Therapeutic effects of selumetinib on diffuse neurofibroma and optic pathway glioma in neurofibromatosis type 1.

Selumetinib is approved for the treatment of inoperable plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1). However, its efficacy in treating NF1-associated diffuse neurofibromas (NF1-DN) or optic pathway gliomas (NF1-OPG) remains unclear. We evaluated the efficacy and safety of selumetinib in these subgroups. This was a sub-analysis of a Korean phase II open-label trial focusing on non-target treatment effects on NF1-DN and NF1-OPG. A total of 88 pediatric and adult patients with NF1-PN (59 children and 29 adults) in this trial had been treated for at least 2 years (~ 26 cycles, 28-day cycle) with oral selumetinib (20 or 25 mg/m², or 50 mg/dose every 12 h). Tumor volume, quality of life (QoL), and visual acuity were assessed. Among the 88 included patients, NF1-DN was diagnosed in 25 (28%), and NF1-OPG in 3 (3%). All NF1-DN patients exhibited disfigurement, two experienced pain, and a partial response (PR; ≥20% tumor reduction at a single time) was achieved in 9 of these cases (36%). The median time to PR was 6 cycles (range, 6-12), and the median time to best response was 18 cycles (range, 6-26), with a median volume change of - 11.9% (range, - 55.4% to + 36.3%). Confirmed PR (cPR; PR sustained for > 6 cycles) was observed in 6 NF1-DN patients (24%), stable disease (SD) was observed in 9 of these patients (36%), and progressive disease (PD) in 10 cases (40%). In a paired comparison, cPR was significantly lower for NF1-DN than for NF1-PN (24% vs. 88%, P < 0.001), and the median best volume reduction was also smaller (- 11.9% vs. -42.1%, P < 0.001). For the 3 NF1-OPG patients, visual impairment was present in all cases at baseline. One patient achieved PR at cycle 12 (- 36.1% from baseline) and complete response (CR) at cycle 26 but the visual acuity did not improve in this case. SD was maintained in the other two patients. Within these subgroups, QoL improved in 16 patients (57%) by cycle 26. No serious adverse events or treatment discontinuations were reported. Selumetinib shows therapeutic potential against NF1-DN, although with a lower response than that observed against NF1-PN. The NF1-OPG findings herein for this drug were exploratory only because of the small number of cases, but they may provide an additional clinical context for evaluating the broader effects of selumetinib across NF1-associated lesions. KCT0003700, cris.nih.go.kr/cris/search/detailSearch.do/19,080, first submission March 4, 2019; first patient enrolled May 14, 2019.