Efficacy and safety of FCN-159, a MEK1/2 inhibitor in pediatric participants with neurofibromatosis type 1: Results from a phase 2 trial.

3096 Background: Neurofibromatosis type 1(NF1) is an autosomal dominant tumor predisposition syndrome characterized by NF1 gene variants, resulting in over-activation of the RAS pathway. Plexiform neurofibroma (PN) is benign tumors that arise from nerve tissue and are a hallmark feature of NF1. They typically grow along nerves and cause disfigurement, pain, and other complications depending on their location and size. FCN-159, a highly potent and selective inhibitor of MEK1/2 by targeting inhibition of the RAS pathway, holds promise as a therapeutic agent for treating NF1-related PN. Methods: A multi-center, open-label phase 1/2 clinical trial was conducted to assess the safety and efficacy in pediatric patients(pts) with NF1-related PN. Here, we reported the safety and efficacy outcomes observed during phase 2 in pediatric pts, who received FCN-159 at the 5 mg/m 2 dose once daily on a continuous basis in a 28-day cycle. Preliminary findings from the phase 1/2 trial were previously disclosed at ASCO 2023. Results: As of November 24, 2023,46 pts enrolled. The median age is 8.0 years (range 2-17). The most frequent PN related complications were disfigurement (69.6%) and pain (63.0%). Median volume of target neurofibroma were 37.7 cm³ (range 2.2-1144.1). Efficacy outcomes are reported for 43 pts (modified intent-to-treat population). With the median follow-up of 15.1 months (range 14.1-16.4), the investigator and Blinded Independent Review Committee (BIRC) assessed ORR were 48.8% and 30.2%, respectively. The mDoR and median mPFS were not reached. Preliminary efficacy data are presented in the table. Among the 16 pediatric subjects with tumor pain at baseline (overall tumor pain NRS≥1) and at least one post-baseline assessment, pain scores decreased by at least 2 points in 81.3% (13/16) pts, and pain scores reduced to 0 points (indicating no pain sensation) in 81.3% (13/16) pts, signifying clinically meaningful improvement. 43 pts (93.5%) experienced TRAEs with grade ≥3 TRAEs occurred in 8 pts (17.4%), including dermatitis acneiform (4.3%), folliculitis (4.3%), pneumonia (2.2%), upper respiratory tract infection (2.2%), ejection fraction decreased (2.2%), and blood creatine phosphokinase increased (2.2%). 2 pts (4.3%) reported treatment-related serious adverse events (one case of dermatitis acneiform and pneumonia each). No TRAEs resulting in dose reduction, discontinuation or death. Conclusions: FCN-159 demonstrated good tolerability and exhibited notable anti-tumor activity in pediatric pts with NF1-related PN. Clinical trial information: NCT04954001 . [Table: see text]