Background: PN in NF1 can cause substantial morbidity, and there are no approved medical therapies. In a phase I trial of selumetinib, 17/24 (71%) patients (pts) had a partial response (PR)(Dombi, et al. N Engl J Med 2016; 375:2550-2560). This open-label phase II study (NCT01362803) determines the PR rate of PN treated with selumetinib and changes in PN related morbidities. Methods: Patients 2-18 years old with NF1, inoperable PN and ≥ 1 PN related morbidity received selumetinib at the recommended phase II dose (25 mg/m² PO BID) with continuous dosing (1 cycle = 28 days). Response was evaluated with volumetric MRI analysis (PR = target PN volume decrease ≥20%) and PN related morbidities (pain, disfigurement, functional morbidities) assessed with standardized evaluations after every 4 cycles. Results: Fifty children (30 male, median age 10.2 years, range 3.5, 17.4) enrolled. Disfigurement (n=44), motor dysfunction (n=33) and pain (n=28) were the most frequent PN related morbidities. As of November 5, 2017: median cycle number 19.5 (range 0, 29) with 38 pts remaining on treatment; median change in PN volume from baseline -27.7% (range -50.6%, 2.2%); best response PR (36 pts, 72%), stable disease (12 pts, 24%); 2 subjects (4%) had no re-staging. Of the 36 total PR, 32 were confirmed on ≥ two consecutive restaging scans and 22 continue to have a PR ≥ 1 year after it was first achieved. Between baseline and end of year 1 evaluations, parent and child-reported pain intensity and pain interference scores significantly improved (p <0.01), as did strength (0-5 scale) and range of motion (degrees) of affected muscle groups/joints (p < 0.01). The most frequent toxicities were nausea/vomiting, diarrhea, asymptomatic creatine kinase increase, acneiform rash and paronychia. Selumetinib dose was reduced in 12 pts, of which 5 were removed from treatment. Conclusions: The response rate from this study (72%) confirms our previously observed response rate (71%). Most responses were sustained ≥6 months. Improvements in PN related pain and motor impairment demonstrate that selumetinib can provide clinical benefit. Data validation and further analyses are ongoing. Clinical trial information: NCT01362803