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><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0728" target="_blank">See related commentary by Tripathi et al., p. 1964</a>.</i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-9-ITI" target="_blank">This article is featured in Selected Articles from This Issue, p. 1949</a></i></p></div>