Abstract Background: Neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) are locally invasive tumors that can cause debilitating complications including pain, disfigurement, and functional limitations. The primary treatment option is surgical debulking, which is often challenging and can lead to recurrence. As these tumors demonstrate increased activation of the MAP kinase (MAPK) pathway, inhibition of MAPK kinase (MEK) represents a rational therapeutic strategy. Selumetinib, an oral MEK inhibitor, has recently received breakthrough designation for NF1-related PN based on two early phase studies for children with NF1 and inoperable PN showing unprecedented 71% and 74% response rates (RR). Here we report the initial results of an ongoing phase II study of selumetinib in adults with NF1 and inoperable PN, which includes pharmacodynamic (PD) evaluation of serial PN and cutaneous neurofibroma (cNF) biopsies, as well as patient-reported outcomes (PROs) (NCT02407405). Materials and Methods: Open-label Simon 2-stage single-site study in patients ≥18 years old with NF1, inoperable PN, and ≥1 PN-related morbidity; overall target RR of 45%. Selumetinib 50 mg is administered twice daily orally on a continuous dosing schedule (28-day cycles). The primary study objective is to determine the partial response (PR; ≥20% volume decrease) and complete response (CR) rate of PN using volumetric MRI analysis; secondary objectives include PD studies on mandatory pre- and on-treatment biopsies of PN and cNF, and assessment of clinical benefit using PROs (Numeric Rating Scale-11 and Pain Interference Index). Results: As of August, 2019, a total of 26 patients (pts) have been enrolled (69% male; median age 33 years, range 18-60). We report outcomes for 21 pts who to date have a 1-year minimum time on study. Eighteen pts had a typical PN target lesion on baseline imaging. The most common baseline PN-related morbidities were motor weakness (13 pts) and disfigurement (11 pts). Nineteen pts underwent serial photography. Fourteen pts (14/21; 67%) achieved a PR, with 11 pts confirmed on ≥2 consecutive restaging scans. Three pts had a biopsy-confirmed atypical neurofibroma (aNF) as a target lesion, of which 2 are PRs. Nineteen pts had percutaneous neurofibroma and/or cNF biopsy with confirmed neurofibroma pathology. The median change in PN volume at the time of best response was -22% (range -41% to +5.5%). Four pts were dose-reduced due to toxicity (rash=3 pts, transaminitis=1 pt); two of these pts required a second reduction in dose. Grade ≥3 drug-related toxicities included transaminitis (5 pts, 23%), rash (4 pts, 19%), and pancreatic enzyme elevation (4 pts, 19%). Between baseline and end of 1-year evaluation, patient-reported target tumor pain intensity and pain interference scores both have significantly improved (p<0.002). PD analysis continues, with baseline PN core biopsies and cNF shave biopsies delivering sufficient protein yield and phospho- ERK/phospho-MEK levels for PD target inhibition assessment. Twenty-one pts (80%) remain on study; 4 pts discontinued treatment (rash, surgical resection, patient choice, and non-compliance). Conclusion: Selumetinib shows significant objective responses and subjective clinical benefit in adult patients with symptomatic NF1-associated PN. PD marker analysis is ongoing, and stage 2 enrollment is continuing. Funded by NCI Contract No HHSN261200800001E. Citation Format: Geraldine O'Sullivan Coyne, Andrea Gross, Eva Dombi, Jennifer DeSanto, Amanda Carbonell, Joanne Derdak, Dominique Pichard, Brad Wood, Cecilia Tibery, Pam Wolters, Trish Whitcomb, Staci Martin, Diana Bradford, Apurva Srivastava, William Herrick, Ralph Parchment, Kara Heisey, Austin Doyle, Naoko Takebe, James H Doroshow, Alice P Chen, Brigitte Widemann. Phase II Trial of the MEK 1/2 inhibitor selumetinib (AZD6344, ARRY-142886 hydrogen sulphate) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR07. doi:10.1158/1535-7163.TARG-19-PR07