Abstract CT215: Fibroblast growth factor receptor (FGFR) inhibition demonstrates anti-tumor activity in succinate dehydrogenase deficient gastrointestinal stromal tumor (SDHd GIST)

作者：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 Andrew Van Tine, Seth M. Pollack, Gabriel Tinoco, Jonathan C. Trent, Breelyn A. Wilky, Nicola Bothwick, Shahanawaz Jiwani, Peter Wu, Lorraine Pelosof, Matthew L. Hemming, Geoffrey I. Shapiro, George D. Demetri, B Bernstein, Suzanne George · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-ct215 · 被引用次数：2 · 研究领域：Gastrointestinal Tumor Research and Treatment、Fibroblast Growth Factor Research、Cancer, Hypoxia, and Metabolism

Abstract Background: SDHd GIST is defined by alterations in an SDH complex subunit gene or SDHC promotor methylation leading to genome-wide DNA hypermethylation. Recent studies showed excess methylation disrupts genomic insulators and chromatin topology, inducing aberrant production of oncogenic ligands FGF3 and FGF4 and downstream signaling largely through FGFR1. Preclinical work demonstrated FGFR inhibition suppressed tumor growth. We assessed additional FGFR inhibitors (FGFRi) in a patient-derived xenograft (PDX) model of SDHd GIST to evaluate a potential class effect of FGFRi, and performed a Phase II trial of FGFRi in patients (pts) with advanced SDHd GIST. Methods: FGFRi rogaratinib (R) and pemigatinib (P) were evaluated separately in SDHd GIST PDX (PG-20) and compared to vehicle, sunitinib, and regorafenib. Dosing was administered daily for 28-35 days and growth rates evaluated. A multi-center phase 2 trial (NCT04595747) of R in advanced SDHd GIST was conducted. Pts received R 800 mg twice daily. Primary objective was response rate by RECIST 1.1. Secondary objectives included progression-free survival (PFS) and tolerability. Exploratory studies include whole exome sequencing and RNA sequencing of tumor samples from study pts. Results: Evaluation of SDHd PDX model: significant tumor growth suppression was seen following dosing with either R or P, but not sunitinib or regorafenib. In the clinical trial, 24 pts with SDHd GIST enrolled; 50% had mutations in SDHA. Median nu...