{"doi":"10.1158/2159-8290.c.6749764.v1","title":"Data from RLY-4008, the First Highly Selective FGFR2 Inhibitor with Activity across <i>FGFR2</i> Alterations and Resistance Mutations","abstract":"<div>Abstract<p>Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates <i>FGFR2</i> driver status in <i>FGFR2</i> fusion–positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of <i>FGFR2</i> resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. <i>In vitro</i>, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. <i>In vivo</i>, RLY-4008 induces regression in multiple xenograft models—including models with <i>FGFR2</i> resistance mutations that drive clinical progression on current pan-FGFRi—while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting.</p>Significance:<p>Patients with <i>FGFR2</i>-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1–4-mediated toxicities and acquired <i>FGFR2</i> resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential.</p></div>","journal":null,"year":2023,"id":409685,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9339,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":225417,"name":"Vaibhav Sahai","orcid":"0000-0003-1892-1548","position":1,"is_corresponding":false},{"id":249249,"name":"Dejan Maglic","orcid":"0000-0002-5683-8350","position":2,"is_corresponding":false},{"id":1189197,"name":"Kamil Bruderek","orcid":"0009-0006-9098-2088","position":3,"is_corresponding":false},{"id":1189198,"name":"B. 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