Phase 1 Study of Luvometinib Use in Pediatric Patients with Neurofibromatosis Type 1-Related Unresectable Plexiform Neurofibromas.
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BACKGROUND: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by plexiform neurofibromas (PNs), which are present in 20-60% of NF1 and may cause potentially life-threatening complications. Complete surgical resection of these PNs is generally not feasible, and regrowth after incomplete surgical resection has been observed. Luvometinib is a novel, oral, highly potent selective MEK1/2 inhibitor that has shown activity in adult NF1-related PN. OBJECTIVE: To evaluate the safety and preliminary efficacy of luvometinib in a phase 1 trial in pediatric patients with NF1-related PN. PATIENTS AND METHODS: This multicenter, single-arm, phase 1 study included pediatric patients (2-18 years old) with unresectable NF1-related PN. Patients received luvometinib orally once daily in 28-day cycles until progression or unacceptable toxicity, using a population pharmacokinetics model-informed approach to identify the starting dose of 4 mg/m2. Primary endpoints were dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D). Tumor response was a secondary endpoint. RESULTS: In total, 19 patients were enrolled; 10 at 4 mg/m2 and 9 at 5 mg/m2. Median age was 10.0 years (range 5-17). No DLTs were reported. The maximum tolerated dose (MTD) was not reached; the RP2D was 5 mg/m2. The most common treatment-related adverse events (TRAEs) were paronychia (52.6%) and mouth ulceration (42.1%), with a single grade ≥ 3 TRAE reported for each: paronychia (5.3%), prolonged QT on electrocardiogram (5.3%), and ingrown nail (5.3%). There was one discontinuation owing to a treatment-related serious AE (SAE) of rhabdomyolysis, the only treatment-related SAE. Within the 5 mg/m2 group, six out of nine patients (66.7%) had a confirmed response; within the 4 mg/m2 group, none did. Among patients with tumor pain (numerical rating scale [NRS] ≥ 2) at baseline and at least one post-baseline measurement, 2/3 (66.7%) reported an improvement of ≥ 2 points in the 4 mg/m2 dose group and 3/3 (100.0%) in the 5 mg/m2 dose group. CONCLUSIONS: Luvometinib had a manageable safety profile in pediatric patients with unresectable NF1-related PN. Encouraging preliminary efficacy was observed, particularly among patients receiving the RP2D of 5 mg/m2, supporting further investigation of luvometinib in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04954001 (first posted: 8 July 2021).