Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial
Summary
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 facto
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# Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial
*Published: 2026 May 26*
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 .
DOI: 10.1038/s41591-026-04376-9