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Background <p>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.</p> Objective <p>To evaluate the safety and preliminary efficacy of luvometinib in a phase 1 trial in pediatric patients with NF1-related PN.</p> Patients and Methods <p>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/m<sup>2</sup>. Primary endpoints were dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D). Tumor response was a secondary endpoint.</p> Results <p>In total, 19 patients were enrolled; 10 at 4 mg/m<sup>2</sup> and 9 at 5 mg/m<sup>2</sup>. 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/m<sup>2</sup>. 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/m<sup>2</sup> group, six out of nine patients (66.7%) had a confirmed response; within the 4 mg/m<sup>2</sup> 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/m<sup>2</sup> dose group and 3/3 (100.0%) in the 5 mg/m<sup>2</sup> dose group.</p> Conclusions <p>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/m<sup>2</sup>, supporting further investigation of luvometinib in this setting.</p> Trial Registration <p>ClinicalTrials.gov, NCT04954001 (first posted: 8 July 2021).</p>

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Phase 1 Study of Luvometinib Use in Pediatric Patients with Neurofibromatosis Type 1-Related Unresectable Plexiform Neurofibromas

  • 期刊论文

  • 发表日期：

    2025年10月26日

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  • Xiaojie Hu,
  • Zhuli Wu,
  • Jinhu Wang,
  • Wenbin Li,
  • Kang Zeng,
  • Yanling Li,
  • Juan Tao,
  • Zhonghai Guan,
  • Zhuang Kang,
  • Zhongyuan Xu,
  • Yaohui Ma,
  • Liu Yang,
  • Xingli Wang,
  • Pu Han,
  • Hongmei Lin,
  • Lei Diao,
  • Yan Tan,
  • Wen Zhong,
  • Ai-Min Hui,
  • Changxing Li,
  • Xiaoxi Lin

摘要

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).