Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial

Abstract

Authors' Contributions 1.JF -Substantial contributions to acquisition, analysis and interpretation of data, drafting the work, final approval of the version to be published and agreement to be accountable for all aspects of the work. 2.AO -Substantial contributions to the conception and design of the work, analysis and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 3.TP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 4.SW -Substantial contributions to the conception and design of the work, analysis and interpretation of data, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 5.AL -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 6.NL -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 7.AB -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 8.RP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 9.LK -Substantial revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 10.SG -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 11.IP -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 12.IQ -Substantial contributions to revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable for all aspects of the work. 13.RJ -Substantial contributions to the conception and design of the work, revising it critically for important intellectual content, final approval of the version to be published and agreement to be accountable ...

Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1

“…A phase 2 trial of the MEK-inhibitor selumetinib in patients with NF1-associated recurrent, refractory, or progressive low-grade glioma showed a confirmed objective response in 10 of 25 evaluable patients (40%) and disease control in all 25 patients. The progression-free survival at 2 years was 96% (95% confidence interval 74-99%) [6]. In inoperable plexiform neurofibromas, early phase trials have shown promising activity with trametinib and selumetinib with a confirmed objective response rate of 46-70%.…”

“…Treatment with MEK-inhibitor monotherapy is associated with distinct adverse events, including fatigue, muscular (muscle cramps, creatine kinase increase, rhabdomyolysis), cardiovascular (arterial hypertension, left ventricular ejection fraction decrease), ocular (serous retinopathy, retinal vein occlusion), digestive (nausea, vomiting, diarrhea), and most commonly cutaneous adverse events (acneiform dermatitis, paronychia). Grade 1-2 rash appears in 40-64% of patients, grade 3-4 rash in 4-12% [6,7]. Twenty-five to forty percent of patients treated with MEK-inhibitors require a dose reduction for skin toxicity; permanent treatment interruptions related to cutaneous adverse events are rare but have been reported [6,7].…”

Evolution in the Management of Childhood Low-Grade Gliomas and Neuronal/Mixed Neuronal-Glial Tumors

“…Some degree of radiographic response was seen in approximately 70% of sporadic BRAF-fusion LGGs and nearly 40% had greater than a 50% shrinkage of tumor. The results were even more impressive in patients with NF1-related progressive PAs, as some degree of radiographic response was seen in over 90% and a 50% reduction seen in 40-50% of patients [17]. Anecdotally, some patients responding to treatment also had clinical improvement, although this information was not well gathered by the largest prospective study done to date.…”

“…This visual risk, although rare, is of significant concern in all of patients receiving this class of drug and is especially problematic in children with visual pathway tumors and already impaired vision. The durability of response of both MEK and V600E inhibitors is also just being clarified [17]. The impact of these drugs on senescence, a mechanism by which these low-grade tumors seem, in many cases to, eventually turn themselves off in older childhood and adolescence is unknown.…”

Therapeutic Development in Neurofibromatosis

“…Recently, small molecule inhibitors have been used for refractory OPG in clinical trials ( Table 2). Among these agents, selumetinib has shown promising results in phase II studies and was proven to be active in recurrent, refractory or progressive NF1-associated pediatric low-grade glioma [39].…”