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Excess methylation in SDH-deficient gastrointestinal stromal tumors disrupts genomic insulators, inducing aberrant expression of oncogenic ligands\n                    <jats:italic>FGF3<\/jats:italic>\n                    ,\n                    <jats:italic>FGF4<\/jats:italic>\n                    , 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\n                    <jats:italic>FGF3<\/jats:italic>\n                    and\n                    <jats:italic>FGF4<\/jats:italic>\n                    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\u2009months (95% confidence interval 20.2\u2013not reached), and 1-year PFS was 77.4% (95% confidence interval 61.7\u201397.1). 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 (\n                    <jats:italic>SDHx<\/jats:italic>\n                    ) as expected. This trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation. Clinicaltrials.gov identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04595747\" ext-link-type=\"uri\">NCT04595747<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04376-9","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T09:02:40Z","timestamp":1779786160000},"page":"2191-2200","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-998X","authenticated-orcid":false,"given":"Priscilla","family":"Merriam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3417-6966","authenticated-orcid":false,"given":"James J.","family":"Morrow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Mazzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0002-0975","authenticated-orcid":false,"given":"Nicole L.","family":"Solimini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-5921","authenticated-orcid":false,"given":"Prafulla 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P.C.G. reports grants or contracts from Treeline Biosciences and Amphista Therapeutics. P.C. reports personal honoraria, advisory boards or consulting from Deciphera, Ningbo NewBay Medical Technology; institutional research funding from Pfizer\/Array, Deciphera, Ningbo NewBay Medical Technology; grants from the NIH\/NCI, Department of Defense, Cycle for Survival\u2019s Equinox Innovation Award in Rare Cancers to Sarcoma Research Collector Fund, and GIST Cancer Research Fund. A.P.C. reports The National Cancer Institute has Cooperative Research and Development Agreements (CRADAs) that provide resources for co-development of experimental agents. M.A. reports consulting roles for AADi and Boehringer Ingelheim; speakers\u2019 bureau role for Deciphera and institutional research funding from Exelixis. N.S. reports research funding from Bayer, Deciphera, IDRX, Cogent, Boehringer Ingelheim, Ascentage, Astrazeneca; advisor role for Deciphera and Ipsen. B.A.V.T. reports grants from Polaris; personal fees from Deciphera Pharmaceuticals, Daiichi Sankyo, Inc., EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Inc., Boxer Capital LLC, Acuta Capital Partners, LLC, Aadi, Hinge Bio, Crisper Therapeutics, Galapagos, Sonata Therapeutics, Iterion Therapeutics, Inc., Total Health Conference, Oncology Education, Beijing Biostar Pharmaceuticals Co., Ltd, Intellisphere (MJH Life Sciences), Apexigen, Inc., Bayer US Medical Affairs Oncology, PTC Therapuetics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Curis, Syneos Health, Merck KGaA; nonfinancial support from Adaptimmune; a patent for Accuronix Therapeutics issued to Polaris. S.M.P. reports consulting or advisory roles with Bayer, Rain Therapeutics, Deciphera, Boehringer Ingelheim, SpringWorks, Adaptimmune, Ipsen, Daiichi Sankyo, EMD-Serono and Replimmune; paid speakers\u2019 bureau role for Deciphera and SpringWorks; laboratory research agreement with Obsidian Therapeutics. G.T. reports advisory role with Daiichi Sankyo and Deciphera. J.T. reports consulting with Bayer, Lilly, Boerhinger Ingelheim and Aadi; research support from Daiichi, Servier, Deciphera, Merck, IDRX-42, Theseus, Foghorn and Cogent. B.A.W. reports consulting or advisory role from SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx; research funding from Exelixis; travel from Agenus. G.I.S. reports research funding from Merck KGaA\/EMD-Serono, Tango Therapeutics, Bristol Myers Squibb, Merck & Co., Artios, Lilly and Pfizer; advisory role for Merck KGaA\/EMD-Serono, Circle Pharmaceuticals, Concarlo Therapeutics, Schrodinger, FoRx Therapeutics and Cybrexa Therapeutics; patents entitled, \u2018Dosage regimen for sapacitabine and seliciclib\u2019 and \u2018Compositions and methods for predicting response and resistance to CDK4\/6 inhibition\u2019. G.D. reports being a consultant or SAB member with minor equity holding with G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, CellCarta, Ikena Oncology, Aadi Biosciences\/Whitehawk Therapeutics, Acrivon Therapeutics, Blueprint Medicines, Tessellate Bio, Boundless Bio; scientific consulting role with EMD-Serono\/Merck KGaA, GSK, Ipsen Pharma, Minghui Pharmaceuticals, PharmaMar, Sumitomo Pharma America and WCG\/Arsenal Capital. B.B. reports financial interests in HiFiBio, Arsenal Biosciences, Chroma Medicine and Cell Signaling Technologies. S.G. reports an immediate family member having stock and other ownership interests in Abbott Laboratories and Pfizer; consulting or advisory role with Deciphera, UpToDate, Kayothera, Alexion Pharmaceuticals, Bluejay; research funding from BioAtla; institutional research funding from Blueprint Medicines, Deciphera, Merck, Eisai, TRACON Pharma, Theseus Pharmaceuticals, IDRX-42, NewBay Pharma, Acrivon; patents, royalties, other intellectual property from UptoDate; reports other relationships with WCG. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}