Multicenter phase 2 trial of rogaratinib for succinate dehydrogenase-deficient gastrointestinal stromal tumors

Approximately 10-15% of gastrointestinal stromal tumors (GISTs) exhibit functional loss of the succinate dehydrogenase (SDH) complex and genome-wide DNA hypermethylation. Excess methylation in SDH-deficient GISTs disrupts genomic insulators, inducing aberrant expression of oncogenic ligands FGF2 and FGF4, and activating an autocrine signaling loop mediated through FGFR1. A multicenter phase 2 trial in the USA evaluated the pan-FGFR inhibitor rogaratinib in patients with advanced SDH-deficient GIST. The primary objective was to estimate objective response rate (ORR), secondary objectives were to estimate progression-free survival (PFS) and assess safety and tolerability. Twenty-four patients received rogaratinib. Ten patients experienced partial responses for an ORR of 41.7%; twelve patients (50%) had stable disease; median PFS was 31.0 months, with 1-year PFS rate 77.4% (95% CI 61.7-97.1). Toxicities were manageable and included hyperphosphatemia, fatigue, and diarrhea. Whole-exome and next-generation sequencing revealed alterations in the SDH subunit coding genes as expected. The authors conclude that this trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation.