana después. No amamantes durante ni 1 semana después.
Bibliografía reciente (PubMed)
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts. Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease. The diagnosis of NF1 is established in a proband with two or more of the characteristic clinical features or one characteristic clinical feature and a heterozygous NF1 pathogenic variant. Treatment of manifestations: Referral to specialists for treatment of abnormalities of the eye, central or peripheral nervous system, cardiovascular system, lungs, endocrine system, spine, or long bones. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Surgical removal or other non-surgical methods to ablate disf
Currently, no worldwide approved therapies exist for adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas. The KOMET study aimed to evaluate selumetinib (ARRY-142886, AZD6244) efficacy and safety in this population. This ongoing multicentre, international, randomised, placebo-controlled, phase 3, parallel, double-blind trial randomly assigned adults with NF1-plexiform neurofibroma 1:1 to 28-day cycles of oral selumetinib 25 mg/m2 twice daily, or placebo with crossover to selumetinib at confirmed radiological progression or the end of cycle 12. The primary endpoint was objective response rate (confirmed partial or complete response) established by use of independent central review per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria by cycle 16 (selumetinib vs placebo). This study (KOMET) is registered with ClinicalTrials.gov, NCT04924608 and is ongoing. Overall, of 184 participants enrolled, 145 adults were randomly assigned to selumetinib (n=71) or placebo (n=74). Selumetinib led to a rapid response (median 3·7 months), with an objective response rate of 20% (n=14/71; 95% CI 11·2 to 30·9) by cycle 16 versus 5% (n=4/74; 1·5 to 13·3) with placebo (p=0·011). Participants with baseline chronic pain intensity scores of at least 3 had a greater reduction in score at cycle 12 with selumetinib versus placebo (least-squares mean [SE] -2·0 [0·30] -2·6 to -1·4, vs -1·3 [0·29] -1·8 to -0·7; p=0·070), although this did not reach significance; and a clinically meaningful improvement from baseline. Change from baseline to cycle 12 in PlexiQoL total scores between treatment groups was not significant (least-squares mean difference [SE] -0·1 [0·59]; -1·2 to 1·1). Adverse events were consistent with the known selumetinib safety profile. In the first international, randomised, placebo-controlled trial in adults with NF1-plexiform neurofibromas, selumetinib achieved a significant objective response rate versus plac
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. 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). 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. 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.
Neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome, occurs when NF1 gene variants result in loss of neurofibromin, a negative regulator of RAS activity. Plexiform neurofibromas (PN) are peripheral nerve sheath tumors that develop in patients with NF1 and are associated with substantial morbidity and for which, until recently, the only treatment was surgical resection. However, surgery carries several risks and a proportion of PN are considered inoperable. Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN. In a phase I/II trial, most children (approximately 70%) achieved reduction in tumor volume accompanied by improvements in patient-reported outcomes (decreased tumor-related pain and improvements in quality of life, strength, and range of motion). Selumetinib is currently the only licensed medical therapy indicated for use in pediatric patients with symptomatic, inoperable NF1-PN, with approval based on the results of this pivotal clinical study. Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN. Careful consideration of multiple aspects of both disease and treatments is vital to reduce morbidity and improve outcomes in patients with this complex and heterogeneous disease, and clinicians should be fully aware of the risks and benefits of available treatments. There is no single treatment pathway for patients with NF1-PN; surgery, watchful waiting, and/or medical treatment are options. Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strat