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

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).