Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study.

Abstract

10504 Background: NF-1 loss-of-function alterations are associated with development of plexiform neurofibromas (PNs). NF-1–associated PNs can arise early in life in different locations, with variable and significant morbidity. Many patients (pts) progress following surgery, and currently there are no approved systemic therapies. The MEK inhibitor trametinib is being evaluated in pediatric pts across a spectrum of tumor types in a dose-escalation cohort of a phase I/IIa study (NCT02124772) to determine a recommended dose; disease-expansion cohorts include pts with NF-1 PN. Here we present an interim analysis of safety and clinical benefit of trametinib in pediatric pts with NF-1–associated PN. Methods: Pts aged 1 mo to < 18 y with medically significant, unresectable NF-1–associated PN were treated with trametinib 0.025 to 0.040 mg/kg/d. The primary objective was safety, and secondary objectives included tumor response assessed by independent review (IR) using published MRI volumetric criteria. Results: Twenty-six pts received trametinib (0.025 mg/kg/d, n = 21; 0.032 mg/kg/d, n = 1; 0.040 mg/kg/d, n = 4). Presented here are results from the disease-expansion cohort (n = 10). Median duration of exposure was 408 d (range, 360-429 d), and 8 pts (80%) had treatment ongoing at the data cutoff (September 2017). Median age was 5.5 y (range, 1-16 y), and prior therapies included surgery (n = 5), biologics (n = 1), and targeted therapy (n = 1). Treatment-related AEs (TRAEs) were reported in 9 of 10 pts (90%), and 1 pt discontinued due to a TRAE. The most frequent TRAEs were paronychia (50%) and rash (40%). No deaths occurred on treatment. Analysis of the full NF-1 PN cohort (n = 26) is ongoing; across this cohort, 12 of 26 pts (46%) had a PR (≥ 20% volume reduction) by IR, and 10 of the 12 responses (83%) were ongoing. Conclusions: Trametinib demonstrated a manageable safety profile in pediatric pts with NF-1–associated PN. Using volumetric criteria for response determination, the objective responses observed with trametinib support continued investigation in this pt population. Clinical trial information: NCT02124772.