Abstract CT215: Fibroblast growth factor receptor (FGFR) inhibition demonstrates anti-tumor activity in succinate dehydrogenase deficient gastrointestinal stromal tumor (SDHd GIST)
Authors: Priscilla Merriam, James J. Morrow, Emanuele Mazzola, Nicole L. Solimini, Prafulla C. Gokhale, Ping Chi, Alice Chen, Mark Agulnik, Melissa Burgess, Scott Schuetze, Neeta Somaiah, Brian A. Van Tine, Seth Pollack, Gabriel Tinoco, Jonathan Trent, Breelyn Wilky, Nicola Bothwick, Shahanawaz Jiwani, Peter Wu, Lorraine Pelosof, Matthew Hemming, Geoffrey Shapiro, George Demetri, Bradley Bernstein, Suzanne George
Journal: Cancer Research (2025)

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 number of prior therapies =1 (range 0-6). Median follow-up at last data cut = 17.8 months (95% CI 13.4-NA) and 9 pts remain on R treatment. Best response: partial responses (PR) in 10 pts (41.7%), stable disease in 12 pts (50%). Median PFS = 31.1 months (95% CI 20.4-NA). Adverse events (AEs) were mostly grade 1 and 2 and typical of FGFR inhibitors: hyperphosphatemia (84%), fatigue (52%), alopecia (52%), diarrhea (45%), and nausea (45%). Grade 3 AEs in 2 or more pts: hypertension, diarrhea, dyspnea. No grade 4/5 AEs. RNAseq showed increased expression of FGF3 and FGF4, consistent with preclinical modeling. Objective responses were independent of SDH subunit alteration. Conclusion: FGFR inhibition demonstrates notable activity in SDHd GIST. Preclinical data suggest this is a class effect of drugs which inhibit FGFRs. This work supports targeting aberrant FGFR signaling arising from epigenetic alterations in pts with SDHd GIST. Citation Format: Priscilla Merriam, James J. Morrow, Emanuele Mazzola, Nicole L. Solimini, Prafulla C. Gokhale, Ping Chi, Alice Chen, Mark Agulnik, Melissa Burgess, Scott Schuetze, Neeta Somaiah, Brian A. Van Tine, Seth Pollack, Gabriel Tinoco, Jonathan Trent, Breelyn Wilky, Nicola Bothwick, Shahanawaz Jiwani, Peter Wu, Lorraine Pelosof, Matthew Hemming, Geoffrey Shapiro, George Demetri, Bradley Bernstein, Suzanne George. Fibroblast growth factor receptor (FGFR) inhibition demonstrates anti-tumor activity in succinate dehydrogenase deficient gastrointestinal stromal tumor (SDHd GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT215.