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<p>The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient-reported outcomes and pharmacodynamic effects in PN biopsies. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies (<i>P</i> ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: <a href="https://clinicaltrials.gov/study/NCT02407405">NCT02407405</a>.</p>

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Selumetinib in adults with NF1 and inoperable plexiform neurofibroma: a phase 2 trial

  • 期刊论文

  • 发表日期：

    2025年1月6日

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  • Andrea M. Gross,
  • Geraldine O’Sullivan Coyne,
  • Eva Dombi,
  • Cecilia Tibery,
  • William G. Herrick,
  • Staci Martin,
  • Steven P. Angus,
  • Jack F. Shern,
  • Steven D. Rhodes,
  • Jared C. Foster,
  • Larry V. Rubinstein,
  • Andrea Baldwin,
  • Christopher Davis,
  • Shelley A. H. Dixon,
  • Margaret Fagan,
  • Mary Jane Ong,
  • Pamela L. Wolters,
  • Mary Anne Tamula,
  • Olivia Reid,
  • Hari Sankaran,
  • Fang Fang,
  • Jeevan Prasaad Govindharajulu,
  • Alice T. Browne,
  • Rosandra N. Kaplan,
  • Kara Heisey,
  • Thomas J. On,
  • Xiaoling Xuei,
  • Xiyuan Zhang,
  • Barry C. Johnson,
  • Ralph E. Parchment,
  • D. Wade Clapp,
  • Apurva K. Srivastava,
  • James H. Doroshow,
  • Alice P. Chen,
  • Brigitte C. Widemann

摘要

The MEK inhibitor selumetinib induces objective responses and provides clinical benefit in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). To evaluate whether similar outcomes were possible in adult patients, in whom PN growth is generally slower than in pediatric patients, we conducted an open-label phase 2 study of selumetinib in adults with NF1 PNs. The study was designed to evaluate objective response rate (primary objective), tumor volumetric responses, patient-reported outcomes and pharmacodynamic effects in PN biopsies. The objective response rate was 63.6% (21/33 participants). Median maximal PN volume decrease was 23.6% (range: −48.1% to 5.5%). No disease progression relative to baseline PN volumes occurred before data cutoff, with a median of 28 cycles completed (range: 1–78, 28 d per cycle). Participants experienced decreased tumor pain intensity and pain interference. Adverse events (AEs) were similar to those of the pediatric trial; acneiform rash was the most prevalent AE. Phosphorylation ratios of ERK1/2 decreased significantly (ERK1 median change: −64.6% (range: −99.5% to 90.7%), ERK2 median change: −57.3% (range: −99.9% to 84.4%)) in paired PN biopsies (P ≤ 0.001 for both isoforms) without compensatory phosphorylation of AKT1/2/3. The sustained PN volume decreases, associated improvement in pain and manageable AE profile indicate that selumetinib provides benefit to adults with NF1 and inoperable PNs. ClinicalTrials.gov identifier: NCT02407405.