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<p>Although mitogen-activated protein kinase pathway inhibitors have been approved for adult histiocytic neoplasms, none has been approved for pediatric Langerhans cell histiocytosis (LCH). This single-arm, open-label, phase 2 trial (NCT05997602) evaluated the efficacy and safety of luvometinib, a MEK1/2 inhibitor, in recurrent/refractory pediatric LCH, regardless of genotypes. Primary endpoint was independent review committee-assessed objective response rate (ORR) per positron emission tomography response criteria (PRC). Between September 21, 2023, and February 19, 2025, 46 patients were enrolled. The median follow-up was 15.1 months (range, 6.0–22.7). Among 42 patients in efficacy analysis set, the ORR and disease control rate assessed by IRC per PRC were 90.5% (95% CI, 77.4–97.3) and 95.2% (95% CI, 83.8–99.4), respectively. Based on Histiocyte Society Evaluations and Treatment guidelines, investigator-assessed ORR was 97.8% (95% CI, 88.5–99.9) and 12-month progression-free survival rate was 97.8% (95% CI, 85.6–99.7). Variant allele frequency of MAPK pathway mutations in cell-free DNA became undetectable in 78.9% (15/19) of patients. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 4 (8.7%) patients. No TRAE led to treatment discontinuation. In the first prospective genotype-agnostic phase 2 study in pediatric LCH, luvometinib demonstrated profound response in the recurrent/refractory setting across diverse genotypes with an acceptable safety profile. <b>Trial registration</b>: This study was registered with ClinicalTrials.gov on August 8, 2023 (Identifier: NCT05997602).</p>

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Luvometinib in recurrent/refractory pediatric Langerhans cell histiocytosis: a single-arm, multi-center, phase 2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Rui Zhang,
  • Rong Liu,
  • Jie Yu,
  • Jianpei Fang,
  • Ju Gao,
  • Aiguo Liu,
  • Sixi Liu,
  • Wei Liu,
  • Xuequn Luo,
  • Yongmin Tang,
  • Jian Ge,
  • Xingli Wang,
  • Zhuli Wu,
  • Xin Huang,
  • Zhen Wei,
  • Yang Zheng

摘要

Although mitogen-activated protein kinase pathway inhibitors have been approved for adult histiocytic neoplasms, none has been approved for pediatric Langerhans cell histiocytosis (LCH). This single-arm, open-label, phase 2 trial (NCT05997602) evaluated the efficacy and safety of luvometinib, a MEK1/2 inhibitor, in recurrent/refractory pediatric LCH, regardless of genotypes. Primary endpoint was independent review committee-assessed objective response rate (ORR) per positron emission tomography response criteria (PRC). Between September 21, 2023, and February 19, 2025, 46 patients were enrolled. The median follow-up was 15.1 months (range, 6.0–22.7). Among 42 patients in efficacy analysis set, the ORR and disease control rate assessed by IRC per PRC were 90.5% (95% CI, 77.4–97.3) and 95.2% (95% CI, 83.8–99.4), respectively. Based on Histiocyte Society Evaluations and Treatment guidelines, investigator-assessed ORR was 97.8% (95% CI, 88.5–99.9) and 12-month progression-free survival rate was 97.8% (95% CI, 85.6–99.7). Variant allele frequency of MAPK pathway mutations in cell-free DNA became undetectable in 78.9% (15/19) of patients. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 4 (8.7%) patients. No TRAE led to treatment discontinuation. In the first prospective genotype-agnostic phase 2 study in pediatric LCH, luvometinib demonstrated profound response in the recurrent/refractory setting across diverse genotypes with an acceptable safety profile. Trial registration: This study was registered with ClinicalTrials.gov on August 8, 2023 (Identifier: NCT05997602).