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<p>While most gastrointestinal stromal tumors are driven by oncogenic mutations in <i>KIT</i> or <i>PDGFRA</i>, 10–15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands <i>FGF3</i>, <i>FGF4</i>, and activating an autocrine signaling loop mediated through FGFR1. We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate. Secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Exploratory objectives were to evaluate serial measurements of <i>FGF3</i> and <i>FGF4</i> and fibroblast growth factor receptors in serial biopsies, to perform whole-exome sequencing in serial biopsies and to explore rogaratinib exposure with pharmacodynamic effects. Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2–not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7–97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes (<i>SDHx</i>) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: <a href="https://clinicaltrials.gov/study/NCT04595747">NCT04595747</a>.</p>

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Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Priscilla Merriam,
  • James J. Morrow,
  • Emanuele Mazzola,
  • Nicole L. Solimini,
  • Prafulla C. Gokhale,
  • Ping Chi,
  • Alice P. Chen,
  • Mark Agulnik,
  • Melissa Burgess,
  • Scott M. Schuetze,
  • Neeta Somaiah,
  • Brian A. Van Tine,
  • Seth M. Pollack,
  • Gabriel Tinoco,
  • Jonathan Trent,
  • Breelyn A. Wilky,
  • Nicola Bothwick,
  • Benjamin K. Eschle,
  • Vivian Nguyen,
  • Jan H. Beumer,
  • Noushin Rastkari,
  • Shahanawaz Jiwani,
  • Peter I-Fan Wu,
  • Lorraine Pelosof,
  • Matthew L. Hemming,
  • Geoffrey I. Shapiro,
  • George Demetri,
  • Bradley Bernstein,
  • Suzanne George

摘要

While most gastrointestinal stromal tumors are driven by oncogenic mutations in KIT or PDGFRA, 10–15% exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands FGF3, FGF4, and activating an autocrine signaling loop mediated through FGFR1. We conducted a phase 2 trial of pan-fibroblast growth factor receptor inhibitor rogaratinib in patients with sarcoma and report here on the cohort of patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate. Secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Exploratory objectives were to evaluate serial measurements of FGF3 and FGF4 and fibroblast growth factor receptors in serial biopsies, to perform whole-exome sequencing in serial biopsies and to explore rogaratinib exposure with pharmacodynamic effects. Twenty-four patients received rogaratinib and ten experienced partial responses for an objective response rate of 41.7%. Median PFS was 31.0 months (95% confidence interval 20.2–not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7–97.1). Toxicities were manageable and included hyperphosphatemia, fatigue and diarrhea. Elevations in phosphorous were seen across the cohort, consistent with target engagement of FGFR1. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes (SDHx) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier: NCT04595747.